Spatial omics techniques and data analysis for cancer immunotherapy applications.

In-depth profiling of cancer cells/tissues is expanding our understanding of the genomic, epigenomic, transcriptomic, and proteomic landscape of cancer. However, the complexity of the cancer microenvironment, particularly its immune regulation, has made it difficult to exploit the potential of cancer immunotherapy. High-throughput spatial omics technologies and analysis pipelines have emerged as powerful tools for tackling this challenge. As a result, a potential revolution in cancer diagnosis, prognosis, and treatment is on the horizon. In this review, we discuss the technological advances in spatial profiling of cancer around and beyond the central dogma to harness the full benefits of immunotherapy. We also discuss the promise and challenges of spatial data analysis and interpretation and provide an outlook for the future.

"Their Happiness, Not Neurotypical Success": Autistic Adults Reflect on the Parenting of Autistic Children.

PURPOSE: Parenting has implications for psychosocial adjustment well into adulthood. While much is known about the parenting behaviors that influence adjustment in autistic children, little is known about how the effects of parenting persist in autistic adults. Further, autistic adults' perspectives on how they were parented have not been investigated to date. This study aimed to examine autistic adults' perspectives on their experiences of being parented in childhood and the advice they would like to offer to parents of autistic children in the context of their lived experience. METHODS: Ninety-six Australian autistic adults responded to open-ended questions in a larger survey assessing childhood experiences of being parented, adult attachment, psychological flexibility, and adult adjustment. RESULTS: A total of 10 themes were identified. Autistic adults emphasized the importance of embracing early diagnosis and that the goal of parents should be their child's happiness rather than "neurotypical" success. They highlighted the importance of unconditional love and understanding of their autistic child, recognizing that autistic children have similar fundamental needs as other children. Participants discussed the importance of structure and predictability in the home to feelings of safety. Parents were encouraged to meet them halfway. Finally, autistic adults reflected on the role of parents in advocacy and parental well-being. Parental neurodivergence was discussed as a possible bane or boon. CONCLUSIONS: Autistic adults emphasized the importance of unconditional acceptance from their parents, with the goal being their child's happiness. Findings from this study will inform future programs for families of autistic children.

Chemical probe mediated visualization of protein S-palmitoylation in patient tissue samples.

While protein palmitoylation has been studied for decades, our understanding of its clinical importance is minimal compared to other post translational modifications. As a result of the inherent challenges preventing the production of antibodies to palmitoylated epitopes we are unable to correlate levels of protein palmitoylation in biopsied tissues at a meaningful resolution. The most common method for detecting palmitoylated proteins without metabolic labelling is through chemical labeling of palmitoylated cysteines with the acyl-biotinyl exchange (ABE) assay. We have adapted the ABE assay to detect protein palmitoylation in formalin fixed paraffin embedded (FFPE) tissue sections. The assay is sufficient to detect subcellular regions of cells with increased labeling which indicates areas enriched in palmitoylated proteins. To visualize specific palmitoylated proteins in both cultured cells and in FFPE preserved tissue arrays we have integrated the ABE assay with a proximity ligation assay (ABE-PLA). Our findings demonstrate for the first time that FFPE preserved tissues can be labelled with unique chemical probes to detect either areas enriched in palmitoylated proteins or the localization of specific palmitoylated proteins using our ABE-PLA methodology.

Childhood experiences of being parented, adult attachment, psychological inflexibility, social engagement, and mental health of autistic adults.

BACKGROUND: Autistic adults have an increased risk of poor mental health. Although parental care and overprotection in childhood influence later attachment and mental health in the general adult population, this has not been investigated in the autistic population. Likewise, the roles of psychological inflexibility and social engagement in influencing mental health outcomes for autistic adults have yet to be examined. AIMS: To examine if retrospectively recalled childhood experiences of parental care and overprotection, as well as current adult attachment, psychological inflexibility and social engagement are associated with mental health in autistic adulthood. Further, to examine mediators of the association between parental care and overprotection and mental health in autistic adults. METHODS AND PROCEDURES: A community-recruited convenience sample of 126 Australian autistic adults completed an online survey assessing childhood experiences of parental care and overprotection and current adult attachment, psychological inflexibility, social engagement, and mental health. OUTCOMES AND RESULTS: Linear regressions showed that psychological inflexibility was the strongest predictor of depression, anxiety, and stress, followed by attachment anxiety (depression, anxiety) and attachment avoidance (anxiety, stress). Mediation analyses revealed that psychological inflexibility and attachment anxiety mediated the associations between parental care and overprotection and mental health outcomes in autistic adulthood. CONCLUSIONS AND IMPLICATIONS: Psychological inflexibility and adult attachment (anxious and avoidant attachment) are important to understanding mental health of autistic adults. Psychological inflexibility and attachment anxiety mediate associations between recalled childhood experiences of parental care and overprotection and mental health in autistic adulthood.

Hallux valgus with second metatarsalgia: Is second metatarsal Weil osteotomy necessary?

BACKGROUND: The role of concomitant Weil osteotomy to address second toe metatarsalgia during hallux valgus correction is unclear. We aimed to critically analyse outcomes of an additional Weil osteotomy versus isolated Scarf osteotomy.in the management of hallux valgus and second metatarsalgia. METHODS: Patients with second toe metatarsalgia who underwent first metatarsal Scarf osteotomy for hallux valgus were enrolled retrospectively. Demographics, radiographic measurements and functional outcomes were assessed at baseline, 6-months and 2-years postoperatively. Between-group significance was established with Fisher exact test, Chi-square or Mann-Whitney U test. Within-group changes from baseline were assessed with paired t-test and Wilcoxon signed-rank test. RESULTS: 48 feet (34 isolated Scarf, 14 concomitant Weil osteotomy) were included. Both cohorts demonstrated significant improvements across all measures of functional outcome. However, patients with additional Weil osteotomy reported poorer short-term outcomes. CONCLUSION: Superiority of additional Weil osteotomy versus isolated Scarf osteotomy in addressing second toe metatarsalgia or improving functional outcomes was not demonstrated.

Healthcare professionals' perspectives on facilitators of and barriers to CKD management in primary care: a qualitative study in Singapore clinics.

INTRODUCTION: The burden of chronic kidney disease (CKD) is rising globally including in Singapore. Primary care is the first point of contact for most patients with early stages of CKD. However, several barriers to optimal CKD management exist. Knowing healthcare professionals' (HCPs) perspectives is important to understand how best to strengthen CKD services in the primary care setting. Integrating a theory-based framework, we explored HCPs' perspectives on the facilitators of and barriers to CKD management in primary care clinics in Singapore. METHODS: In-depth interviews were conducted on a purposive sample of 20 HCPs including 13 physicians, 2 nurses and 1 pharmacist from three public primary care polyclinics, and 4 nephrologists from one referral hospital. Interviews were audio recorded, transcribed verbatim and thematically analyzed underpinned by the Theoretical Domains Framework (TDF) version 2. RESULTS: Numerous facilitators of and barriers to CKD management identified. HCPs perceived insufficient attention is given to CKD in primary care and highlighted several barriers including knowledge and practice gaps, ineffective CKD diagnosis disclosure, limitations in decision-making for nephrology referrals, consultation time, suboptimal care coordination, and lack of CKD awareness and self-management skills among patients. Nevertheless, intensive CKD training of primary care physicians, structured CKD-care pathways, multidisciplinary team-based care, and prioritizing nephrology referrals with risk-based assessment were key facilitators. Participants underscored the importance of improving awareness and self-management skills among patients. Primary care providers expressed willingness to manage early-stage CKD as a collaborative care model with nephrologists. Our findings provide valuable insights to design targeted interventions to enhance CKD management in primary care in Singapore that may be relevant to other countries. CONCLUSIONS: The are several roadblocks to improving CKD management in primary care settings warranting urgent attention. Foremost, CKD deserves greater priority from HCPs and health planners. Multipronged approaches should urgently address gaps in care coordination, patient-physician communication, and knowledge. Strategies could focus on intensive CKD-oriented training for primary care physicians and building novel team-based care models integrating structured CKD management, risk-based nephrology referrals coupled with education and motivational counseling for patients. Such concerted efforts are likely to improve outcomes of patients with CKD and reduce the ESKD burden.

MALT1 Is a Targetable Driver of Epithelial-to-Mesenchymal Transition in Claudin-Low, Triple-Negative Breast Cancer.

MALT1 is the effector protein of the CARMA/Bcl10/MALT1 (CBM) signalosome, a multiprotein complex that drives pro-inflammatory signaling pathways downstream of a diverse set of receptors. Although CBM activity is best known for its role in immune cells, emerging evidence suggests that it plays a key role in the pathogenesis of solid tumors, where it can be activated by selected G protein-coupled receptors (GPCR). Here, we demonstrated that overexpression of GPCRs implicated in breast cancer pathogenesis, specifically the receptors for Angiotensin II and thrombin (AT1R and PAR1), drove a strong epithelial-to-mesenchymal transition (EMT) program in breast cancer cells that is characteristic of claudin-low, triple-negative breast cancer (TNBC). In concert, MALT1 was activated in these cells and contributed to the dramatic EMT phenotypic changes through regulation of master EMT transcription factors including Snail and ZEB1. Importantly, blocking MALT1 signaling, through either siRNA-mediated depletion of MALT1 protein or pharmacologic inhibition of its activity, was effective at partially reversing the molecular and phenotypic indicators of EMT. Treatment of mice with mepazine, a pharmacologic MALT1 inhibitor, reduced growth of PAR1+, MDA-MB-231 xenografts and had an even more dramatic effect in reducing the burden of metastatic disease. These findings highlight MALT1 as an attractive therapeutic target for claudin-low TNBCs harboring overexpression of one or more selected GPCRs. IMPLICATIONS: This study nominates a GPCR/MALT1 signaling axis as a pathway that can be pharmaceutically targeted to abrogate EMT and metastatic progression in TNBC, an aggressive form of breast cancer that currently lacks targeted therapies.

Group VIII Metal Carbonyl Cluster-Boronic Acid Conjugates: Cytotoxicity and Mode of Action Studies.

A set of metal carbonyl cluster-boronic acid conjugates of the group VIII metals (Fe, Ru, and Os) were synthesized and their antiproliferative effects measured against two breast cancer cell lines (MCF-7 and MDA-MB-231) and a noncancerous breast epithelial (MCF-10A) cell line. The cytotoxicity followed the order Ru > Os > Fe for the MDA-MB-231 cells, although the latter two exhibited similar cytotoxicity against MCF-7 and MCF-10A cells. The osmium species {Os3(CO)10(µ-H)[µ-SC6H4-p-B(OH)2]} (2) could be chemically oxidized to its hydroxy analogue [Os3(CO)10(µ-H)(µ-SC6H4 -p-OH)] (2-OH), which showed comparable cytotoxicity. Mode of action studies pointed to an apoptotic pathway for cell death.

Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis.

The epidermal growth factor receptor (EGFR) is an essential driver of oncogenic signalling, and EGFR inhibitors are some of the earliest examples of successful targeted therapies in multiple types of cancer. The tractability of EGFR as a therapeutic target is overshadowed by the inevitable drug resistance that develops. Overcoming resistance mechanisms requires a deeper understanding of EGFR regulation in cancer cells. In this review, we discuss our recent discovery that the palmitoyltransferase DHHC20 palmitoylates EGFR on the C-terminal domain and plays a critical role in signal regulation during oncogenesis. Inhibiting DHHC20 expression or mutating the palmitoylation site on EGFR alters the EGF-induced signalling kinetics from a transient signal to a sustained signal. The change in signalling is accompanied by a decrease in cell proliferation in multiple human cancer cell lines. Our in vivo studies demonstrate that ablating the gene Zdhhc20 by CRISPR/Cas9-mediated inhibition in a mouse model of oncogenic Kras-driven lung adenocarcinoma potently inhibits tumorigenesis. The negative effect on tumorigenesis is mediated by EGFR since the expression of a palmitoylation-resistant mutant form of EGFR also inhibits Kras-driven lung adenocarcinoma. Finally, reducing EGFR palmitoylation increases the sensitivity of multiple cancer cell lines to existing inhibitors of EGFR and downstream signalling effector pathways. We will discuss the implications of these effects and strategies for targeting these new vulnerabilities.

Normative FJS-12 scores for the knee in an Asian population: a cross-sectional study.

BACKGROUND: The Forgotten Joint Score is a patient-reported outcome measure validated in assessing patients post knee arthroplasty, anterior cruciate ligament (ACL) reconstruction surgery and patellar dislocation. A previous study had established the normative scores of a population in the USA but included knees with pathology. The aim of our study is to obtain normative Forgotten Joint Scores in young Asian adults without any pre-existing knee pathologies to increase the interpretability of the Forgotten Joint Score-12 (FJS-12) score. METHODS: We conducted a cross-sectional study across young healthy Asian adults via electronic platforms. Participants who had sought either Western medical consultation, physiotherapy or traditional medical therapies were excluded. Demographic data, occupation, type of sport played, and FJS-12 scores were collected. Scores were stratified into subgroups and analysed. RESULTS: There were 172 participants who met our inclusion criteria for this study. The average age of participants in our study was 28.1 ± 10.5 years (range 14-70 years), with 83 (47.7%) participants falling into the ages 21-25 years. Average body mass index (BMI) was 21.9 ± 3.3 kg/m2 (range 14.7-36.3 kg/m2). The average FJS-12 score was 62.8 ± 25.6. The median FJS-12 was 63.5 with a range of 4.2-100. Nine participants (5.2%) scored the maximum score possible, and 56 (32.6%) participants scored below the midpoint score of 50. The percentiles for each subgroup of participants were tabulated and reported. Notably, males aged 46-70 years old scored the highest average FJS-12 score of 73.4 ± 5.5, and females aged 31-45 years old scored the lowest FJS-12 score of 57.1 ± 25.1. Females scored lower than males, although the difference was not statistically significant (p = 0.157). There were no significant correlations between BMI, age, or type of sport played with FJS-12; however, interestingly, we observed that women reported similar FJS-12 scores across all age groups, while men reported better scores with increasing age.Interestingly, we observed that women reported similar FJS-12 scores across all age groups, while men reported better scores with increasing age.  CONCLUSION: Having normative values provides opportunities for benchmarking and comparing individuals against age- and gender-matched peers in the general population. Knowledge of normative values for FJS-12 scores would aid evaluating and tracking progress in patients recovering from injuries or undergoing post-surgery rehabilitation. This would help clinicians  determine if they return to 'normal' post intervention.

Polymetatarsia of the Foot without Polydactyly: A Case Report.

CASE: We report a rare case of polymetatarsia without polydactyly. Our patient presented with pain and difficulty with shoewear. Radiographs showed an accessory metatarsal arising from the lateral aspect of the fourth metatarsal proximal metaphysis, fusing distally with the medial aspect of the fifth metatarsal head to form a single metatarsophalangeal joint. He was treated with a chevron osteotomy of the conjoined complex and an Akins osteotomy of the fifth proximal phalanx. Our patient recovered functionally, and his pain improved postoperatively. CONCLUSION: The chevron osteotomy is an option for treating polymetatarsia without polydactyly with the aim of reducing the forefoot width. LEVEL OF EVIDENCE: Case study, level 5.

Leveraging advances in immunopathology and artificial intelligence to analyze in vitro tumor models in composition and space.

Cancer is the leading cause of death worldwide. Unfortunately, efforts to understand this disease are confounded by the complex, heterogenous tumor microenvironment (TME). Better understanding of the TME could lead to novel diagnostic, prognostic, and therapeutic discoveries. One way to achieve this involves in vitro tumor models that recapitulate the in vivo TME composition and spatial arrangement. Here, we review the potential of harnessing in vitro tumor models and artificial intelligence to delineate the TME. This includes (i) identification of novel features, (ii) investigation of higher-order relationships, and (iii) analysis and interpretation of multiomics data in a (iv) holistic, objective, reproducible, and efficient manner, which surpasses previous methods of TME analysis. We also discuss limitations of this approach, namely inadequate datasets, indeterminate biological correlations, ethical concerns, and logistical constraints; finally, we speculate on future avenues of research that could overcome these limitations, ultimately translating to improved clinical outcomes.

Dinoprostone vaginal insert (DVI) versus adjunctive sweeping of membranes and DVI for term induction of labor.

AIM: To compare the efficacy and safety of dinoprostone vaginal insert (DVI) alone versus DVI with adjunctive sweeping of membranes (ASM) for induction of labor (IOL). METHODS: Single-center, prospective, randomized controlled trial; women with singleton term pregnancies, cervical dilation ≥1 and <3 cm, intact membranes allocated to either DVI or DVI with ASM. The primary outcome was vaginal delivery within 24 h of insertion. Secondary outcomes included mean time from insertion to delivery, tachysystole, operative delivery for non-reassuring fetal status (NRFS), tocolytics, fetal outcomes, pain information, and subject satisfaction. RESULTS: One hundred and four received DVI (Group 1) alone and 104 DVI with ASM (Group 2). The rate of vaginal delivery within 24 h was 53% versus 56%, cesarean rate 8.7% versus 10.6% in Groups 1 and 2 respectively. Although the duration of labor was similar in both groups, about 6% of women required additional ripening with dinoprostone vaginal tablets in Group 2 compared to 11.5% in Group 1 (p-value = 0.2). The frequency of hyperstimulation syndrome, failed induction, analgesic requirements, and fetal outcomes were comparable. The majority (83%-86%) in either cohort were satisfied with their labor experience. Multivariate logistic regression demonstrated a slightly better chance for vaginal delivery within 24 h (odds ratio [OR] 1.22 [95% confidence interval, CI 0.65-2.29]; p-value 0.53] for DVI with ASM, although statistically insignificant. Younger maternal age and multiparity (OR 10.36 [95% CI 4.88-23.67]; p-value <0.0001) contributed to successful IOL. CONCLUSION: DVI with ASM is at least as efficacious as DVI for cervical ripening with no increase in morbidity. Although DVI with ASM group less often needed additional dinoprostone tablets to complete the process of IOL (p-value = 0.2), adjunctive sweeping has not been shown to have a significant impact on the duration of labor or mode of delivery.

Lying and Theory of Mind: A Meta-Analysis.

This meta-analysis investigated the link between lying and theory-of-mind (ToM) by integrating findings from 81 studies involving 7,826 children between 2 and 14 years of age from 14 different collectivist and individualist cultures. Overall, there was a small, significant positive association (r = .23). Four main moderators were examined: facet of lying (understanding, instigated production, spontaneous production, maintenance); valence of lies (antisocial, prosocial); type of ToM (first-order, second-order); and culture (collectivist, individualist). Facet of lying and type of ToM were significant moderators. ToM was positively related to all facets of lying, but most strongly linked to lie maintenance and weakest for spontaneous production. Both first-order and second-order ToM were positively related to lying, but the link was stronger for the former.

Distal oblique osteotomy versus cheilectomy for moderate-advanced hallux rigidus: A 2-year propensity-score-matched study.

BACKGROUND: The surgical treatment of moderate-advanced hallux rigidus is controversial. Cheilectomy is widely used but has recurrence rates of up to 30%. Dorsal oblique metatarsal osteotomy (DOO) has also shown good results, however, there is no study comparing outcomes of the DOO against cheilectomy. METHODS: This was a retrospective propensity score matched study based on registry data from a single tertiary institution. Between 2007 and 2017, all patients who had undergone dorsal cheilectomy or DOO for hallux rigidus were included. Patients with previous foot surgery, revision surgeries, and concomitant surgical procedures were excluded. Clinical outcomes, complication rates, revision rates and patient satisfaction were assessed at 2 years postoperatively. RESULTS: There were 44 patients (34 cheilectomy, 10 DOO). After propensity score matching, 17 cheilectomy and all 10 DOO cases were selected for comparison. Patients in both groups had a significant improvement in visual analogue pain scores (VAS) and AOFAS 1st toe scores 2-years post-operatively (P<0.001) with high levels of post-operative satisfaction (85.1%). Overall there were no statistically significant differences in post-operative scores, improvement in scores, complication rates, revision rates, and levels of patient satisfaction between groups. CONCLUSIONS: Both the DOO and cheilectomy give similarly good outcomes for moderate-advanced hallux rigidus. Further studies are needed to elucidate differences in indications for each procedure.

Perceived barriers and facilitators to chronic kidney disease care among patients in Singapore: a qualitative study.

OBJECTIVE: To outline the facilitators and barriers to patients' self-management of predialysis chronic kidney disease (CKD). DESIGN: Qualitative. SETTING: Three polyclinics in a public primary care institution in Singapore. PARTICIPANTS: 20 patients entered and completed the study. Inclusion criteria were: (1) English speaking, (2) aged 40 years and above, (3) identified by clinical coding as 'DM (diabetes mellitus) nephropathy-overt' and 'DM nephropathy-incipient', by their physicians in the polyclinic, with an estimated glomerular filtration rate of less than 60 mL/min/1.73 m2 (based on electronic health records) and (4) aware of their CKD illness. Exclusion criteria were: (1) receiving dialysis or had received a kidney transplant, (2) suffered from any visual, auditory or cognitive impairment which could hinder their ability to participate in the study or (3) pregnant. RESULTS: We found that the major barriers to CKD management were a lack of knowledge and awareness of CKD, a passive attitude toward self-management and insufficient patient-physician communication. Major facilitators included patient trust and satisfaction with the physician and family support. Many patients reported that there was an overload of information and too little guidance on how to manage their condition, especially regarding dietary recommendations. CONCLUSION: We identified several barriers and facilitators to the management of predialysis CKD among patients. A multi-pronged approach for raising CKD awareness is required: improving patient-physician communication, implementing CKD workshops and home-visits and disseminating accurate online information about CKD. Strategies should also focus on increasing patient engagement and optimising family support by involving family members in patients' care. Furthermore, clear dietary recommendations and patient-specific advice are needed to empower patients to manage their own condition.

A Review of the Gillquist Maneuver: Modifications for a Safer and Easily Reproducible Approach for Knee Transintercondylar Notch Posterior Compartment Arthroscopy.

The original Gillquist maneuver is done by passing the arthroscope through a portal in the patella tendon between the medial femoral condyle and posterior cruciate ligament to enter the posterior compartment. This is done blind and has been documented to result in broken cameras and damaged equipment. It is also necessary to do a notchplasty to aid the advancement of the camera in patients. In our paper, we have made modifications to allow the Gillquist maneuver to be done safely under direct visualization, with just the aid of a simple switching stick. Our technique starts with the arthroscope in the anteromedial portal. We insert a long, cannulated switching stick through the anterolateral portal and pass it between the medial femoral condyle and the posterior cruciate ligament. The switching stick, being tapered and narrow, is able to traverse the transcondylar notch with minimal trauma. Once the switching stick enters the posterior compartment, the camera and trocar are removed and the trocar sleeve is guided over the switching stick past the intercondylar notch gently. The switching stick is then replaced by the arthroscope, which is advanced through the trocar sleeve and into the posterior compartment.

The Forgotten Joint Score-12 in Anterior Cruciate Ligament injuries.

PURPOSE: The Forgotten Joint Score (FJS-12) is a scoring system initially created to assess post arthroplasty outcomes. It has since been used to evaluate Anterior Cruciate Ligament surgery outcomes. Our study aims to evaluate the applicability and validity of the FJS-12 in post Anterior Cruciate Ligament reconstructed patients, and to assess correlation with established Patient Reported Outcome Measure Scores in the same population. DESIGN: Case series, level 3 evidence. METHODS: We conducted a cross sectional study across patients who had undergone Anterior Cruciate Ligament reconstruction and carried out the FJS-12 questionnaire by phone interview. Patients who had undergone primary Anterior Cruciate Ligament reconstruction were considered for the study. RESULTS: The average Forgotten Joint Score-12 for all 82 patients was 71.4 (±22.9), which corresponded to a normal distribution. The average Lysholm and Tegner score at the 2-year post-operative visit was 93.5 ± 9.5 and 5.8 ± 1.8 respectively and the distribution was non-normal. We noticed a large ceiling effect of 42.7% in the Lysholm scores, but only 8.4% in FJS-12. There was a weak correlation with Lysholm and a positive correlation with Tegner. CONCLUSIONS: Forgotten Joint Score-12 seems to be a promising patient reported outcome measure that can be used in evaluating post Anterior Cruciate Ligament reconstruction outcomes. It is more discerning than traditional scores and is easy to administer thus it can used in the clinical follow-up of patients. With the scores being normally distributed, it makes for a meaningful PROMS and would allow more accurate application of parametric statistical tests.

Utility of In Vitro Bioactivity as a Lower Bound Estimate of In Vivo Adverse Effect Levels and in Risk-Based Prioritization.

Use of high-throughput, in vitro bioactivity data in setting a point-of-departure (POD) has the potential to accelerate the pace of human health safety evaluation by informing screening-level assessments. The primary objective of this work was to compare PODs based on high-throughput predictions of bioactivity, exposure predictions, and traditional hazard information for 448 chemicals. PODs derived from new approach methodologies (NAMs) were obtained for this comparison using the 50th (PODNAM, 50) and the 95th (PODNAM, 95) percentile credible interval estimates for the steady-state plasma concentration used in in vitro to in vivo extrapolation of administered equivalent doses. Of the 448 substances, 89% had a PODNAM, 95 that was less than the traditional POD (PODtraditional) value. For the 48 substances for which PODtraditional < PODNAM, 95, the PODNAM and PODtraditional were typically within a factor of 10 of each other, and there was an enrichment of chemical structural features associated with organophosphate and carbamate insecticides. When PODtraditional < PODNAM, 95, it did not appear to result from an enrichment of PODtraditional based on a particular study type (eg, developmental, reproductive, and chronic studies). Bioactivity:exposure ratios, useful for identification of substances with potential priority, demonstrated that high-throughput exposure predictions were greater than the PODNAM, 95 for 11 substances. When compared with threshold of toxicological concern (TTC) values, the PODNAM, 95 was greater than the corresponding TTC value 90% of the time. This work demonstrates the feasibility, and continuing challenges, of using in vitro bioactivity as a protective estimate of POD in screening-level assessments via a case study.

PI3K Catalytic Subunits α and ß Modulate Cell Death and IL-6 Secretion Induced by Talc Particles in Human Lung Carcinoma Cells.

Hydrated magnesium silicate (or "talc" particles) is a sclerosis agent commonly used in the management of malignant pleural effusions, a common symptom of metastatic diseases, including lung cancers. However, the direct effects of talc particles to lung carcinoma cells, which can be found in the malignant pleural effusion fluids from patients with lung cancer, are not fully understood. Here, we report a study of the signaling pathways that can modulate the cell death and IL-6 secretion induced by talc particles in human lung carcinoma cells. We found that talc-sensitive cells have higher mRNA and protein expression of PI3K catalytic subunits α and ß. Further experiments confirmed that modulation (inhibition or activation) of the PI3K pathway reduces or enhances cellular sensitivity to talc particles, respectively, independent of the inflammasome. By knocking down specific PI3K isoforms, we also confirmed that both PI3Kα and -ß mediate the observed talc effects. Our results suggest a novel role of the PI3K pathway in talc-induced cell death and IL-6 secretion in lung carcinoma cells. These cellular events are known to drive fibrosis, and thus further studies of the PI3K pathway may provide a better understanding of the mechanisms of talc sclerosis in the malignant pleural space.