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For the first time, to the best of our knowledge, in the soliton regime, we demonstrate an L-band fiber laser mode-locked by all polarization-maintaining (all-PM) nonlinear polarization rotation (NPR). A numerical study suggests that lengthening the NPR section boosts modulation depth and lowers saturation power of the artificial saturable absorber (SA). With the longest NPR section to date (21 m), the laser emits 1.25-ps soliton pulses at 1584.2 nm and a 3.9-MHz repetition rate. Our laser provides a promising L-band seed source, exhibiting improved repeatability and stability compared with non-PM L-band pulse fiber lasers.

Accurate delineation of gross tumor volumes remains a barrier to radiotherapy dose escalation and boost dosing in the treatment of solid tumors, such as prostate cancer. Magnetic resonance imaging (MRI) of tumor targets has the power to enable focal dose boosting, particularly when combined with technological advances such as MRI-linear accelerator. Fibroblast activation protein (FAP) is overexpressed in stromal components of >90% of epithelial carcinomas. Herein, the authors compare targeted MRI of prostate specific membrane antigen (PSMA) with FAP in the delineation of orthotopic prostate tumors. Control, FAP, and PSMA-targeting iron oxide nanoparticles were prepared with modification of a lymphotropic MRI agent (FerroTrace, Ferronova). Mice with orthotopic LNCaP tumors underwent MRI 24 h after intravenous injection of nanoparticles. FAP and PSMA nanoparticles produced contrast enhancement on MRI when compared to control nanoparticles. FAP-targeted MRI increased the proportion of tumor contrast-enhancing black pixels by 13%, compared to PSMA. Analysis of changes in R2 values between healthy prostates and LNCaP tumors indicated an increase in contrast-enhancing pixels in the tumor border of 15% when targeting FAP, compared to PSMA. This study demonstrates the preclinical feasibility of PSMA and FAP-targeted MRI which can enable targeted image-guided focal therapy of localized prostate cancer., (© 2023 The Authors. Small published by Wiley-VCH GmbH.)

Fasting metabolism and immunity are tightly linked; however, it is largely unknown how immune cells contribute to metabolic homeostasis during fasting in healthy subjects. Here, we combined cell-type-resolved genomics and computational approaches to map crosstalk between hepatocytes and liver macrophages during fasting. We identified the glucocorticoid receptor (GR) as a key driver of fasting-induced reprogramming of the macrophage secretome including fasting-suppressed cytokines and showed that lack of macrophage GR impaired induction of ketogenesis during fasting as well as endotoxemia. Mechanistically, macrophage GR suppressed the expression of tumor necrosis factor (TNF) and promoted nuclear translocation of hepatocyte GR to activate a fat oxidation/ketogenesis-related gene program, cooperatively induced by GR and peroxisome proliferator-activated receptor alpha (PPARα) in hepatocytes. Together, our results demonstrate how resident liver macrophages directly influence ketogenesis in hepatocytes, thereby also outlining a strategy by which the immune system can set the metabolic tone during inflammatory disease and infection., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Although homebound older adults are among the highest users of hospital services, the existing health and social services that are provided to them in the community are limited and fragmented. This study attempts to bring this group of older adults to providers' attention by designing a health-social-oriented self-care mobile Health (mHealth) program and subjecting it to empirical testing. The aim of this study is to shift the current reactive, cure-oriented approach to a preventive and health-promoting model, empowering homebound older adults to take an active role in their health, be responsive to their care needs, and subsequently improve their holistic health., Methods: This is a pilot randomized controlled trial. The study is supported by 5 community centers with an estimated sample size of 68 subjects. The subjects will be randomly assigned to video-based mHealth or control groups when they (1) are aged 60 or over, (2) go outdoors less than once a week in the current 6 months, (3) live within the service areas, and (4) use a smartphone. Subjects in the video-based mHealth group will receive a 3-month program comprising 2 main interventions: nurse case management supported by a social service team and video messages covering self-care topics, delivered via smartphone. The control group will receive usual care. Data will be collected at 2 time points - pre-intervention (T1) and post-intervention (T2). The primary outcome will be self-efficacy, and secondary outcomes will include health outcomes (activities of daily living, instrumental activities of daily living, and medication adherence), perceived well-being outcomes (quality of life and depression), and health service utilization outcomes (outpatient clinic, emergency room, and hospital admission)., Discussion: The current study will add to the knowledge gap in using mHealth supported by a health-social team to enhance quality of life and self-care and meet the needs of these particularly vulnerable older adults., (© 2021 S. Karger AG, Basel.)

Objective: The coronavirus disease 2019 outbreak and its containment through public health strategies has resulted in a parallel pandemic of psychological distress. Increased loneliness and social isolation are associated with adverse health outcomes, yet there is a gap in brief interventions that specifically target loneliness. This article introduces a brief intervention to strengthen connectedness, LOVE. In a systematic way, this solution-focused approach encourages openness and sharing of current struggles with the existing circle of support. There are four steps in LOVE: L ist people in one's life, O rganise them on the helpfulness-availability matrix, V erify what they know to map them onto circles of trust and E ngage them through self-disclosure., Conclusion: The article details each concept, its importance, the pragmatics involved and top tips to guide practice. The memorable acronym provides logical sequence and structure. It is time efficient in training and delivery, with no former mental health knowledge required so there is potential for wide application. It facilitates collaboration between health professionals and people in distress and promotes empowerment and self-resilience. Adapted from the safety planning component of PROTECT, a pre-existing suicide prevention framework, LOVE has to be fine-tuned as a brief intervention in the wider context of the pandemic.

The recent advent of CRISPR and other molecular tools enabled the reconstruction of cell lineages based on induced DNA mutations and promises to solve the ones of more complex organisms. To date, no lineage reconstruction algorithms have been rigorously examined for their performance and robustness across dataset types and number of cells. To benchmark such methods, we decided to organize a DREAM challenge using in vitro experimental intMEMOIR recordings and in silico data for a C. elegans lineage tree of about 1,000 cells and a Mus musculus tree of 10,000 cells. Some of the 22 approaches submitted had excellent performance, but structural features of the trees prevented optimal reconstructions. Using smaller sub-trees as training sets proved to be a good approach for tuning algorithms to reconstruct larger trees. The simulation and reconstruction methods here generated delineate a potential way forward for solving larger cell lineage trees such as in mouse., Competing Interests: Declaration of interests The authors declare no competing interests. Worm image in Figure 1 was modified from Caenorhabditis elegans hermaphrodite adult-en.svg from Wikimedia Commons by K. D. Schroeder, CC-BY-SA 3.0. The schematic cell lineage of C. elegans in Figures 1 and 6 was generated using the cell lineage web visualization tool CeLaVi available at http://celavi.pro (Salvador-Martínez et al., 2020)., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Liver fibrosis is a strong predictor of long-term mortality in individuals with metabolic-associated fatty liver disease; yet, the mechanisms underlying the progression from the comparatively benign fatty liver state to advanced non-alcoholic steatohepatitis (NASH) and liver fibrosis are incompletely understood. Using cell-type-resolved genomics, we show that comprehensive alterations in hepatocyte genomic and transcriptional settings during NASH progression, led to a loss of hepatocyte identity. The hepatocyte reprogramming was under tight cooperative control of a network of fibrosis-activated transcription factors, as exemplified by the transcription factor Elf-3 (ELF3) and zinc finger protein GLIS2 (GLIS2). Indeed, ELF3- and GLIS2-controlled fibrosis-dependent hepatokine genes targeting disease-associated hepatic stellate cell gene programs. Thus, interconnected transcription factor networks not only promoted hepatocyte dysfunction but also directed the intra-hepatic crosstalk necessary for NASH and fibrosis progression, implying that molecular "hub-centered" targeting strategies are superior to existing mono-target approaches as currently used in NASH therapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

During multicellular development, spatial position and lineage history play powerful roles in controlling cell fate decisions. Using a serine integrase-based recording system, we engineered cells to record lineage information in a format that can be read out in situ . The system, termed integrase-editable memory by engineered mutagenesis with optical in situ readout (intMEMOIR), allowed in situ reconstruction of lineage relationships in cultured mouse cells and flies. intMEMOIR uses an array of independent three-state genetic memory elements that can recombine stochastically and irreversibly, allowing up to 59,049 distinct digital states. It reconstructed lineage trees in stem cells and enabled simultaneous analysis of single-cell clonal history, spatial position, and gene expression in Drosophila brain sections. These results establish a foundation for microscopy-readable lineage recording and analysis in diverse systems., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

A variety of genetic techniques have been devised to determine cell lineage relationships during tissue development. Some of these systems monitor cell lineages spatially and/or temporally without regard to gene expression by the cells, whereas others correlate gene expression with the lineage under study. The G AL4 T echnique for R eal-time a nd C lonal E xpression (G-TRACE) system allows for rapid, fluorescent protein-based visualization of both current and past GAL4 expression patterns and is therefore amenable to genome-wide expression-based lineage screens. Here we describe the results from such a screen, performed by undergraduate students of the University of California, Los Angeles (UCLA) Undergraduate Research Consortium for Functional Genomics (URCFG) and high school summer scholars as part of a discovery-based education program. The results of the screen, which reveal novel expression-based lineage patterns within the brain, the imaginal disc epithelia, and the hematopoietic lymph gland, have been compiled into the G-TRACE Expression Database (GED), an online resource for use by the Drosophila research community. The impact of this discovery-based research experience on student learning gains was assessed independently and shown to be greater than that of similar programs conducted elsewhere. Furthermore, students participating in the URCFG showed considerably higher STEM retention rates than UCLA STEM students that did not participate in the URCFG, as well as STEM students nationwide., (Copyright © 2019 Olson et al.)

Objectives: This study aimed to determine the prevalence of mental illness in offenders referred to psychiatrists from January 2011 to March 2016 and any associations between crime and mental illness in these offenders., Methods: Case notes of offenders referred to psychiatrists at the Siu Lam Psychiatric Centre from 1 January 2011 to 31 March 2016 were reviewed. Data on sex, age on admission, educational level, principal psychiatric diagnosis, index offence, source and reason of referral, and outcome were collected., Results: Case notes were reviewed for 4492 offenders (75% males) aged 14 to 93 (mean, 40.6) years. Of these, 68% were referred by the courts for psychiatric report and 32% were referred by correctional institutions for psychiatric assessment and treatment. Approximately 73% of them had a diagnosable mental disorder. The most common principal psychiatric diagnoses were schizophrenia and related disorders (25%), mental and behavioural disorders due to psychoactive substance use (20%), and mood disorders (9%). The most common index offences were theft and related offences (22%), acts intended to cause injury (20%), and illicit drug offences (11%). Offences involving violence were more prevalent in males than in females (p < 0.001). In terms of the three most common principal psychiatric diagnoses, 'acts intended to cause injury' was most prevalent in those with 'schizophrenia and other related disorders' than in those with the other two diagnoses (31% vs 19% vs 17%, p < 0.001). 'Theft and related offences' was most prevalent in those with mood disorders than in those with other two diagnoses (38% vs 20% vs 18%, p < 0.001). 'Illicit drug offences' was most prevalent in those with 'mental and behavioural disorders due to psychoactive substance' than those with other two diagnoses (22% vs 8% vs 6%, p < 0.001)., Conclusions: The prevalence of mental disorders among offenders referred to psychiatrists is high. The pattern of associations between crime and mental disorders in these offenders is comparable with that reported in overseas studies. As Siu Lam Psychiatric Centre is the only facility in Hong Kong for mentally ill offenders, our sample is representative, and our results provide cross-sectional pattern of forensic psychiatric service utilisation in Hong Kong.

Objectives: This study aimed to validate the Correctional Mental Health Screen (CMHS) in the Hong Kong prison population and determine the prevalence of psychiatric disorders among remand prisoners in Hong Kong and the associated factors of mental illness., Methods: This cohort study was conducted at the Lai Chi Kok Reception Centre and the Tai Lam Centre for Women in Hong Kong. Remand prisoners aged ≥21 years were recruited between May and August 2014. Sociodemographic and clinical data were collected. Each remand prisoner was assessed using the appropriate CMHS for males or for females, then interviewed by a specialist psychiatrist using the Structured Clinical Interview for DSM-IV for current affective disorder and psychotic disorder for cross-validation., Results: A total of 245 remand prisoners were recruited (150 males and 95 females; mean age, 25.8 years). Of them, 51% (55% males and 44% females) had a lifetime history of psychiatric disorder, whereas 39.6% (46% males and 29.5% females) had a current psychiatric disorder. The most common psychiatric disorder was substance use disorder (>36%), followed by mood disorder (>20%), psychotic disorder (5.3%), and lifetime neurotic disorder (3.7%). Living in a public housing estate (odds ratio [OR] = 1.99), a history of childhood conduct problem (OR = 2.40), and a forensic history (OR = 1.97) were associated with an increased risk of having a psychiatric disorder. The CMHS had good diagnostic efficiency after cross-validation with the Structured Clinical Interview for DSM-IV., Conclusion: Psychiatric disorders are prevalent in remand prisoners in Hong Kong. The CMHS is an effective tool to screen remand prisoners for timely treatment of prisoners with mental health needs.

Reconstructing the lineage relationships and dynamic event histories of individual cells within their native spatial context is a long-standing challenge in biology. Many biological processes of interest occur in optically opaque or physically inaccessible contexts, necessitating approaches other than direct imaging. Here we describe a synthetic system that enables cells to record lineage information and event histories in the genome in a format that can be subsequently read out of single cells in situ. This system, termed memory by engineered mutagenesis with optical in situ readout (MEMOIR), is based on a set of barcoded recording elements termed scratchpads. The state of a given scratchpad can be irreversibly altered by CRISPR/Cas9-based targeted mutagenesis, and later read out in single cells through multiplexed single-molecule RNA fluorescence hybridization (smFISH). Using MEMOIR as a proof of principle, we engineered mouse embryonic stem cells to contain multiple scratchpads and other recording components. In these cells, scratchpads were altered in a progressive and stochastic fashion as the cells proliferated. Analysis of the final states of scratchpads in single cells in situ enabled reconstruction of lineage information from cell colonies. Combining analysis of endogenous gene expression with lineage reconstruction in the same cells further allowed inference of the dynamic rates at which embryonic stem cells switch between two gene expression states. Finally, using simulations, we show how parallel MEMOIR systems operating in the same cell could enable recording and readout of dynamic cellular event histories. MEMOIR thus provides a versatile platform for information recording and in situ, single-cell readout across diverse biological systems.

In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.

Background: Avulsion of the abducens nerve in the setting of geniculate ganglion injury after temporal bone fracture is unreported previously. We discuss clinical assessment and management of a patient with traumatic avulsion of cranial nerve (CN) VI in the setting of an ipsilateral CN VII injury after temporal bone fracture and call attention to this unusual injury., Case Description: A 26-year-old man suffered a temporal bone fracture after a motor vehicle accident and developed diplopia and right-sided facial droop. Six weeks after the accident, the patient was readmitted with worsening diplopia and ipsilateral facial weakness. He demonstrated absent lateral gaze on the right suggestive of either restrictive movement or right., Cn Vi Deficit: In addition, he had right-sided facial palsy graded as 6/6 House-Brackmann. High-resolution computed tomography demonstrated a right-sided longitudinal otic capsule-sparing temporal bone fracture that propagated into the facial nerve canal and geniculate fossa. Magnetic resonance imaging revealed discontinuity of the right CN VI between the pons and the Dorello canal, as well as injury to the ipsilateral geniculate ganglion. CN VII was intact proximally, from the pons through the internal auditory canal. Consensus was reached to proceed with conservative management. At 13 months after injury, the patient reported 1/6 House-Brackmann with no improvement in CN VI function., Conclusions: This case illustrates 2 subtle findings on imaging with potential therapeutic implications, notably the role of surgical intervention for facial nerve palsy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose. The goal of this study was to investigate the effects of arm weight support training using the ArmeoSpring for subacute patients after stroke with different levels of hemiplegic arm impairments. Methods. 48 inpatients with subacute stroke, stratified into 3 groups from mild to severe upper extremity impairment, were engaged in ArmeoSpring training for 45 minutes daily, 5 days per week for 3 weeks, in addition to conventional rehabilitation. Evaluations were conducted at three measurement occasions: immediately before training (T1); immediately after training (T2); and at a 3-week follow-up (T3) by a blind rater. Results. Shoulder flexion active range of motion, Upper Extremity Scores in the Fugl-Meyer Assessment (FMA), and Vertical Catch had the greatest differences in gain scores for patients between severe and moderate impairments, whereas FMA Hand Scores had significant differences in gain scores between moderate and mild impairments. There was no significant change in muscle tone or hand-path ratios between T1, T2, and T3 within the groups. Conclusion. Arm weight support training is beneficial for subacute stroke patients with moderate to severe arm impairments, especially to improve vertical control such as shoulder flexion, and there were no adverse effects in muscle tone.

We present a pilot demonstration of an optical fiber based refractive index (RI) sensor involving the deposition of graphene onto the surface of a segment of a photonic crystal fiber (PCF) in a fiber-based Mach-Zehnder Interferometer (MZI). The fabrication process is relatively simple and only involves the fusion splicing of a PCF between two single mode fibers. The deposition process relies only on the cold transfer of graphene onto the PCF segment, without the need for further physical or chemical treatment. The graphene overlay modified the sensing scheme of the MZI RI sensor, allowing the sensor to overcome limitations to its detectable RI range due to free spectral range issues. This modification also allows for continuous measurements to be obtained without the need for reference values for the range of RIs studied and brings to light the potential for simultaneous dual parameter sensing. The sensor was able to achieve a RI sensitivity of 9.4 dB/RIU for the RIs of 1.33-1.38 and a sensitivity of 17.5 dB/RIU for the RIs of 1.38-1.43. It also displayed good repeatability and the results obtained were consistent with the modeling.

Glioblastoma is a devastating cancer with universally poor outcomes in spite of current standard multimodal therapy. Immunotherapy is an attractive new treatment modality given its potential for exquisite specificity and its favorable side effect profile; however, clinical trials of immunotherapy in GBM have thus far shown modest benefit. Optimally combining radiation with immunotherapy may be the key to unlocking the potential of both therapies given the evidence that radiation can enhance anti-tumor immunity. Here we review this evidence and discuss considerations for combined therapy.

Institutional aggression in forensic psychiatric setting is an under-researched subject, despite the magnitude of the problem. No studies have been conducted on the assessment of risk and the examination of predictors of aggression among the Chinese forensic psychiatric population. Our study aimed to examine the determinants of aggression in the only forensic psychiatric institution in Hong Kong, and to test the psychometric properties of a risk-assessment instrument, the Dynamic Appraisal of Situational Aggression (DASA). We recruited a representative sample of 530 consecutively admitted detainees. Qualified nurses completed two risk-assessment instruments, the DASA and the Brøset Violence Checklist (BVC), once daily during the participants׳ first 14 days of admission. Aggressive incidents were recorded using the revised Staff Observation Aggression Scale (SOAS-R), and participants׳ data were collected for multivariate analyses. We showed that female gender, diagnoses of personality disorder and substance-related disorder, and admission at other correctional institutions were associated with institutional aggression. Aggression was perpetrated by 17.7% of the participants, and the DASA was demonstrated to have good psychometric properties in assessing and predicting aggressive incidents. Our findings preliminarily support the use of daily in-patient risk-assessment and affirm the role of dynamic factors in institutional aggression., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

We present an all-fiber passively mode-locked fiber laser incorporating three-dimensional (3D) graphene as a saturable absorber (SA) for the first time to the best of our knowledge. The 3D graphene is synthesized by template-directed chemical vapor deposition (CVD). The SA is then simply formed by sandwiching the freestanding 3D graphene between two conventional fiber connectors without any deposition process. It is demonstrated that such 3D graphene based SA is capable to produce high quality mode-locked pulses. A passively mode-locked fiber laser is constructed and stable output pulses with a fundamental repetition rate of ~9.9 MHz and a pulse width of ~1 ps are generated from the fiber laser. The average output power of the laser is ~10.5 mW while the output pulse is operating at single pulse region. The results imply that the freestanding 3D graphene can be applied as an effective saturable absorption material for passively mode-locked lasers.

We demonstrate the generation of dark pulses from carbon nanotube (CNT) incorporated erbium-doped fiber ring lasers with net anomalous dispersion. A side-polished fiber coated with CNT layer by optically-driven deposition method is embedded into the laser in order to enhance the birefringence and nonlinearity of the laser cavity. The dual-wavelength domain-wall dark pulses are obtained from the developed CNT-incorporated fiber laser at a relatively low pump threshold of 50.6 mW. Dark pulses repeated at the fifth-order harmonic of the fundamental cavity frequency are observed by adjusting the intra-cavity polarization state.

Purpose: Breath analysis has a potential prospect to benefit the medical field based on its perceived advantages to become a point-of-care, easy to use, and cost-effective technology. Early studies done by mass spectrometry show that volatile organic compounds from human breath can represent certain disease states of our bodies, such as lung cancer, and revealed the potential of breath analysis. But mass spectrometry is costly and has slow-turnaround time. The authors' goal is to develop a more portable and cost effective device based on Raman spectroscopy and hollow core-photonic crystal fiber (HC-PCF) for breath analysis., Methods: Raman scattering is a photon-molecular interaction based on the kinetic modes of an analyte which offers unique fingerprint type signals that allow molecular identification. HC-PCF is a novel light guide which allows light to be confined in a hollow core and it can be filled with a gaseous sample. Raman signals generated by the gaseous sample (i.e., human breath) can be guided and collected effectively for spectral analysis., Results: A Raman-cell based on HC-PCF in the near infrared wavelength range was developed and tested in a single pass forward-scattering mode for different gaseous samples. Raman spectra were obtained successfully from reference gases (hydrogen, oxygen, carbon dioxide gases), ambient air, and a human breath sample. The calculated minimum detectable concentration of this system was ∼15 parts per million by volume, determined by measuring the carbon dioxide concentration in ambient air via the characteristic Raman peaks at 1286 and 1388 cm(-1)., Conclusions: The results of this study were compared to a previous study using HC-PCF to trap industrial gases and backward-scatter 514.5 nm light from them. The authors found that the method presented in this paper has an advantage to enhance the signal-to-noise ratio (SNR). This SNR advantage, coupled with the better transmission of HC-PCF in the near-IR than in the visible wavelengths led to an estimated seven times improvement in the detection sensitivity. The authors' prototype device also demonstrated a 100-fold improvement over a recently reported detection limit of a reflective capillary fiber-based Raman cell for breath analysis. Continued development is underway to increase the detection sensitivity further to reach practical clinical applications.

Background Aims: Outcomes for patients with glioblastoma remain poor despite aggressive multimodal therapy. Immunotherapy with genetically modified T cells expressing chimeric antigen receptors (CARs) targeting interleukin (IL) 13Rα2, human epidermal growth factor receptor 2, epidermal growth factor variant III or erythropoietin-producing hepatocellular carcinoma A2 has shown promise for the treatment of glioma in preclinical models. On the basis of IL13Rα2 immunotoxins that contain IL13 molecules with one or two amino acid substitutions (IL13 muteins) to confer specificity to IL13Rα2, investigators have constructed CARS with IL13 muteins as antigen-binding domains. Whereas the specificity of IL13 muteins in the context of immunotoxins is well characterized, limited information is available for CAR T cells., Methods: We constructed four second-generation CARs with IL13 muteins with one or two amino acid substitutions, and evaluated the effector function of IL13-mutein CAR T cells in vitro and in vivo., Results: T cells expressing all four CARs recognized IL13Rα1 or IL13Rα2 recombinant protein in contrast to control protein (IL4R) as judged by interferon-γ production. IL13 protein produced significantly more IL2, indicating that IL13 mutein-CAR T cells have a higher affinity to IL13Rα2 than to IL13Rα1. In cytotoxicity assays, CAR T cells killed IL13Rα1- and/or IL13Rα2-positive cells in contrast to IL13Rα1- and IL13Rα2-negative controls. Although we observed no significant differences between IL13 mutein-CAR T cells in vitro, only T cells expressing IL13 mutein-CARs with an E13K amino acid substitution had anti-tumor activity in vivo that resulted in a survival advantage of treated animals., Conclusions: Our study highlights that the specificity/avidity of ligands is context-dependent and that evaluating CAR T cells in preclinical animal model is critical to assess their potential benefit., (Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

We present an all-fiber bidirectional passively mode-locked soliton laser with a graphene-based saturable absorber for the first time to the best of our knowledge. Our design includes a four-port circulator to introduce different sections of cavity for the two counter-propagating pulses, so they have distinct output characteristics. Simultaneous bidirectional operation is achieved by appropriately adjusting the net cavity birefringence and loss. In the clockwise direction, the laser emits ~750 fs pulses at 1561.6 nm, with a repetition rate of 7.68 MHz. In the counter clockwise direction, the central wavelength, pulse width, and repetition rate are 1561.0 nm, ~850 fs, and 6.90 MHz, respectively.

We experimentally investigate the stability of dispersion-managed mode-locked fiber lasers using carbon-nanotube-based saturable absorbers (SAs) with different modulation depths. An unstable operation region of the mode-locked fiber laser with near-zero net cavity dispersion is observed, where the laser produces random pulse burst rather than stable pulse train. Through the implementation of high-contrast SAs in the laser, the unstable region is found to be shrunk by ~31.3% when the modulation depth of the SAs increases from 6.4% to 12.5%. The numerical simulation is consistent with the experimental observation.

Glioblastoma (GBM) is the most common primary brain tumor, and despite aggressive therapy with surgery, radiation, and chemotherapy, average survival remains at about 1.5 years. The highly infiltrative and invasive nature of GBM requires that alternative treatments for this disease be widespread and targeted to tumor cells. Immunotherapy in the form of tumor vaccines has the potential to meet this need. Vaccines against GBM hold the promise of triggering specific and systemic antitumor immune responses that may be the key to eradicating this unrelenting cancer. In this review, we will discuss past and present clinical trials of various GBM vaccines and their potential impact on the future care of GBM patients. There have been many promising phase I and phase II GBM vaccine studies that have led to ongoing and upcoming phase III trials. If the results of these randomized trials show a survival benefit, immunotherapy will become a standard part of the treatment of this devastating disease.

Preclinical and early clinical studies have demonstrated that chimeric antigen receptor (CAR)-redirected T cells are highly promising in cancer therapy. We observed that targeting HER2 in a glioblastoma (GBM) cell line results in the emergence of HER2-null tumor cells that maintain the expression of nontargeted tumor-associated antigens. Combinational targeting of these tumor-associated antigens could therefore offset this escape mechanism. We studied the single-cell coexpression patterns of HER2, IL-13Rα2, and EphA2 in primary GBM samples using multicolor flow cytometry and immunofluorescence, and applied a binomial routine to the permutations of antigen expression and the related odds of complete tumor elimination. This mathematical model demonstrated that cotargeting HER2 and IL-13Rα2 could maximally expand the therapeutic reach of the T cell product in all primary tumors studied. Targeting a third antigen did not predict an added advantage in the tumor cohort studied. We therefore generated bispecific T cell products from healthy donors and from GBM patients by pooling T cells individually expressing HER2 and IL-13Rα2-specific CARs and by making individual T cells to coexpress both molecules. Both HER2/IL-13Rα2-bispecific T cell products offset antigen escape, producing enhanced effector activity in vitro immunoassays (against autologous glioma cells in the case of GBM patient products) and in an orthotopic xenogeneic murine model. Further, T cells coexpressing HER2 and IL-13Rα2-CARs exhibited accentuated yet antigen-dependent downstream signaling and a particularly enhanced antitumor activity.

We present a scheme of fiber-connector-type carbon-nanotube-based saturable absorber (CNT-SA) with enhanced thermal damage threshold, in which the CNTs are deposited on the fiber connector end in a ring pattern for evanescent-field interaction instead of direct interaction. The thermal damage threshold of such CNT-SA is found to be increased by around 130% compared with an evenly deposited one. An all-fiber Fabry-Perot (FP) linear cavity passively mode-locked laser is further constructed incorporating the prepared CNT-SA, where the optical power is confined in a relatively short laser cavity to investigate the thermal damage threshold and the performance of the CNT-SA. Stable output pulses with a fundamental repetition rate of 211.84 MHz and a pulse width of 680 fs are generated from the fiber laser. The mode-locking operation can be maintained an intra-cavity average power of 30 mW, indicating that the CNT-SA can withstand a relatively high optical power without performance degradation.

Cancer-associated fibroblasts (CAFs), the principle component of the tumor-associated stroma, form a highly protumorigenic and immunosuppressive microenvironment that mediates therapeutic resistance. Co-targeting CAFs in addition to cancer cells may therefore augment the antitumor response. Fibroblast activation protein-α (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. To target FAP-positive CAFs in the tumor-associated stroma, we genetically modified T cells to express a FAP-specific chimeric antigen receptor (CAR). The resulting FAP-specific T cells recognized and killed FAP-positive target cells as determined by proinflammatory cytokine release and target cell lysis. In an established A549 lung cancer model, adoptive transfer of FAP-specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co-targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors.

Outcomes for patients with glioblastoma (GBM) remain poor despite aggressive multimodal therapy. Immunotherapy with genetically modified T cells expressing chimeric antigen receptors (CARs) targeting interleukin (IL)-13Rα2, epidermal growth factor receptor variant III (EGFRvIII), or human epidermal growth factor receptor 2 (HER2) has shown promise for the treatment of gliomas in preclinical models and in a clinical study (IL-13Rα2). However, targeting IL-13Rα2 and EGFRvIII is associated with the development of antigen loss variants, and there are safety concerns with targeting HER2. Erythropoietin-producing hepatocellular carcinoma A2 (EphA2) has emerged as an attractive target for the immunotherapy of GBM as it is overexpressed in glioma and promotes its malignant phenotype. To generate EphA2-specific T cells, we constructed an EphA2-specific CAR with a CD28-ζ endodomain. EphA2-specific T cells recognized EphA2-positive glioma cells as judged by interferon-γ (IFN-γ) and IL-2 production and tumor cell killing. In addition, EphA2-specific T cells had potent activity against human glioma-initiating cells preventing neurosphere formation and destroying intact neurospheres in coculture assays. Adoptive transfer of EphA2-specific T cells resulted in the regression of glioma xenografts in severe combined immunodeficiency (SCID) mice and a significant survival advantage in comparison to untreated mice and mice treated with nontransduced T cells. Thus, EphA2-specific T-cell immunotherapy may be a promising approach for the treatment of EphA2-positive GBM.

Purpose: To determine the diagnostic performance of diffusion-weighted (DW) imaging for the prediction of treatment failure in primary head and neck squamous cell carcinoma (HNSCC)., Materials and Methods: The study was approved by the local institutional ethics committee and conducted with informed written consent in patients with primary HNSCC treated with radiation therapy and chemotherapy. DW imaging of the primary tumor was performed before treatment in 37 patients and was repeated within 2 weeks of treatment in 30 patients. Histograms of apparent diffusion coefficients (ADCs) were analyzed, and mean ADC, kurtosis, skewness, and their respective percentage change were correlated for local failure and local control at 2 years by using the Student t test. Univariate and multivariate analyses of the ADC parameters, T stage, and tumor volume were performed by using logistic regression for prediction of local failure., Results: Local failure occurred in 16 of 37 (43%) patients and local control occurred in 21 of 37 (57%) patients. Pretreatment ADC parameters showed no correlation with local failure. There was significant intratreatment increase in mean ADC and a decrease in skewness and kurtosis (P < .001, P < .001, P = .024, respectively) for the whole group of patients when compared with those before treatment. During treatment, primary tumors showed a significantly lower increase in percentage change of mean ADC, higher skewness, and higher kurtosis for local failure than for local control (P = .016, .015, and .040, respectively). These ADC parameters also were significant for predicting local failure with use of univariate but not multivariate analysis., Conclusion: Early intratreatment DW imaging has the potential to allow prediction of treatment response at the primary site in patients with HNSCC.

OBJECTIVES. To obtain information about basic knowledge towards mental disorders and to evaluate public attitudes towards mental disorders in the Hong Kong Chinese population. METHODS. Questionnaires which collected basic demographic information, opinions about potential stigmas and myths, and knowledge on case vignettes depicting fictional characters with symptoms of mental illness were delivered to subjects in a secondary school, 2 homes for the elderly, a private housing estate, and a public housing estate in Hong Kong. RESULTS. Completed questionnaires were collected from 1035 subjects. In general, the participants' acceptance of mental illness was good. Regular contacts with such patients were associated with better knowledge (t = -2.71, p < 0.01) and better acceptance (t = 2.77, p < 0.01) of mental illness. Younger participants aged 15 to 19 years had a lower level of knowledge about mental health problems compared with other age-groups (p < 0.001). CONCLUSIONS. Personal contact with people with mental illness may help to improve knowledge and acceptance. Younger people in secondary school should be the target and prioritised group for mental health education. Apart from the delivery of mental health knowledge, strategies to increase social contact of the public with people having mental illness could be considered in the design and implementation of anti-stigma programmes.

A series of substituted benzylsulfanyl-phenylamines was synthesized, of which four substituted benzylsulfanyl-phenylguanidines (665, 666, 667 and 684) showed potent fungicidal activity (minimal fungicidal concentration, MFC ≤ 10 μM for Candida albicans and Candida glabrata). A benzylsulfanyl-phenyl scaffold with an unsubstituted guanidine resulted in less active compounds (MFC=50-100 μM), whereas substitution with an unsubstituted amine group resulted in compounds without fungicidal activity. Compounds 665, 666, 667 and 684 also showed activity against single C. albicans biofilms and biofilms consisting of C. albicans and Staphylococcus epidermidis (minimal concentration resulting in 50% eradication of the biofilm, BEC50 ≤ 121 μM for both biofilm setups). Compounds 665 and 666 combined potent fungicidal (MFC=5 μM) and bactericidal activity (minimal bactericidal concentration, MBC for S. epidermidis ≤ 4 μM). In an in vivo Caenorhabditis elegans model, compounds 665 and 667 exhibited less toxicity than 666 and 684. Moreover, addition of those compounds to Candida-infected C. elegans cultures resulted in increased survival of Candida-infected worms, demonstrating their in vivo efficacy in a mini-host model., (Copyright © 2011 Elsevier Ltd. All rights reserved.)