Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression.

Immune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) are not fully known. Here, we characterize the function of tumor-derived PGRN in promoting immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN is associated with poor overall survival in PDAC. Multiplex immunohistochemistry shows low MHC class I (MHCI) expression and lack of CD8+ T cell infiltration in PGRN-high tumors. Inhibition of PGRN abrogates autophagy-dependent MHCI degradation and restores MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a PDAC mouse model remarkably decelerates tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as a model antigen are sensitized to gp33-TCR transgenic T cell-mediated cytotoxicity upon PGRN blockade. Overall, our study shows a crucial function of tumor-derived PGRN in regulating immunogenicity of primary PDAC.

Treatment of advanced hepatocellular carcinoma: immunotherapy from checkpoint blockade to potential of cellular treatment.

The absence of potent therapeutic option accounts for the dismal prognosis of advanced hepatocellular carcinoma (HCC) with high mortality and recurrence rate. For a decade, sorafenib is the only approved systemic drug in the first-line setting and warrants as the standard-of-care for HCC in the advanced stage. Given the common failures of chemotherapies and targeted therapies in the field of HCC treatment, promising breakthroughs were eagerly needed and until recently, immunotherapies have opened a new era of anticancer treatment. The liver organ is perceived as "immunotolerant" owing to its functional role, and the hepatic immune balance is found to be deregulated during chronic liver inflammation and HCC tumorigenesis. Restoring a competent immunity by mitigation of immunosuppression signals is a contemporary approach. In this regard, novel immune checkpoint inhibitors have revolutionized cancer pharmacological treatment options with remarkable clinical outcomes in hematologic malignancy and multiple solid tumors including advanced HCC. Nivolumab, an immunotherapeutic agent to block programmed cell death protein 1 (PD-1), showed high efficacy potential for patients progressed with sorafenib and granted accelerated approval by the US Food and Drug Administration (FDA) recently. The development of this class of immunotherapeutic drug is currently based on myriad studies established on the role of T-cell mediated immunosuppression through immune checkpoints. Heterogeneous results have led to further explorations to the profile of oncogenic processes and signaling pathways associated with PD1/PD-L1 axis. Emerging evidence from preclinical studies implicate natural killer (NK) cells as a mediator to the PD-1 checkpoint signaling immunoevasion. The strategy of adopting immunomodulating ability of NK cells by immune checkpoints inhibitors is potential to additive effects in stimulating anticancer immunity. This idea is not entirely newfound but has recently gained prominence because of advances in defining phenotypic heterogeneity of NK cell populations. The physiological significance and synergistic value of NK cells await further investigation in clinical trials. In this review, an overview of the treatment paradigm shift of HCC management is presented. Current knowledge concerning immunological mechanisms of immune checkpoints attributed to T cell is further discussed and relevant ongoing clinical trials are summarized. We proposed that NK cells should be viewed as part of the network of checkpoint immunoevasion and delineate current evidence of translational clinical research in this area. It is conceivable that immune checkpoint inhibitors in combination with NK cell-based therapeutic strategies will be great promise for treatment of advanced HCC.

A mucoadhesive endoluminal wearable sensory system.

Bio- or muco-adhesive anchoring is a challenge for the development of advanced gastrointestinal (GI) surgical instruments, endoluminal monitoring devices and drug delivery systems. In this paper, we present a polymeric bio-adhesive film embedded with an optical sensor that can potentially be used to detect gastrointestinal bleeding. Four different formulas of mucoadhesive polymers were synthesized based on various chemical components and concentration combinations, and they were further layered with miniature photoplethymographic (PPG) sensors. The adhesive ability of the proposed mucoadhesive-sensor module was tested by attaching it to the lumen of a porcine stomach and compared amongst the four formulas. pH testing was also implemented to simulate the performance of the film in gastric cavity. To demonstrate the signal quality of this module, we also tested on the skin of five healthy subjects for hours. The observed shear detachment force between mucoadhesive film and porcine stomach tissue of all four formulations ranged from 0.09 to 1.38 N, and the performance of mucoadhesive film in pH 7 and pH 2 were similar. The module can attach firmly onto the skin for 3-10 hours with comparable PPG signal quality to traditional clip-based setup. With the advent of mucosal tissue anchoring by means of bioadhensive film, a wider extent of endoluminal procedures may become feasible. This emerging technology can also help shape the future of in-body wearable devices in the GI tract or other endoluminal cavities.

Validating the language domain subtest in a developmental assessment scale for preschool children.

This study reports on the validation of the language domain subtest of a developmental assessment scale for Cantonese Chinese preschool children. Three hundred and seventy eight multi-stage randomly selected children between 3;4 and 6;3 years of age were tested on the 104-item subtest. Fifty-four of these children, spreading across three age groups, demonstrated developmental problems. Results from the Rasch analyses suggested that the original and the shortened 66-item version demonstrated adequate measurement properties, including targeting and uni-dimensionality. Statistical analyses of the shortened version suggested that the subtest demonstrated strong test-retest reliability, and adequate convergent and criterion validity. This study contributes to good practice in the development of standardized normative tests, particularly those for investigations of language problems in Chinese children given that reports on existing tests' psychometric properties were often incomplete.

Development of the language subtest in a developmental assessment scale to identify Chinese preschool children with special needs.

This study reports on the development of the language subtest in the Preschool Developmental Assessment Scale (PDAS) for Cantonese-Chinese speaking children. A pilot pool of 158 items covering the two language modalities and the three language domains was developed. This initial item set was subsequently revised based on Rasch analyses of data from 324 multi-stage randomly selected children between 3 and 6 years of age. The revised 106-item set demonstrated adequate measurement properties, including targeting and uni-dimensionality. The revised 106-item set successfully discriminated preschool children in the three age groups, and between preschool children and their age peers with special education needs (SEN). Results from this study support the collection of normative data from a larger population sample of children to examine its accuracy in identifying language impairment in children with SEN. Test development procedures reported in this study provide insight for the development of language subtests in multi-domain developmental assessment tools for children speaking other varieties of Chinese.

A survey of augmentative and alternative communication service provision in Hong Kong.

A survey was conducted to understand the service provisions for augmentative and alternative communication (AAC) in Hong Kong. The response rates of special pre-school training centers and special schools were 59% and 71%, respectively. The response rate of adult settings was 18%. Results indicated that a higher proportion of students identified as having complex communication needs had access to AAC service provision in schools for children with intellectual and physical disabilities than those in special pre-school training centres and other types of special schools. Generalization of AAC service beyond the classroom setting remains problematic. Seventy-two percent of the respondents were dissatisfied with the training in AAC that they received during their basic professional preparation. More advocacy work is needed to increase awareness and knowledge of AAC use in Hong Kong.

Working memory and sentence comprehension of Hong Kong Chinese children with specific language impairment.

Children with Specific Language Impairment present with delayed language development, but do not have a history of hearing impairment, mental deficiency, or associated social or behavioral problems. Non-word repetition was suggested as an index to reflect the capacity of phonological working memory. There is a paucity of such studies among Hong Kong Chinese children. This preliminary study aimed to examine the relationship between phonological working memory and Specific Language Impairment, through the processes of non-word repetition and sentence comprehension, of children with Specific Language Impairment and pre-school children with normal language development. Both groups of children were screened by a standardized language test. A list of Cantonese (the commonest dialect used in Hong Kong) multisyllabic nonsense utterances and a set of 18 sentences were developed for this study. t-tests and Pearson correlation were used to study the relationship between non-word repetition, working memory and specific language impairment. Twenty-three pre-school children with Specific Language Impairment (mean age = 68.30 months; SD = 6.90) and another 23 pre-school children (mean age = 67.30 months; SD = 6.16) participated in the study. Significant difference performance was found between the Specific Language Impairment group and normal language group in the multisyllabic nonsense utterances repetition task and the sentence comprehension task. Length effect was noted in Specific Language Impairment group children, which is consistent with the findings of other literature. In addition, correlations were also observed between the number of nonsense utterances repeated and the number of elements comprehended. Cantonese multisyllabic nonsense utterances might be worth further developing as a screening tool for the early detection of children with Specific Language Impairment.