Cytotoxic antimelanoma drugs suppress the activation of M2 macrophages

Together with regulatory T cells (Tregs), tumor‐associated macrophages (TAMs) play roles in maintaining the tumor microenvironment. Although cytotoxic antimelanoma drugs such as dacarbazine (DTIC), nimustine hydrochloride (ACNU) and vincristine (VCR) have been used for the treatment of malignant melanoma as adjuvant therapy in Japan, the detailed mechanisms of their immunomodulatory effects are not fully understood. As the majority of TAMs are alternatively activated M2 macrophages that favour tumor development, the aim of this study was to elucidate the immunomodulatory effects of these reagents on human monocyte‐derived M2 macrophages. First, mRNA expressions and protein production of immune checkpoint molecules, PD‐L1 and chemokines by CD163⁺ CD206⁺ M2 macrophages derived from peripheral blood mononuclear cells were investigated to determine the immunomodulatory effects of DTIC, ACNU, and VCR. DTIC and VCR significantly decreased PD‐L1 mRNA expression, which was confirmed by flow cytometry. Moreover, the mRNA expression and production of CCL22 were significantly decreased by DTIC, which suggested that DTIC might suppress the recruitment of Tregs in the tumor site. Furthermore, the decreased expression of PD‐L1 and production of CCL22 were validated in vivo, using the B16F10 mouse melanoma model, leading to abrogation of the suppressive function of T‐cell proliferation. The present report suggests one of the possible antimelanoma mechanisms of DAV combination chemotherapy for melanoma patients.     

Enhancing viral vaccine production using engineered knockout vero cell lines – A second look

The global adoption of vaccines to combat disease is hampered by the high cost of vaccine manufacturing. The work described herein follows two previous publications (van der Sanden et al., 2016; Wu et al., 2017) that report a strategy to enhance poliovirus and rotavirus vaccine production through genetic modification of the Vero cell lines used in large-scale vaccine manufacturing. CRISPR/Cas9 gene editing tools were used to knockout Vero target genes previously shown to play a role in polio- and rotavirus production. Subsequently, small-scale models of current industry manufacturing systems were developed and adopted to assess the increases in polio- and rotavirus output by multiple stable knockout cell lines. Unlike previous studies, the Vero knockout cell lines failed to achieve desired target yield increases. These findings suggest that additional research will be required before implementing the genetically engineered Vero cell lines in the manufacturing process for polio- and rotavirus vaccines to be able to supply vaccines at reduced prices.     

Retrospective Assessment of Exposure to Chemicals for a Microelectronics and Business Machine Manufacturing Facility

A retrospective exposure assessment was performed for use in a health outcomes study of a facility manufacturing circuit boards, business machines, and other equipment during the years 1969–2002. A matrix was developed identifying chemical use by department-year based on company-provided information. Use of six chemical agents (fiberglass, lead, methylene chloride, methyl chloroform, perchloroethylene, and trichloroethylene) and six chemical classes (acid-base, aromatic hydrocarbons, chlorinated hydrocarbons, other hydrocarbons, chlorofluorocarbons, and metals), and general (including unspecified) chemicals was identified. The matrix also contained an assignment for each department-year categorizing the potential for use of chemicals as negligible, intermittent/incidental, or routine. These department-based exposure matrix data were combined with work history data to provide duration of potential chemical use for workers. Negligible, intermittent/incidental or routine extent-of-chemical-use categories comprised 42.6%, 39.4%, and 17.9%, respectively, of total person-years of employment. Cumulative exposure scores were also developed, representing a relative measure of the cumulative extent of potential exposure to the six chemical agents, six chemical classes, and general (including unspecified) chemicals. Additionally, the study period was divided into manufacturing eras showing trends in chemical use, and showing that process use of trichloroethylene and methylene chloride ended in the mid-1980s and the mid-1990s, respectively. This approach may be useful in other assessments addressing a variety of chemicals, and with data constraints common to retrospective chemical exposure studies.     

Is /h/ phonetically neutral?

Use of /h/ in the phrase, ‘Say /hVC/ again’ has been tacitly assumed to provide a neutral phonetic context in which to study the articulatory characteristics of speech either preceding or following /h/ articulation. Yet, assessment of the stability or neutrality of /h/ has gone untested. The current study sought to determine whether articulation of /h/ differs according to sex and language accent, as well as to examine its influence on subsequent vowel articulation. Selected acoustic features of /hVC/ were measured in 40 speakers of American English (AE) and 40 speakers of Mandarin-accented English (MAE). Results of an analysis of /h/ duration revealed no sex differences within each language group, however considerable variation was found according to accented vs unaccented English. Clear sex differences were found for the production of /?/, occurring more often among male speakers regardless of language variety. Considerable variation in production of /?/ was found between language groups. Analysis of vowel formant frequencies immediately following /h/ articulation indicated minimal coarticulatory effects for both AE and MAE speakers. The present results appear to support the suggestion that /h/ is not exclusively sex-linked and may indeed vary according to non-biological factors. In spite of these variations, /h/ articulation appears to have a negligible influence on neighbouring vowel articulation.     

Tracking speech sound acquisition

This article describes a procedure to aid in the clinical appraisal of child speech. The approach, based on the work by Dinnsen, Chin, Elbert, and Powell (1990; Some constraints on functionally disordered phonologies: Phonetic inventories and phonotactics. Journal of Speech and Hearing Research, 33, 28–37), uses a railway idiom to track gains in the complexity of speech sound production. A clinical case study is reviewed to illustrate application of the procedure. The procedure is intended to facilitate application of an evidence-based procedure to the clinical management of developmental speech sound disorders.     

Investigation of Foot and Mouth Disease hotspots in northern Lao PDR

Foot and mouth disease (FMD) is an endemic transboundary disease in the Mekong region, and FMD records of reports to animal health authorities in Lao PDR between 2009 and 2011 were reviewed. FMD outbreaks occurred in 2 of 3 years in eight districts in three of the eight northern Lao PDR provinces, locations suggested as FMD ‘hotspots’. The relatively higher risk of recurrence of FMD in these districts was likely due to the presence of a dense large ruminant population, extensive animal trading including transboundary movements and ineffective animal movement controls. As an understanding of the epidemiology of FMD in these ‘hotspots’ may offer insights into improved FMD control in the region, a study of an outbreak of FMD occurring in early 2010 following failure to vaccinate was conducted in the endemic ‘hotspot’ area of Paek district in Xiengkhoung province where in early 2009, a major outbreak of FMD in the district had been prevented in two villages by vaccination. The 2010 outbreak included collection of tissue samples 1 week after the onset of FMD that confirmed infection with FMD virus serotype O (Myanmar topotype) in a population of 239 large ruminants, comprising 167 cattle and 72 buffalo. A survey by interview of 30 farmers conducted in July 2010 documented high morbidity in cattle and buffalo (>90%) and identified disease risk factors, including increased trading of animals at the end of the rice harvest, plus several failures of biosecurity. In late 2010 and early 2011, a total of 40 and 72 serum samples were collected from large ruminants prior to and post‐FMD vaccination respectively and tested by LPB‐ELISA. Antibodies were present in the pre‐vaccination samples attributable to previous exposure to FMD virus and significantly rising post‐vaccination titres indicated likely temporary protection against future FMDV infection. It was concluded that to provide sufficient control of FMD in this ‘hotspot’, regular vaccination, particularly prior to the peak risk period in December‐February, plus improved farmer knowledge of disease transmission risk and biosecurity, is required. Although low rural education standards and language barriers because of multiple ethnic groups pose a challenge for the successful delivery of extension programmes in northern Lao PDR, training to improve disease recognition and reporting plus village‐level biosecurity practices is considered important in FMD ‘hotspots’ if sustainable regional initiatives directed at FMD control are to be achieved.     

Production of influenza pseudotyped lentiviral particles and their use in influenza research and diagnosis: an update

Pseudotyped viral particles are being used as safe surrogates to mimic the structure and surface of many viruses, including highly pathogenic viruses such as avian influenza H5N1, to investigate biological functions mediated by the envelope proteins derived from these viruses. The first part of this article evaluates and discusses the differences in the production and characterization of influenza pseudoparticles. The second part focuses on the applications that such a flexible tool can provide in modern influenza research, in particular in the fields of drug discovery, molecular biology and diagnosis.     

New developments in lentiviral vector design,production and purification

Introduction: Lentiviruses are a very potent class of viral vectors for which there is presently a rapidly growing interest for a number of gene therapy. However, their construction, production and purification need to be performed according to state-of-the-art techniques in order to obtain sufficient quantities of high purity material of any usefulness and safety.

Areas covered: The recent advances in the field of recombinant lentivirus vector design, production and purification will be reviewed with an eye toward its utilization for gene therapy. Such a review should be helpful for the potential user of this technology.

Expert opinion: The principal hurdles toward the use of recombinant lentivirus as a gene therapy vector are the low titer at which it is produced as well as the difficulty to purify it at an acceptable level without degrading it. The recent advances in the bioproduction of this vector suggest these issues are about to be resolved, making the retrovirus gene therapy a mature technology.     

Cantonese tone production performance of mainstream school children with hearing impairment

Abstract

This study investigated the Cantonese tone production ability of children with hearing impairment studying in mainstream schools. The participants were 87 Cantonese-speaking children with mild-to-profound degrees of hearing loss aged 5.92–13.58 in Hong Kong. Most of the children were fitted with hearing aids (n = 65); 17 of them had profound hearing impairment, one who had severe hearing loss had cochlear implantation, and four who had mild hearing loss were without any hearing device. The Hong Kong Cantonese Articulation Test was administered, and the tones produced were rated by two of the authors and a speech-language pathologist. Group effects of tones, hearing loss level, and also an interaction of the two were found to be significant. The children with profound hearing impairment performed significantly worse than most of the other children. Tone 1 was produced most accurately, whereas tone 6 productions were the poorest. No relationship was found between the number of years of mainstreaming and tone production ability. Tone production error pattern revealed that confusion patterns in tone perception coincided with those in production. Tones having a similar fundamental frequency (F0) at the onset also posed difficulty in tone production for children with hearing impairment.