A sustained high-temperature fusion plasma regime facilitated by fast ions.

Nuclear fusion is one of the most attractive alternatives to carbon-dependent energy sources1. Harnessing energy from nuclear fusion in a large reactor scale, however, still presents many scientific challenges despite the many years of research and steady advances in magnetic confinement approaches. State-of-the-art magnetic fusion devices cannot yet achieve a sustainable fusion performance, which requires a high temperature above 100 million kelvin and sufficient control of instabilities to ensure steady-state operation on the order of tens of seconds2,3. Here we report experiments at the Korea Superconducting Tokamak Advanced Research4 device producing a plasma fusion regime that satisfies most of the above requirements: thanks to abundant fast ions stabilizing the core plasma turbulence, we generate plasmas at a temperature of 100 million kelvin lasting up to 20 seconds without plasma edge instabilities or impurity accumulation. A low plasma density combined with a moderate input power for operation is key to establishing this regime by preserving a high fraction of fast ions. This regime is rarely subject to disruption and can be sustained reliably even without a sophisticated control, and thus represents a promising path towards commercial fusion reactors.

Iron-based biomarkers for personalizing pharmacological ascorbate therapy in glioblastoma: insights from a phase 2 clinical trial.

BACKGROUND: Pharmacological ascorbate (intravenous delivery reaching plasma concentrations ≈ 20 mM; P-AscH-) has emerged as a promising therapeutic strategy for glioblastoma. Recently, a single-arm phase 2 clinical trial demonstrated a significant increase in overall survival when P-AscH- was combined with temozolomide and radiotherapy. As P-AscH- relies on iron-dependent mechanisms, this study aimed to assess the predictive potential of both molecular and imaging-based iron-related markers to enhance the personalization of P-AscH- therapy in glioblastoma participants. METHODS: Participants (n = 55) with newly diagnosed glioblastoma were enrolled in a phase 2 clinical trial conducted at the University of Iowa (NCT02344355). Tumor samples obtained during surgical resection were processed and stained for transferrin receptor and ferritin heavy chain expression. A blinded pathologist performed pathological assessment. Quantitative susceptibility mapping (QSM) measures were obtained from pre-radiotherapy MRI scans following maximal safe surgical resection. Circulating blood iron panels were evaluated prior to therapy through the University of Iowa Diagnostic Laboratory. RESULTS: Through univariate analysis, a significant inverse association was observed between tumor transferrin receptor expression and overall and progression-free survival. QSM measures exhibited a significant, positive association with progression-free survival. Subjects were actively followed until disease progression and then were followed through chart review or clinical visits for overall survival. CONCLUSIONS: This study analyzes iron-related biomarkers in the context of P-AscH- therapy for glioblastoma. Integrating molecular, systemic, and imaging-based markers offers a multifaceted approach to tailoring treatment strategies, thereby contributing to improved patient outcomes and advancing the field of glioblastoma therapy.

HIGHLIGHTS: Pharmacological ascorbate shows significant promise to enhance glioblastoma clinical outcomes. Transferrin receptor and ferritin heavy chain expression represent potential molecular markers to predict pharmacological ascorbate treatment response. Quantitative Susceptibility Mapping is an MRI technique that can serve as a non-invasive marker of iron metabolism to evaluate progression-free survival. Systemic iron metabolic markers are readily available diagnostic tests that can potentially be used to prognosticate overall survival.

Glycaemic control and microvascular complications among paediatric type 2 diabetes mellitus patients in Hong Kong at 2 years after diagnosis.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is becoming increasingly common among children and adolescents worldwide, including those in Hong Kong. This study analysed the characteristics and prevalence of microvascular complications among paediatric T2DM patients in Hong Kong at diagnosis and 2 years after diagnosis. METHODS: All patients aged <18 years who had been diagnosed with DM at public hospitals in Hong Kong were recruited into the Hong Kong Childhood Diabetes Registry. Data collected at diagnosis and 2 years after diagnosis were retrospectively retrieved from the Registry for patients diagnosed from 2014 to 2018. RESULTS: Median haemoglobin A1c (HbA1c) levels were 7.5% (n=203) at diagnosis and 6.5% (n=135) 2 years after diagnosis; 59.3% of patients achieved optimal glycaemic control (HbA1c level <7%) at 2 years. A higher HbA1c level at diagnosis was associated with worse glycaemic control at 2 years (correlation coefficient=0.39; P<0.001). The presence of dyslipidaemia (adjusted odds ratio [aOR]=3.19; P=0.033) and fatty liver (aOR=2.50; P=0.021) at 2 years were associated with suboptimal glycaemic control. Diabetic neuropathy and retinopathy were rare in our cohort, but 18.6% of patients developed microalbuminuria (MA) within 2 years after diagnosis. Patients with MA had a higher HbA1c level at 2 years (median: 7.2% vs 6.4%; P=0.037). Hypertension was a risk factor for MA at 2 years, independent of glycaemic control (aOR=4.61; P=0.008). CONCLUSION: These results highlight the importance of early diagnosis and holistic management (including co-morbidity management) for paediatric T2DM patients.

Issues for patchy tissues: defining roles for gut-associated lymphoid tissue in neurodevelopment and disease.

Individuals diagnosed with neurodevelopmental conditions such as autism spectrum disorder (ASD; autism) often experience tissue inflammation as well as gastrointestinal dysfunction, yet their underlying causes remain poorly characterised. Notably, the largest components of the body's immune system, including gut-associated lymphoid tissue (GALT), lie within the gastrointestinal tract. A major constituent of GALT in humans comprises secretory lymphoid aggregates known as Peyer's patches that sense and combat constant exposure to pathogens and infectious agents. Essential to the functions of Peyer's patches is its communication with the enteric nervous system (ENS), an intrinsic neural network that regulates gastrointestinal function. Crosstalk between these tissues contribute to the microbiota-gut-brain axis that altogether influences mood and behaviour. Increasing evidence further points to a critical role for this signalling axis in neurodevelopmental homeostasis and disease. Notably, while the neuroimmunomodulatory functions for Peyer's patches are increasingly better understood, functions for tissues of analogous function, such as caecal patches, remain less well characterised. Here, we compare the structure, function and development of Peyer's patches, as well as caecal and appendix patches in humans and model organisms including mice to highlight the roles for these essential tissues in health and disease. We propose that perturbations to GALT function may underlie inflammatory disorders and gastrointestinal dysfunction in neurodevelopmental conditions such as autism.

The Emerging Role of the Gut-Brain-Microbiota Axis in Neurodevelopmental Disorders.

Autism spectrum disorder (ASD; autism) is a prevalent neurodevelopmental disorder associated with changes in gut-brain axis communication. Gastrointestinal (GI) symptoms are experienced by a large proportion of individuals diagnosed with autism. Several mutations associated with autism modify cellular communication via neuronal synapses. It has been suggested that modifications to the enteric nervous system, an intrinsic nervous system of the GI tract, could contribute to GI dysfunction. Changes in gut motility, permeability, and the mucosal barrier as well as shifts in the large population of microbes inhabiting the GI tract could contribute to GI symptoms. Preclinical research has demonstrated that mice expressing the well-studied R451C missense mutation in Nlgn3 gene, which encodes cell adhesion protein neuroligin-3 at neuronal synapses, exhibit GI dysfunction. Specifically, NL3R451C mice show altered colonic motility and faster small intestinal transit. As well as dysmotility, macrophages located within the gut-associated lymphoid tissue of the NL3R451C mouse caecum show altered morphology, suggesting that neuro-inflammation pathways are modified in this model. Interestingly, NL3R451C mice maintained in a shared environment demonstrate fecal microbial dysbiosis indicating a role for the nervous system in regulating gut microbial populations. To better understand host-microbe interactions, further clarification and comparison of clinical and animal model profiles of dysbiosis should be obtained, which in turn will provide better insights into the efforts taken to design personalized microbial therapies. In addition to changes in neurophysiological measures, the mucosal component of the GI barrier may contribute to GI dysfunction more broadly in individuals diagnosed with a wide range of neurological disorders. As the study of GI dysfunction advances to encompass multiple components of the gut-brain-microbiota axis, findings will help understand future directions such as microbiome engineering and optimisation of the mucosal barrier for health.

A spontaneous missense mutation in the chromodomain helicase DNA-binding protein 8 (CHD8) gene: a novel association with congenital myasthenic syndrome.

AIMS: Congenital myasthenic syndromes (CMS) are characterized by muscle weakness, ptosis and episodic apnoea. Mutations affect integral protein components of the neuromuscular junction (NMJ). Here we searched for the genetic basis of CMS in female monozygotic twins. METHODS: We employed whole-exome sequencing for mutation detection and Sanger sequencing for segregation analysis. Immunohistology was done with antibodies against CHD8, rapsyn, ß-catenin (ßCAT) and golgin on fi-bro-blasts, human and mouse muscle. We recorded superresolution images of the NMJ using 3D-structured illumination microscopy. RESULTS: We discovered a spontaneous missense mutation in CHD8 [chr14:g.21,884,051G>A, GRCh37.p11 | c.1732C>T, NM_00117062 | p.(R578C)], the gene encoding chromodomain helicase DNA-binding protein 8. This is the first missense mutation affecting Duplin, the short 110 kDa isoform of CHD8. It is known that CHD8/Duplin negatively regulates ßCAT signalling in the WNT pathway and plays a role in chromatin remodelling. Inactivating CHD8 mutations are associated with autism spectrum disorder and intellectual disability in combination with facial dysmorphism, overgrowth and macrocephalus. No muscle-specific phenotype has been reported to date. Co-immunostaining with rapsyn on human and mouse muscle revealed a strong presence of CHD8 at the NMJ being located towards the sarcoplasmic side of the rapsyn cluster, where it co-localizes with ßCAT. CONCLUSION: We hypothesize CHD8 to have a role in the maintenance of the structural integrity and function of the NMJ. Both patients benefited from treatment with 3,4-diaminopyridine, a reversible blocker of voltage-gated potassium channels at the nerve terminal that prolongs the action potential and increases acetylcholine release.

A case of arrhythmogenic right ventricular cardiomyopathy with right ventricle thrombus: A case report.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited cardiomyopathy characterised by right ventricular dysfunction, ventricular arrhythmias and increased risk of sudden cardiac death. Due to the replacement of myocardium with fibro-fatty and fibrous tissue, patients with ARVC are prone to develop ventricular tachycardia. Histologically, it is often reported as the 'triangle of dysplasia' involving the inflow tract, outflow tract and apex of the right ventricle.2 We describe a 20-years-old patient who collapsed during a futsal match and was subsequently diagnosed to have ARVC with a right ventricular thrombus from cardiac magnetic resonance imaging.

Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.

BACKGROUND: Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade. PATIENTS AND METHODS: We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD. RESULTS: A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival [hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868-7.440] and overall survival (HR, 5.079; 95% CI, 3.136-8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7-CD45RA- T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate. CONCLUSION: HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.

Down-regulation of natural resistance-associated macrophage protein-1 (Nramp1) is associated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/1-methyl-4-phenylpyridinium (MPP+ )-induced α-synuclein accumulation and neurotoxicity.

AIMS: The accumulation of α-synuclein is a hallmark in the pathogenesis of Parkinson's disease (PD). Natural resistance-associated macrophage protein-1 (Nramp1) was previously shown to contribute to the degradation of extracellular α-synuclein in microglia under conditions of iron overload. This study was aimed at investigating the role of Nramp1 in α-synuclein pathology in the neurone under 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/1-methyl-4-phenylpyridinium (MPP+ ) treatment. METHODS: The expression of Nramp1 and pathological features (including iron and α-synuclein accumulation) were examined in the dopaminergic neurones of humans (with and without PD) and of mice [with and without receiving chronic MPTP intoxication]. The effects of Nramp1 expression on low-dose MPP+ -induced α-synuclein expression and neurotoxicity were determined in human dopaminergic neuroblastoma SH-SY5Y cells. RESULTS: Similar to the findings in the substantia nigra of human PD, lower expression of Nramp1 but higher levels of iron and α-synuclein were identified in the dopaminergic neurones of mice receiving chronic MPTP intoxication, compared to controls. In parallel to the loss of dopaminergic neurones, the numbers of glial fibrillary acidic protein- and ionized calcium-binding adapter molecule-1-positive cells were significantly increased in the substantia nigra of MPTP-treated mice. Likewise, in human neuroblastoma SH-SY5Y cells exposed to low-dose MPP+ , Nramp1 expression and cathepsin D activity were decreased, along with an increase in α-synuclein protein expression and aggregation. Overexpression of functional Nramp1 restored cathepsin D activity and attenuated α-synuclein up-regulation and neuronal cell death caused by MPP+ treatment. CONCLUSIONS: These data suggest that the neuronal expression of Nramp1 is important for protecting against the development of MPTP/MPP+ -induced α-synuclein pathology and neurotoxicity.

Acute myocarditis mimicking ST-elevation myocardial infarction: A diagnostic challenge for frontline clinicians.

The clinical presentation of acute myocarditis is highly variable ranging from no symptoms to cardiogenic shock. Despite considerable progress, it remains a challenge for frontline physicians to discriminate between acute myocarditis and myocardial infarction, especially in the early phase. Our case serves as a reminder that acute presentation of myocarditis could resemble ST elevation myocardial infarction potentially misdirecting the therapeutic decision. The clinical presentation, electrocardiographic and laboratory findings of the patient are not specific enough to distinguish acute myocarditis from myocardial infarction. The gold standard tests such coronary angiography and cardiovascular magnetic resonance (CMR) can reliably differentiate the two entities.

Diagnostic value of electrocardiogram in cardiac tamponade.

INTRODUCTION: We aim to study the diagnostic value of electrocardiogram (ECG) in cardiac tamponade. METHODS: This study was a single centre, retrospective casecontrol study. We recruited 42 patients diagnosed with cardiac tamponade of various aetiologies confirmed by transthoracic echocardiography and 100 controls between January 2011 and December 2015. The ECG criteria of cardiac tamponade we adopted was as follows: 1) Low QRS voltage in a) the limb leads alone, b) in the precordial leads alone or, c) in all leads, 2) PR segment depression, 3) Electrical alternans, and 4) Sinus tachycardia. RESULTS: Malignancy was the most common causes of cardiac tamponade, the two groups were of similar proportion of gender and ethnicity. We calculated the sensitivity (SN), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV) of each ECG criteria. Among the ECG abnormalities, we noted the SN of 'low voltage in all chest leads' (69%), 'low voltage in all limb leads' (67%) and 'sinus tachycardia' (69%) were higher as compared to 'PR depression' (12%) and 'electrical alternan' (5%). On the other hand, 'low voltage in all chest leads' (98%), 'low voltage in all leads' (99%), 'PR depression' (100%) and 'electrical alternans' (100%) has highest SP. CONCLUSION: Our study reaffirmed the findings of previous studies that electrocardiography cannot be used as a screening tool for diagnosing cardiac tamponade due to its low sensitivity. However, with clinical correlation, electrocardiography is a valuable adjuvant test to 'rule in' cardiac tamponade because of its high specificity.

Efficacy, Immunogenicity, and Safety of a 9-Valent Human Papillomavirus Vaccine: Subgroup Analysis of Participants From Asian Countries.

Background: A 9-valent human papillomavirus-6/11/16/18/31/33/45/52/58 (9vHPV) vaccine extends coverage to 5 next most common oncogenic types (31/33/45/52/58) in cervical cancer versus quadrivalent HPV (qHPV) vaccine. We describe efficacy, immunogenicity, and safety in Asian participants (India, Hong Kong, South Korea, Japan, Taiwan, and Thailand) from 2 international studies: a randomized, double-blinded, qHPV vaccine-controlled efficacy study (young women aged 16-26 years; NCT00543543; Study 001); and an immunogenicity study (girls and boys aged 9-15 years; NCT00943722; Study 002). Methods: Participants (N = 2519) were vaccinated at day 1 and months 2 and 6. Gynecological samples (Study 001 only) and serum were collected for HPV DNA and antibody assessments, respectively. Injection-site and systemic adverse events (AEs) were monitored. Data were analyzed by country and vaccination group. Results: 9vHPV vaccine prevented HPV-31/33/45/52/58-related persistent infection with 90.4%-100% efficacy across included countries. At month 7, ≥97.9% of participants seroconverted for each HPV type. Injection-site AEs occurred in 77.7%-83.1% and 81.9%-87.5% of qHPV and 9vHPV vaccine recipients in Study 001, respectively, and 62.4%-85.7% of girls/boys in Study 002; most were mild to moderate. Conclusions: The 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Asian participants. Data support 9vHPV vaccination programs in Asia. Clinical Trials Registration: NCT00543543; NCT00943722.

Differentiating bipolar disorders from unipolar depression by applying the Brief Assessment of Cognition in Affective Disorders.

BACKGROUND: Scholars continue to argue about whether bipolar disorders (BD) and unipolar depression (UD) are distinguishable with regard to neurocognitive function. This study aims to explore the cognitive profiles of UD and BD by applying the Brief Assessment of Cognition in Affective Disorders (BAC-A) for neuropsychological assessment. METHOD: This cross-sectional study included 68 patients with UD, 67 patients with BD, and 135 healthy control subjects. We evaluated the participants' cognitive functions at euthymic status using the BAC-A, which is made up of six traditional cognitive subtests and the Affective Processing Test. We then used a discriminant function analysis (DFA) to determine whether cognitive performance can be used to distinguish these participant groups. RESULTS: Healthy controls demonstrated better performance in all subtests of the BAC-A than both the UD and BD patients, with the exception of delayed recognition of affective interference. Compared with the BD group, the UD group exhibited better performance in working memory and emotion inhibition. Furthermore, using all BAC-A indexes, a total of 70% of participants could be correctly classified using a DFA model, and the discriminating validity between UD and BD was superior to using either the traditional cognitive domains or the Affective Processing Test alone. CONCLUSIONS: We have found that UD patients may exhibit an intermediate performance between healthy subjects and BD patients in working memory and emotional inhibition tests. The BAC-A can potentially assist in differentiating BD patients from UD patients at euthymic status in clinical settings.

Immunohistochemical and molecular analysis of spitzoid neoplasms with pulverocyte subclones.

BACKGROUND: Clonal naevi are characterized by a focal proliferation of pigmented melanocytes in an otherwise banal naevus. These subclones are often composed of aggregates of larger, epithelioid melanocytes with nuclear atypia and dusty-grey cytoplasmic pigmentation, which are referred to as 'pulverocytes', and this finding may lead to a misdiagnosis of malignant melanoma (MM). AIM: To characterize the significance of subclones of dusty-grey pigmented epithelioid melanocytes within spitzoid neoplasms. METHODS: We studied the histological and molecular features of a series of 20 spitzoid neoplasms with pulverocyte subclones encountered in our practice, including both atypical Spitz tumours (ASTs) and invasive MMs. RESULTS: Pulverocytes were predominantly dermal, and the percentage of subclones ranged from 2% to 40%, with a median of 10% in ASTs and 25% in lesions we classified as MM. In cases with > 10% subclones, there was an increased odds of fluorescence in situ hybridization positivity (OR = 12; 95% CI 1.2-293.4; P = 0.03) and an increased odds of homozygous 9p21 deletion (OR = 3.6; 95 CI 0.28-89.82; P = 0.33), although the latter did not reach statistical significance. CONCLUSIONS: We consider spitzoid lesions with a small subclone population to be a variant of a clonal naevus with indolent behaviour, whereas lesions with larger pulverocyte populations are more likely to have chromosomal copy number aberrations and in some cases may represent malignant transformation.

Improving medication safety for home nursing clients: A prospective observational study of a novel clinical pharmacy service-The Visiting Pharmacist (ViP) study.

WHAT IS KNOWN AND OBJECTIVE: Polypharmacy, medication errors and adverse events are common in older people receiving home nursing medication management support. Access to clinical pharmacists is limited. In Australia, few home nursing clients receive a general practitioner (GP)-initiated pharmacist-led Home Medicines Review, despite their eligibility and community nurses' (CN) efforts to facilitate this. An integrated home nursing clinical pharmacy service, in which CNs directly referred clients to a pharmacist, was therefore developed and piloted. The aim was to explore the number and type of medication-related problems (MRPs) and medication treatment authorization (medication order) discrepancies identified and addressed by clinical pharmacists. METHODS: Two part-time clinical pharmacists were employed. They reviewed and reconciled clients' medications, educated clients/carers about their medicines, provided advice and support to CNs and worked with clients' GPs and other prescribers to optimize medication regimens and revise/update nurses' medication treatment authorizations. Evaluation involved review of clients' medicines data, including treatment authorizations and pharmacist medication review reports. RESULTS AND DISCUSSION: Eighty-four clients (median 86 years, 6 health conditions, 13 medications) were reviewed. The pharmacists identified 334 MRPs (median 4 per client) and 307 medication discrepancies in treatment authorizations (median 2 per client). The pharmacists made 282 recommendations to prescribers to address MRPs; 148 (52.5%) recommendations were acted on, resulting in 190 medication changes for 60 (71.4%) clients (median 2 per client). The pharmacists prepared, or assisted GPs to update, treatment authorizations for 68 (81%) clients. WHAT IS NEW AND CONCLUSION: Integrating pharmacists into a home nursing service identified and addressed MRPs and medication treatment authorization discrepancies, hence contributing to enhanced medication safety.

Dental visiting behaviours among primary schoolchildren: Application of the health belief model.

OBJECTIVES: This study aimed to develop and validate a new instrument based on the health belief model and to use the instrument to investigate the determinants of regular dental attendance among primary schoolchildren. METHODS: A cross-sectional study was conducted using a newly developed measurement scale based on the HBM, 4 health-promoting schools participated in the study and 958 students studying in grades 4-6 completed the questionnaire. The psychometric properties of the instrument were analysed, and a path analysis model was used to identify the determinants of regular dental attendance. RESULTS: The instrument had good internal consistency (Cronbach's α = 0.826-0.925) and a factor structure identical to HBM. Overall, the schoolchildren's health beliefs on caries treatment were positive. The determinants of regular dental visit were school location (ß = -0.13), mother's education level (ß = 0.15), susceptibility (ß = -0.18) and barriers (ß = -0.11). CONCLUSION: This study provided evidence that HBM is applicable to children's dental visiting behaviour and their health beliefs towards adherence to caries treatment. Although children had a positive attitude towards dental visits, environmental obstacles would interfere with dental visits. The newly developed instrument could be used to identify high-risk children and help design oral health interventions for these children. Moreover, policy makers should increase the accessibility of dental resources to enhance the utilization of dental care among schoolchildren.

Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma.

BACKGROUND: We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC). METHODS: The PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected to in vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling. RESULTS: The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations of FGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib. CONCLUSIONS: FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.

Modelling end-pumped passively Q-switched Nd-doped crystal lasers: manifestation by a Nd:YVO4/Cr4+:YAG system with a concave-convex resonator.

A theoretical model for the passively Q-switched (PQS) operation which includes the spatial overlapping between the pump and lasing modes under the thermal lensing effect is developed to give a transcendental equation that can directly determine the critical parameters such as pulse energy, pulse repetition rate, and pulse width for the PQS performance. More importantly, an analytical function which gives the approximate solution for the transcendental equation as well as a specific critical criterion for good PQS operation are derived for practical analyses and design. A Nd:YVO4/Cr4+:YAG system with a concave-convex resonator which can achieve fairly stable PQS pulse trains even at a high pump level is further exploited to manifest the proposed spatially dependent model. The good agreement between the experimental results and the theoretical predictions is verified to show the feasibility of the proposed model for designing high-power PQS lasers with high accuracy.

Generation of terahertz optical beating from a simultaneously self-mode-locked Nd:YAG laser at 1064 and 1123 nm.

The reflectivity of the output coupler is designed to achieve the synchronously self-mode-locked operation at 1064 and 1123 nm in a diode-end-pumped Nd:YAG laser. Numerical analyses are performed to confirm that the designed output coupler can lead the emission lines to be predominant at 1064 and 1123 nm. Moreover, the crossover of the threshold pump powers for the 1064 and 1123 nm emission lines can be exploited to obtain the single central wavelength of 1064 nm or the single central wavelength of 1123 nm or, simultaneously, dual-central-wavelength self-mode-locked operation by finely adjusting the cavity alignment. For the dual-central-wavelength mode-locked emissions, the pulse repetition rate and the pulse duration are 4.5 GHz and 50.8 ps, respectively. The maximum output power can be up to 2.47 W at a pump power of 7.5 W. The synchronization of the 1064 and 1123 nm mode-locked pulses generates the optical beating pulse trains with repetition rates up to 14.7 THz.