A lissencephaly-associated BAIAP2 variant causes defects in neuronal migration during brain development.

Lissencephaly is a neurodevelopmental disorder characterized by a loss of brain surface convolutions caused by genetic variants that disrupt neuronal migration. However, the genetic origins of the disorder remain unidentified in nearly one-fifth of people with lissencephaly. Using whole-exome sequencing, we identified a de novo BAIAP2 variant, p.Arg29Trp, in an individual with lissencephaly with a posterior more severe than anterior (P>A) gradient, implicating BAIAP2 as a potential lissencephaly gene. Spatial transcriptome analysis in the developing mouse cortex revealed that Baiap2 is expressed in the cortical plate and intermediate zone in an anterior low to posterior high gradient. We next used in utero electroporation to explore the effects of the Baiap2 variant in the developing mouse cortex. We found that Baiap2 knockdown caused abnormalities in neuronal migration, morphogenesis and differentiation. Expression of the p.Arg29Trp variant failed to rescue the migration defect, suggesting a loss-of-function effect. Mechanistically, the variant interfered with the ability of BAIAP2 to localize to the cell membrane. These results suggest that the functions of BAIAP2 in the cytoskeleton, cell morphogenesis and migration are important for cortical development and for the pathogenesis of lissencephaly in humans.

Trypanosoma cruzi infection reduces the population fitness of Mepraia spinolai, a Chagas disease vector.

The hematophagous insect Mepraia spinolai (Hemiptera: Reduviidae: Triatominae) is naturally infected with the protozoan parasite Trypanosoma cruzi, the agent of Chagas disease in humans. In this study, we compared the demographic parameters of M. spinolai with and without T. cruzi infection. We collected the immature life table data of 479 M. spinolai individuals of control cohort (reared on mice without T. cruzi infection) and 563 M. spinolai individuals of treatment cohort (reared on mice with T. cruzi infection). Nymphs were maintained in individual compartments inside a growth chamber (26°C; 65-75%) until adult emergence; moulting and survival were recorded daily. For the adult life table study of the control, we used 24 pairs of adults from the control cohort. For the adult life table study of T. cruzi-infected cohort, 25 infected females were paired with 25 males from the control cohort. Life table data were analysed using bootstrap-match technique based on the age-stage, two-sex life table. The preadult survival rate (0.5282) of the control cohort was significantly higher than that of the infected cohort (0.2913). However, the mean fecundity of reproductive females (Fr = 22.29 eggs/♀) and net reproductive rate of population (R0 = 5.07 offspring/individual) of the 0.5th percentile bootstrap-match control cohort were not significantly different from those of the infected cohort (Fr = 23.35 eggs/♀, R0 = 3.77 offspring/individual). Due to the shorter total preoviposition period and higher proportion of reproductive female, the intrinsic rate of increase (r = 0.0053 d-1 ) and finite rate of increase (λ = 1.0053 d-1 ) of control cohort of M. spinolai were significantly higher than those of the T. cruzi-infected cohort (r = 0.0035 d-1 , λ = 1.0035 d-1 ). These results suggest that T. cruzi infection reduces the population fitness of the Chagas disease vector M. spinolai.

Developing an entrustable professional activity for providing health education and consultation in occupational therapy and examining its validity.

BACKGROUND: Entrustable Professional Activities (EPA)-based assessment is easily and intuitively used in evaluating the learning outcomes of competency-based medical education (CBME). This study aimed to develop an EPA for occupational therapy focused on providing health education and consultation (TP-EPA3) and examine its validity. METHODS: Nineteen occupational therapists who had completed online training on the EQual rubric evaluation participated in this study. An expert committee identified six core EPAs for pediatric occupational therapy. TP-EPA3 was developed following the EPA template and refined through consensus meetings. The EQual rubric, a 14-item, five-point criterion-based anchor system, encompassing discrete units of work (DU), entrustable, essential, and important tasks of the profession (EEIT), and curricular role (CR), was used to evaluate the quality of TP-EPA3. Overall scores below 4.07, or scores for DU, EEIT, and CR domains below 4.17. 4.00, and 4.00, respectively, indicate the need for modifications. RESULTS: The TP-EPA3 demonstrated good validity, surpassing the required cut-off score with an average overall EQual score of 4.21 (SD = 0.41). Specific domain scores for DU, EEIT, and CR were 3.90 (SD = 0.69), 4.46 (SD = 0.44), and 4.42 (SD = 0.45), respectively. Subsequent revisions clarified observation contexts, enhancing specificity and focus. Further validation of the revised TP-EPA3 and a thorough examination of its reliability and validity are needed. CONCLUSION: The successful validation of TP-EPA3 suggests its potential as a valid assessment tool in occupational therapy education, offering a structured approach for developing competency in providing health education and consultation. This process model for EPA development and validation can guide occupational therapists in creating tailored EPAs for diverse specialties and settings.

Chief complaints and computed tomography results in the emergency department: a three-year retrospective cohort study.

BACKGROUND: Computed tomography (CT) is frequently performed in the patients who admitted to the emergency department (ED), discharged but returned to ED within 72 h. It is unknown whether the main complaints of patients assist physicians to use CT effectively. This study aimed to find the association between chief complaints and the CT results. METHODS: This three-year retrospective cohort study was conducted in the ED of a tertiary medical center. Adult patients who returned to the ED after the index visit were included from 2019 to 2021. Demographics, pre-existing diseases, chief complaints, and CT region were recorded by independent ED physicians. A logistic regression model with an odds ratio (OR) and 95% confidence interval (CI) was used to determine the relationship between chief complaints and positive CT results. RESULTS: In total, 7,699 patients revisited ED after the index visit; 1,202 (15.6%) received CT. The top chief complaints in patients who received CT were abdominal pain, dizziness, and muscle weakness. Patients with abdominal pain or gastrointestinal symptoms had a significantly higher rate of positive abdominopelvic CT than those without it (OR 2.83, 95% CI 1.98-4.05, p < 0.001), while the central nervous system and cardiopulmonary chief complaints were not associated (or negatively associated) with new positive CT findings. CONCLUSION: Chief complaints of patients on revisit to the ED are associated with different yields of new findings when CT scans of the chest, abdomen and head are performed. Physicians should consider these differential likelihoods of new positive findings based on these data.

Characterization of Mammary Tumors Arising from MMTV-PyVT Transgenic Mice.

Among genetically engineered mouse models of breast cancer, MMTV-PyVT is a mouse strain in which the oncogenic polyoma virus middle T antigen is driven by the mouse mammary tumor virus promoter. The aim of the present study was to perform morphologic and genetic analyses of mammary tumors arising from MMTV-PyVT mice. To this end, mammary tumors were obtained at 6, 9, 12, and 16 weeks of age for histology and whole-mount analyses. We conducted whole-exome sequencing to identify constitutional and tumor-specific mutations, and genetic variants were identified using the GRCm38/mm10 mouse reference genome. Using hematoxylin and eosin analysis and whole-mount carmine alum staining, we demonstrated the progressive proliferation and invasion of mammary tumors. Frameshift insertions/deletions (indels) were noted in the Muc4. Mammary tumors showed small indels and nonsynonymous single-nucleotide variants but no somatic structural alterations or copy number variations. In summary, we validated MMTV-PyVT transgenic mice as a multistage model for mammary carcinoma development and progression. Our characterization may be used as a reference for guidance in future research.

Physiological responses and Ethylene-Response AP2/ERF Factor expression in Indica rice seedlings subjected to submergence and osmotic stress.

BACKGROUND: The increased frequency of heavy rains in recent years has led to submergence stress in rice paddies, severely affecting rice production. Submergence causes not only hypoxic stress from excess water in the surrounding environment but also osmotic stress in plant cells. We assessed physiological responses and Ethylene-Response AP2/ERF Factor regulation under submergence conditions alone and with ionic or nonionic osmotic stress in submergence-sensitive IR64 and submergence-tolerant IR64-Sub1 Indica rice cultivars. RESULTS: Our results indicate that both IR64 and IR64-Sub1 exhibited shorter plant heights and root lengths under submergence with nonionic osmotic stress than normal condition and submergence alone. IR64-Sub1 seedlings exhibited a significantly lower plant height under submergence conditions alone and with ionic or nonionic osmotic stress than IR64 cultivars. IR64-Sub1 seedlings also presented lower malondialdehyde (MDA) concentration and higher survival rates than did IR64 seedlings after submergence with ionic or nonionic osmotic stress treatment. Sub1A-1 affects reactive oxygen species (ROS) accumulation and antioxidant enzyme activity in rice. The results also show that hypoxia-inducible ethylene response factors (ERF)-VII group and alcohol dehydrogenase 1 (ADH1) and lactate dehydrogenase 1 (LDH1) genes exhibited different expression levels under nonionic or ionic osmotic stress during submergence on rice. CONCLUSIONS: Together, these results demonstrate that complex regulatory mechanisms are involved in responses to the aforementioned forms of stress and offer new insights into the effects of submergence and osmotic stress on rice.

Differences in the characteristics and patterns of adult emergency department return visits before and after the coronavirus disease 2019 outbreak.

BACKGROUND: Data about changes in the characteristics of ED return visits before and after the COVID-19 outbreak are limited. This study aimed to report the differences on utility in ED return visits after the COVID-19 outbreak. METHODS: This retrospective cohort study was conducted from 2019 to 2020. Adult patients with ED return visits were included in the analysis. Variables including demographic characteristics, pre-comorbidities, triage levels, vital signs, chief complaints, management, and diagnosis were recorded and confirmed via a manual assessment. RESULTS: The proportion of patients with ED visits decreased by 23%. Hence, that of patients with ED return visits also reduced from 2580 to 2020 patients (22%) after the COVID-19 outbreak. The average age (60-57.8 years) of patients with return visits was significantly younger, and the proportion of female patients decreased remarkably. Further, the proportion of patients with chronic pre-existing diseases at the return visit significantly differed after the COVID-19 outbreak. The proportion of patients with chief complaints including dizziness, dyspnea, cough, vomiting, diarrhea, and chills during the return visits significantly differed before and after the COVID-19 pandemic. In the multivariable logistic regression model, age, high triage level were significantly associated with unfavorable outcome return visit. CONCLUSION: The use of services in the ED has changed since the COVID-19 outbreak. Hence, the proportion of patients with unplanned return visits within 72 h decreased. After the COVID-19 outbreak, people are now cautious whether they should return to the ED, as in the pre-pandemic situation, or just treat conservatively at home.

Global water quality changes posing threat of increasing infectious diseases, a case study on malaria vector Anopheles stephensi coping with the water pollutants using age-stage, two-sex life table method.

BACKGROUND: Water pollution due to uncontrolled release of chemical pollutants is an important global problem. Its effect on medically important insects, especially mosquitoes, is a critical issue in the epidemiology of mosquito-borne diseases. METHODS: In order to understand the effect of water pollutants on the demography of Anopheles stephensi, colonies were reared in clean, moderately and highly polluted water for three consecutive generations at 27 °C, 75% RH, and a photoperiod of 12:12 h (L:D). The demographic data of the 4th generation of An. stephensi were collected and analysed using the age-stage, two-sex life table. RESULTS: The intrinsic rate of increase (r), finite rate of increase (λ), mean fecundity (F) and net reproductive rate (R0) of An. stephensi in clean water were 0.2568 d-1, 1.2927 d-1, 251.72 eggs, and 109.08 offspring, respectively. These values were significantly higher than those obtained in moderately polluted water (r = 0.2302 d-1, λ = 1.2589 d-1, 196.04 eggs, and R0 = 65.35 offspring) and highly polluted water (r = 0.2282 d-1, λ = 1.2564 d-1, 182.45 eggs, and R0 = 62.03 offspring). Female adult longevity in moderately polluted (9.38 days) and highly polluted water (9.88 days) were significantly shorter than those reared in clean water (12.43 days), while no significant difference in the male adult longevity was observed among treatments. CONCLUSIONS: The results of this study showed that An. stephensi can partially adapt to water pollution and this may be sufficient to extend the range of mosquito-borne diseases.

Building lexical networks: Preschoolers extract different types of information in cross-situational learning.

Children's everyday learning environment is semantically structured. For example, semantically related things (e.g., fork and spoon) usually co-occur in the same contexts. The current study examines the effects of semantically structured contexts on preschool-age children's (N = 65, 33 girls, age range: 52-68 months) use of statistical information to learn novel word-object mappings. Children were assigned into one of two conditions, in which objects from the same semantic category repeatedly co-occurred in the same trials (Same-category condition) or objects from different categories repeatedly co-occurred in the same trials (Different-categories condition). Children's word learning performance in the two conditions were comparable. However, their errors at test suggested that information extracted by children in the two conditions differed. Importantly, children in the Same-category condition extracted both statistical and semantic relationships from the stimuli.

Governmental public health in Taiwan.

A healthy and safe public health environment is a fundamental responsibility of government; achieving it requires collaboration across multiple sectors. Public health services include, for example, vaccination and quarantine for infectious diseases; health promotion, such as anti-smoking campaigns for noncommunicable diseases; and health insurance for universal health coverage. All these services require intersectoral actions in which the government must play a fundamental role, either partially or totally. The Taiwanese outlook on governmental public health infrastructure and professionalization of public health is given in this paper. It also describes the national governmental public health measures that were employed during the Covid-19 pandemic and discusses the challenges ahead for the country's governmental public health. Governmental public health is essential and should not be affected by changes in political forms or socioeconomic development. Instead, effective governmental public health will promote these developments while protecting citizens' right to health.

Children with Mycoplasma pneumoniae infection in Taiwan: Changes in molecular characteristics and clinical outcomes.

BACKGROUND: Mycoplasma pneumoniae is a pathogen that causes respiratory diseases in children. Infections caused by M. pneumoniae are usually self-limited but occasionally can be severe. We observed emerging cases of severe mycoplasma infection requiring extracorporeal membrane oxygenation (ECMO). Thus, we investigated chronological changes in the molecular features of the M. pneumoniae and its clinical impacts among the pediatric population. METHODS: From 2011 to 2019, respiratory samples were collected from patients younger than 18 years old with pneumonia in a tertiary children's hospital. Focused multiple-locus variable number of tandem repeats analysis (MLVA) typing was performed on samples positive for M. pneumoniae in 2016 and 2019. Clinical data from the patients' electronic medical records were collected. We described the annual trend of macrolide resistance and MLVA type and analyzed the associations between clinical manifestations and MLVA types. RESULTS: The percentage of macrolide-resistant (MLR) M. pneumoniae gradually increased from 22% (27/122) in 2015 to 70% (82/117) in 2019. Among the MLRM. pneumoniae, the predominant strain shifted from type P (31% [13/42]) to type A (40% [19/46]). The demographics, initial presentations, and clinical courses of the subjects with MLRM. pneumoniae did not differ significantly between 2011 and 2019. However, in 2019, two fulminant cases requiring venovenous ECMO were observed, which indicates that more attention to the clinical severity of MLRM. pneumoniae infections is warranted. CONCLUSION: Obtaining accurate information on macrolide susceptibility is crucial for physicians to initiate appropriate antibiotic treatment in a timely fashion. Although we could not identify significant differences among mycoplasma pneumonias caused by different MLVAs over a span of 9 years, the emergence of severe mycoplasma infections requiring ECMO was clinically significant, and further monitoring was required.

Clinical and epidemiological features in hospitalized young children with acute gastroenteritis in Taiwan: A multicentered surveillance through 2014-2017.

BACKGROUND/PURPOSE: Acute gastroenteritis (AGE) remains a significant health issue in children. The worldwide evolution of pediatric AGE pathogens had been recorded since the introduction of rotavirus vaccine. Ten years after the rotavirus vaccine was introduced to the private sectors in Taiwan, a nationwide study was conducted to elucidate the epidemiological changes among major AGE pathogens. METHODS: From January 2014 to December 2017, children younger than 5 years old, hospitalized with AGE at 10 hospitals across Taiwan were enrolled. Stool specimens were tested for Salmonella spp., Campylobacter spp., Clostridiodes difficile, norovirus, and rotavirus by polymerase chain reaction (PCR). The epidemiological and clinical information was collected. RESULTS: Enteric pathogen were detected in 1983 (42.2%) of 4700 subjects, with Salmonella spp. (12.5%) being the leading cause of AGE, followed by norovirus (11.2%), rotavirus (8.7%), C. difficile (4.2%), Campylobacter spp. (1.0%), and a mixture of at least 2 of 5 above-mentioned pathogens (4.6%). The case distributions varied across different regions. In eastern Taiwan, rotavirus (21/131, 16.0%) remained the most common pathogen detected. The rotavirus vaccine uptake rate is significantly lower in patients with rotavirus AGE. Besides, rotavirus AGE frequently occurred in children with foreign parent(s), Taiwanese indigenous people, and those with the household monthly income < NT$ 60,000. CONCLUSION: Salmonella spp. and norovirus were two major pathogens of pediatric AGE in Taiwan during 2014-17. Providing low-to middle-income households with free rotavirus vaccine nationwide and an industry-led act to reduce salmonellosis should be considered by the authorities.

Pathogenesis and Preventive Tactics of Immune-Mediated Non-Pulmonary COVID-19 in Children and Beyond.

The COVID-19 pandemic has evolved to immune escape and threatened small children and the elderly with a higher severity and fatality of non-pulmonary diseases. These life-threatening non-pulmonary COVID-19 diseases such as acute necrotizing encephalopathies (ANE) and multisystem inflammatory syndrome in children (MIS-C) are more prevalent in children. However, the mortality of multisystem inflammatory syndrome in adults (MIS-A) is much higher than that of MIS-C although the incidence of MIS-A is lower. Clarification of immunopathogenesis and genetic susceptibility of inflammatory non-pulmonary COVID-19 diseases would provide an appropriate guide for the crisis management and prevention of morbidity and fatality in the ongoing pandemic. This review article described three inflammatory non-pulmonary COVID-19 diseases including (1) meningoencephalitis (ME), (2) acute necrotizing encephalopathies (ANE), and (3) post-infectious multisystem inflammatory syndrome in children (MIS-C) and in adults (MIS-A). To prevent these life-threatening non-pulmonary COVID-19 diseases, hosts carrying susceptible genetic variants should receive prophylactic vaccines, avoid febrile respiratory tract infection, and institute immunomodulators and mitochondrial cocktails as early as possible.

The Bottlenecks of Preparing Virus Particles by Size Exclusion for Antibody Generation.

Enterovirus 71 (EV71) is the major etiological agent contributing to the development of hand-foot-mouth disease (HFMD). There are not any global available vaccines or antibody drugs against EV71 released yet. In this study, we perform the virus immunization in a cost-effective and convenient approach by preparing virus particles from size exclusion and immunization of chicken. Polyclonal yolk-immunoglobulin (IgY) was simply purified from egg yolk and monoclonal single-chain variable fragments (scFv) were selected via phage display technology with two scFv libraries containing 6.0 × 106 and 1.3 × 107 transformants. Specific clones were enriched after 5 rounds of bio-panning and four identical genes were classified after the sequence analysis. Moreover, the higher mutation rates were revealed in the CDR regions, especially in the CDR3. IgY showed specific binding activities to both EV71-infected and Coxsackievirus 16-infected cell lysates and high infectivity inhibitory activity of EV71. However, while IgY detected a 37 kDa protein, the selected scFv seemingly detected higher size proteins which could be cell protein instead of EV71 proteins. Despite the highly effective chicken antibody generation, the purity of virus particles prepared by size exclusion is the limitation of this study, and further characterization should be carried out rigorously.

Development of an Objective Structured Clinical Examination Station for Pediatric Occupational Therapy and an Evaluation of Its Quality.

IMPORTANCE: The Objective Structured Clinical Examination (OSCE) is a highly valued measure of students' clinical competencies in medical education. However, few studies have reported on the administration of the OSCE in pediatric occupational therapy education. OBJECTIVE: To describe the development of a pediatric occupational therapy OSCE station to evaluate students' use of a standardized assessment and examine its standard setting, failure rates, and psychometric properties. DESIGN: Prospective, cross-sectional, observational study design. SETTING: Three OSCE stations in a university clinical skills center. PARTICIPANTS: Five experienced occupational therapists, 60 examinees, 44 child standardized patients, 44 chaperones, and 15 examiners. MEASURES: The sum of the rating scale and the global performance scores were used. The rating scale measured the examinee's clinical competences in administering a standardized assessment. The 5-point global performance score was used to evaluate the examinee's whole performance. RESULTS: The OCSE station's expert validity was acceptable (item-level content validity index [CVI] = 0.8-1.0; scale-level CVI = 0.98). Passing scores according to the Angoff method (passing score = 14) and the contrasting-groups M-SD method (passing score = 13) were similar. Failure rates were high (61.7%-73.3%). Internal consistency was acceptable (Cronbach's α = .78). No significant examiner effect was found (p = .554), and interexaminer reliability was acceptable (item score = 0.58-1.00; sum of the rating scale score = 0.97; global performance score = 0.79). CONCLUSIONS AND RELEVANCE: The OSCE station for using a standardized assessment is a reliable and valid measure of students' interpersonal communication skills and assessment skills. What This Article Adds: The OSCE for education in pediatric occupational therapy is both effective and rigorous.

Developing the Occupational Therapy-Specific Mini-Clinical Evaluation Exercise (Mini-CEX) for Evaluating Interns' Clinical Skills and Attitudes in Pediatric Occupational Therapy.

IMPORTANCE: The Mini-Clinical Evaluation Exercise (Mini-CEX) is highly recommended for assessing interns' performance. OBJECTIVE: To develop a pediatric occupational therapy-specific Mini-CEX and examine its psychometrics. DESIGN: Stage 1 had a retrospective design; Stage 2 had a prospective design. SETTING: Pediatric occupational therapy unit in a hospital in Taiwan. PARTICIPANTS: Thirty-four occupational therapy interns were evaluated with the Mini-CEX (physician version), and 57 were evaluated with the occupational therapy-specific Mini-CEX. OUTCOMES AND MEASURES: The occupational therapy-specific Mini-CEX was developed with seven items on a 9-point scale categorized into three levels (unsatisfactory, satisfactory, highly satisfactory). RESULTS: In Stage 1, the frequency of Mini-CEX (physician version) items receiving a rating of not applicable ranged from 1.9% to 88.1%. In Stage 2, the frequency of occupational therapy-specific Mini-CEX items receiving a rating of not applicable ranged from 3.5% to 31.6%. With the theme of evaluation taken into consideration, the frequency of not-applicable ratings was 0% to 8.8%. For the occupational therapy-specific Mini-CEX, content validity (item-level content validity index = 1, scale-level content validity index = 1) and internal consistency (Cronbach's α = .93) were excellent. The interns' scores on the second evaluation were significantly higher than those on their first evaluation, indicating good discriminant validity. CONCLUSIONS AND RELEVANCE: The occupational therapy-specific Mini-CEX appears to be reliable and valid, and it is appropriate for evaluating interns' skills and attitudes in pediatric occupational therapy practice. What This Article Adds: The results support the development of the occupational therapy-specific Mini-CEX and its application in pediatric internship training.

Inoculation Age of Bacillus Calmette-Guérin Tokyo-172 Strain and Vaccine-related Adverse Reactions in Taiwan Birth Cohort of 2012-2017.

BACKGROUND: In 2016 in Taiwan, inoculation with the Bacillus Calmette-Guérin (BCG) Tokyo-172 vaccine was postponed from 24 hours after birth to 5-8 months of age. We reviewed BCG-induced adverse reactions reported to the Vaccine Injury Compensation Program (VICP) to identify differences between early and delayed BCG inoculation. METHODS: Clinical presentations of BCG-related adverse reactions reported to VICP for the 2012-2017 birth cohort were reviewed until the end of 2019. The correlations between inoculation age and complications were evaluated. RESULTS: We analyzed 233 BCG adverse reactions, including regional lymphadenitis (33.9%), injection site reactions (35.2%), osteitis/osteomyelitis (27.9%), and distant soft tissue infections (3.0%). The incidence of osteitis/osteomyelitis was lower when vaccination was done after 5 months of age (relative risk [RR], 0.32; 95% confidence interval [CI], .16-.64). Injection site reactions (RR, 8.82; 95% CI, 5.04-15.44) and lymphadenitis (RR, 2.24; 95% CI, 1.44-3.45) were significantly more common in vaccinees older than 5 months. Shorter onset durations of mild adverse reactions (lymphadenitis and injection site reactions) were reported in vaccinees older than 5 months, while no statistical significance was found regarding osteitis/osteomyelitis. CONCLUSIONS: Osteomyelitis and distant soft tissue infection may occur less frequently when BCG inoculation occurs after 5 months of age, although mild adverse reactions can be more frequent, symptom onset times can be shortened. As few severe reactions might occur more than 2 years after BCG inoculation and the policy of delayed BCG inoculation was implemented in 2016, a longer observational period is needed to clarify the exact severe complications decrement.

Trilostane, a 3ß-hydroxysteroid dehydrogenase inhibitor, suppresses growth of hepatocellular carcinoma and enhances anti-cancer effects of sorafenib.

Background Human 3ß-hydroxysteroid dehydrogenase type 1 (HSD3B1) is an enzyme associated with steroidogenesis, however its' role in hepatocellular carcinoma (HCC) biology is unknown. Trilostane is an inhibitor of HSD3B1 and has been tested as a treatment for patients with breast cancer but has not been studied in patients with HCC. Methods and Results The expression of HSD3B1 in HCC tumors in 57 patients were examined. A total of 44 out of 57 tumors (77.2%) showed increased HSD3B1 expression. The increased HSD3B1 in tumors was significantly associated with advanced HCC. In vitro, the knockdown of HSD3B1 expression in Mahlavu HCC cells by a short hairpin RNA (shRNA) led to significant decreases in colony formation and cell migration. The suppression of clonogenicity in the HSD3B1-knockdown HCC cells was reversed by testosterone and 17ß-estradiol. Trilostane-mediated inhibition of HSD3B1 in different HCC cells also caused significant inhibition of clonogenicity and cell migration. In subcutaneous HCC Mahlavu xenografts, trilostane (30 or 60 mg/kg, intraperitoneal injection) significantly inhibited tumor growth in a dose-dependent manner. Furthermore, the combination of trilostane and sorafenib significantly enhanced the inhibition of clonogenicity and xenograft growth, surpassing the effects of each drug used alone, with no documented additional toxicity to animals. HSD3B1 blockade was found to suppress the phosphorylation of extracellular signal-regulated kinase (ERK). The decreased ERK phosphorylation was reversed by testosterone or 17b-estradiol. Conclusions Trilostane significantly inhibited the growth of HCC by inhibiting HSD3B1 function and augmenting the efficacy of sorafenib.

Overexpression of chitinase-3-like protein 1 is associated with structural recurrence in patients with differentiated thyroid cancer.

We previously identified that the expression of chitinase-3-like protein 1 (CHI3L1) was upregulated during thyroid cancer progression. Here, we investigated the prognostic significance of CHI3L1 expression in thyroid neoplasms and examined the potential oncogenic roles. CHI3L1 immunochemical staining was performed on tissue microarrays of benign and malignant thyroid tumours. Compared with normal thyroid tissue and benign thyroid lesions that had low or no detectable CHI3L1 expression, CHI3L1 was overexpressed in both differentiated and undifferentiated thyroid cancer. High CHI3L1 expression was associated with extrathyroidal extension, lymph node metastasis, and shorter recurrence-free survival in differentiated thyroid cancer. The biological roles of CHI3L1 were further investigated by gain- and loss-of-function assays. CHI3L1 silencing suppressed clonogenicity, migration, invasion, anoikis resistance, and angiogenesis in thyroid cancer cells, although exogenous CHI3L1 treatment promoted these malignant phenotypes. Cysteine-rich angiogenic inducer 61 (CYR61) was identified as a downstream target of CHI3L1 by RNA-seq analysis. CYR61 silencing or treatment reversed the alterations induced by CHI3L1 modulation. Our results demonstrate that CHI3L1 is overexpressed in thyroid cancer and is associated with an increased risk of disease recurrence. Additionally, CYR61 may participate in CHI3L1-mediated tumour progression. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Action prediction during real-time parent-infant interactions.

Social interactions provide a crucial context for early learning and cognitive development during infancy. Action prediction-the ability to anticipate an observed action-facilitates successful, coordinated interaction and is an important social-cognitive skill in early development. However, current knowledge about infant action prediction comes largely from screen-based laboratory tasks. We know little about what infants' action prediction skills look like during real-time, free-flowing interactions with a social partner. In the current study, we used head-mounted eyetracking to quantify 9-month-old infants' visual anticipations of their parents' actions during free-flowing parent-child play. Our findings reveal that infants do anticipate their parents' actions during dynamic interactions at rates significantly higher than would be expected by chance. In addition, the frequency with which they do so is associated with child-led joint attention and hand-eye coordination. These findings are the first to reveal infants' action prediction behaviors in a more naturalistic context than prior screen-based studies, and they support the idea that action prediction is inherently linked to motor development and plays an important role in infants' social-cognitive development. A video abstract of this article can be viewed at https://www.youtube.com/watch?v=9HrmcicfiqE.