The effect of extracellular matrix on the precision medicine utility of pancreatic cancer patient-derived organoids.

The use of patient-derived organoids (PDOs) to characterize therapeutic sensitivity and resistance is a promising precision medicine approach, and its potential to inform clinical decisions is now being tested in several large multiinstitutional clinical trials. PDOs are cultivated in the extracellular matrix from basement membrane extracts (BMEs) that are most commonly acquired commercially. Each clinical site utilizes distinct BME lots and may be restricted due to the availability of commercial BME sources. However, the effect of different sources of BMEs on organoid drug response is unknown. Here, we tested the effect of BME source on proliferation, drug response, and gene expression in mouse and human pancreatic ductal adenocarcinoma (PDA) organoids. Both human and mouse organoids displayed increased proliferation in Matrigel compared with Cultrex and UltiMatrix. However, we observed no substantial effect on drug response when organoids were cultured in Matrigel, Cultrex, or UltiMatrix. We also did not observe major shifts in gene expression across the different BME sources, and PDOs maintained their classical or basal-like designation. Overall, we found that the BME source (Matrigel, Cultrex, UltiMatrix) does not shift PDO dose-response curves or drug testing results, indicating that PDO pharmacotyping is a robust approach for precision medicine.

Dual Inhibition of KRASG12D and Pan-ERBB Is Synergistic in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been developed. We studied one of these compounds, MRTX1133, and found it was specific and effective at low nanomolar concentrations in patient-derived organoid models and cell lines harboring KRASG12D mutations. Treatment with MRTX1133 upregulated the expression and phosphorylation of EGFR and HER2, indicating that inhibition of ERBB signaling may potentiate MRTX1133 antitumor activity. Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer. SIGNIFICANCE: KRAS-mutant pancreatic cancer models, including KRAS inhibitor-resistant models, show exquisite sensitivity to combined pan-ERBB and KRAS targeting, which provides the rationale for testing this drug combination in clinical trials.

Meta-Analysis of the Effects of Insect Pathogens: Implications for Plant Reproduction.

Despite extensive work on both insect disease and plant reproduction, there is little research on the intersection of the two. Insect-infecting pathogens could disrupt the pollination process by affecting pollinator population density or traits. Pathogens may also infect insect herbivores and change herbivory, potentially altering resource allocation to plant reproduction. We conducted a meta-analysis to (1) summarize the literature on the effects of pathogens on insect pollinators and herbivores and (2) quantify the extent to which pathogens affect insect traits, with potential repercussions for plant reproduction. We found 39 articles that fit our criteria for inclusion, extracting 218 measures of insect traits for 21 different insect species exposed to 25 different pathogens. We detected a negative effect of pathogen exposure on insect traits, which varied by host function: pathogens had a significant negative effect on insects that were herbivores or carried multiple functions but not on insects that solely functioned as pollinators. Particular pathogen types were heavily studied in certain insect orders, with 7 of 11 viral pathogen studies conducted in Lepidoptera and 5 of 9 fungal pathogen studies conducted in Hymenoptera. Our results suggest that most studies have focused on a small set of host-pathogen pairs. To understand the implications for plant reproduction, future work is needed to directly measure the effects of pathogens on pollinator effectiveness.

Self-perceived mental health and factors associated with the mental health of Hong Kong's asylum-seekers and refugees - A mixed methods study.

Rationale: The 21st century has seen vast flows of displaced people. In the year 2020 alone, an estimated 11.2 million were forcibly displaced as a result of persecution, conflict or generalized violence. The torment and fear of war, persecution and threat to life, whether in the home country, during the process of fleeing, or in the post-migration host country, can be extremely traumatic to these marginalized populations. Hong Kong is not a signatory to the 1951 UN Refugee Convention, but the territory has signed the 1967 UN(CAT) which requires the former colony to allow people who flee for their lives to have their cases processed in Hong Kong. Currently there are around 14,000 cases in Hong Kong, some of whom have been in Hong Kong for more than a decade, waiting for their claims to be processed, living on meagre government subsidies and with no right to work. Objectives: The paper examines the mental health of asylum-seekers and refugees in Hong Kong and the factors associating with their mental health. Method: A sequential mixed methods approach was conducted among asylum-seekers and refugees in Hong Kong between October 2019 and mid-2020. It comprised a pilot quantitative survey conducted with 47 participants, and follow-up qualitative interviews with 16 of the 47 participants. Survey results were analyzed using statistical measures while the qualitative in-depth interviews were thematically analyzed to identify emergent patterns and categories. Results: Results from the quantitative data identify 52.2% of the asylum-seekers taking part as having symptomatic anxiety, 55.3% as having symptomatic depression and 54.3% as having overall problems. Qualitative results show that asylum-seekers and refugees cited lack of work and poverty as key factors affecting their mental health and well-being. Fear of being sent home was expressed by respondents who were married or having children for the fear of being separated from each other.

Lifetime abstention of sexual intercourse and health in middle-aged and older adults: results from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions.

This study aimed to examine the association of lifetime abstention of sexual intercourse with lifetime Axis I and II psychiatric disorders, attempted suicide, past-year Axis I psychiatric disorder, past-year medical condition, past-year obesity, health-related quality of life, and health service use in middle-aged and older adults in the United States. Face-to-face interviews were conducted in the 2004-2005 Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. Analyses were performed for the subsample aged 40 years and older (males = 14,427; female = 19,860). Lifetime abstinence from sexual intercourse, sociodemographic variables, prevalence of lifetime Axis I and II DSM-IV psychiatric disorders, schizophrenia, and attempted suicide, past-year Axis I psychiatric disorders, 14 medical conditions, obesity, health-related quality of life, and health service use were obtained. The prevalence of lifetime abstinence from sexual intercourse was 0.90 % (0.88 % for males; 1.00 % for females). The adjusted risks of any lifetime and past-year Axis I disorder, any lifetime and past-year substance-use disorders, lifetime alcohol-use disorder, lifetime and past-year alcohol-abuse disorder, lifetime nicotine dependence, lifetime drug-use disorder, and lifetime drug-abuse disorder were significantly lower for who abstained from sexual intercourse than for those who did not. However, those who abstained from sexual intercourse were more likely to have a diagnosis of obesity and lifetime avoidant and dependent personality disorders. The unadjusted risk of dysthymic disorder was also significantly greater for those who abstained from sexual intercourse. Results indicate that the effect of lifetime absence of sexual intercourse on psychiatric disorders is mixed.

Correlates of eating disorder in middle-aged and older adults: evidence from 2007 British National Psychiatric Morbidity Survey.

OBJECTIVE: This study aims to investigate: (a) the association of eating disorders with childhood sexual abuse and recent stressful life events; (b) the coexistence of eating disorders and other common psychiatric disorders; and (c) the impact of eating disorders on obesity, medical conditions, and health service utilization. METHOD: We conducted secondary data analyses based on population-based study, which consists of a nationally representative sample of 2,870 community-dwelling adults aged 50 and above, interviewed in 2006 to 2007. RESULTS AND CONCLUSION: The 12-month prevalence of eating disorders was 2.61%. Multivariate analyses revealed that eating disorders were more common among younger age groups, women, and those who reported stressful life events. In addition, eating disorders were significantly related to anxiety disorders, agoraphobia, panic disorder, obesity, and cancer. DISCUSSION: This study supports the notion that eating disorders in older adults are associated with a number of psychosocial, psychiatric, and medical conditions.