Transcriptome profiling and characterization of peritoneal metastasis ovarian cancer xenografts in humanized mice.

Although immunotherapy has not yet been as successful in ovarian cancer (OC), it remains a potential therapeutic strategy. Preclinical models of OC are necessary to evaluate the efficacy of immuno-oncology (IO) drugs targeting human immune components but have been underutilized. Developing mouse models with a humanized (Hu) immune system can help understand the human immune response to IO drugs which have demonstrated limited effectiveness in OC patients. We established OC xenograft Hu-mouse models by intraperitoneally injecting luciferase-expressing SKOV-3 Luc and OVCAR-3 Luc OC cells into CD34+ Hu-mice. Tumor growth was monitored through bioluminescence imaging (BLI). In the SKOV-3 Luc Hu-mouse model, we assessed the efficacy of PD-1 blockade with pembrolizumab. We observed the presence of human lymphocyte and myeloid cell subsets within the tumors, lymph nodes, blood, and spleens in these models. Notably, these tumors exhibited a high prevalence of tumor-infiltrating macrophages. Furthermore, we identified HDAC class I target genes, and genes associated with epithelial-mesenchymal transition (EMT) and fibroblasts in the tumors of Hu-mice treated with pembrolizumab. Our xenograft Hu-mouse model of OC provides a valuable tool for investigating the efficacy of IO drugs. The insights gained from this model offer useful information to explore potential mechanisms associated with unresponsive anti-PD-1 treatment in OC.

Evaluation of the anti-cancer efficacy of lipid nanoparticles containing siRNA against HPV16 E6/E7 combined with cisplatin in a xenograft model of cervical cancer.

OBJECTIVE: To investigate the anti-cancer efficacy of ENB101-LNP, an ionizable lipid nanoparticles (LNPs) encapsulating siRNA against E6/E7 of HPV 16, in combination therapy with cisplatin in cervical cancer in vitro and in vivo. METHODS: CaSki cells were treated with ENB101-LNP, cisplatin, or combination. Cell viability assessed the cytotoxicity of the treatment. HPV16 E6/E7 gene knockdown was verified with RT-PCR both in vitro and in vivo. HLA class I and PD-L1 were checked by flow cytometry. A xenograft model was made using CaSki cells in BALB/c nude mice. To evaluate anticancer efficacy, mice were grouped. ENB101-LNP was given three times weekly for 3 weeks intravenously, and cisplatin was given once weekly intraperitoneally. Tumor growth was monitored. On day 25, mice were euthanized; tumors were collected, weighed, and imaged. Tumor samples were analyzed through histopathology, immunostaining, and western blot. RESULTS: ENB101-LNP and cisplatin synergistically inhibit CaSki cell growth. The combination reduces HPV 16 E6/E7 mRNA and boosts p21 mRNA, p53, p21, and HLA class I proteins. In mice, the treatment significantly blocked tumor growth and promoted apoptosis. Tumor inhibition rates were 29.7% (1 mpk ENB101-LNP), 29.6% (3 mpk), 34.0% (cisplatin), 47.0% (1 mpk ENB101-LNP-cisplatin), and 68.8% (3 mpk ENB101-LNP-cisplatin). RT-PCR confirmed up to 80% knockdown of HPV16 E6/E7 in the ENB101-LNP groups. Immunohistochemistry revealed increased p53, p21, and HLA-A expression with ENB101-LNP treatments, alone or combined. CONCLUSION: The combination of ENB101-LNP, which inhibits E6/E7 of HPV 16, with cisplatin, demonstrated significant anticancer activity in the xenograft mouse model of cervical cancer.

CD8α+ dendritic cells potentiate antitumor and immune activities against murine ovarian cancers.

Dendritic cell (DC)-based immunotherapies have been shown to be a potential treatment option for various cancers; however, the exact strategies in ovarian cancer remain unknown. Here, we report the effectiveness of mouse CD8α+ DCs derived from bone marrow hematopoietic stem cells (BM-HSCs), equivalent to human CD141+ DCs, which have proven to be a highly superior subset. Mono-DCs from monocytes and stem-DCs from HSCs were characterized by CD11c+ CD80+ CD86+ and CD8α+ Clec9a+ expression, respectively. Despite a lower dose compared with Mono-DCs, mice treated with pulsed Stem-DCs showed a reduced amount of ascitic fluid and lower body weights compared with those of vehicle-treated mice. These mice treated with pulsed stem-DCs appeared to have fewer tumor implants, which were usually confined in the epithelium of tumor-invaded organs. All mice treated with DCs showed longer survival than the vehicle group, especially in the medium/high dose pulsed Stem-DC treatment groups. Moreover, the stem-DC-treated group demonstrated a low proportion of myeloid-derived suppressor cells and regulatory T cells, high interleukin-12 and interferon-γ levels, and accumulation of several tumor-infiltrating lymphocytes. Together, these results indicate that mouse CD8α+ DCs derived from BM-HSCs decrease tumor progression and enhance antitumor immune responses against murine ovarian cancer, suggesting that better DC vaccines can be used as an effective immunotherapy in EOC treatment. Further studies are necessary to develop potent DC vaccines using human CD141+ DCs.

Cognitive impairment as a barrier to utilizing preventive health services among older adults.

OBJECTIVES: This study aimed to examine the influence of cognitive impairment on preventive health services utilization among older adults. METHODS: The study sample came from 1995 to 2014 waves of the Health and Retirement Study (HRS), consisting of 19,644 adults aged 51 years or older. Mixed-effects logistic regression was used to analyze the influence of cognitive impairment, measured using the Telephone Interview for Cognitive Status, on the utilization of four types of preventive health care services, including flu shots, cholesterol tests, mammography for women, and prostate cancer screening for men. RESULTS: Persons with cognitive impairment with no dementia were less likely to receive cholesterol tests (OR=0.68, 95% CI=0.64-0.73, p<.001), flu shots (OR=0.86, CI=0.80-0.92, p<.001), mammograms (OR=0.88, CI=0.78-0.99, p<.05), and prostate cancer screenings (OR=0.71, CI=0.71-0.98, p<.05) compared with those without cognitive impairment. Having dementia was associated with a lower odds of receiving cholesterol tests (OR=0.42, CI=0.38-0.47, p<.001), flu shots (OR=0.65, CI=0.57-0.74, p<.001), mammograms (OR=0.70, CI=0.55-0.89, p<.01), and prostate cancer screening (OR=0.68, CI=0.47-0.99, p<.05). CONCLUSIONS: Cognitive impairment with or without dementia is a significant barrier to utilizing preventive health services among older adults. Targeted health promotion prevention and intervention strategies and caregiver education are warranted to improve preventive services among older adults with cognitive impairment.

Application of Immunoprofiling Using Multiplexed Immunofluorescence Staining Identifies the Prognosis of Patients with High-Grade Serous Ovarian Cancer.

Immunoprofiling has an established impact on the prognosis of several cancers; however, its role and definition in high-grade serous ovarian cancer (HGSOC) are mostly unknown. This study is to investigate immunoprofiling which could be a prognostic factor in HGSOC. We produced tumor microarrays of 187 patients diagnosed with HGSOC. We performed a multiplexed immunofluorescence staining using Opal Multiplex IHC kit and quantitative analysis with Vectra-Inform system. The expression intensities of programmed death-ligand 1 (PD-L1), CD4, CD8, CD20, FoxP3, and CK in whole tumor tissues were evaluated. The enrolled patients showed general characteristics, mostly FIGO stage III/IV and responsive to chemotherapy. Each immune marker showed diverse positive densities, and each tumor sample represented its immune characteristics as an inflamed tumor or noninflamed tumor. No marker was associated with survival as a single one. Interestingly, high ratios of CD8 to FoxP3 and CD8 to PD-L1 were related to the favorable overall survival (77 vs. 39 months, 84 vs. 47 months, respectively), and CD8 to PD-L1 ratio was also a significant prognostic factor (HR 0.621, 95% CI 0.420-0.917, p = 0.017) along with well-known clinical prognostic factors. Additionally, CD8 to PD-L1 ratio was found to be higher in the chemosensitive group (p = 0.034). In conclusion, the relative expression levels of CD8, FoxP3, and PD-L1 were significantly related to the clinical outcome of patients with HGSOC, which could be a kind of significant immunoprofiling of ovarian cancer patients to apply for treatment.

The Influence of Cognitive Impairment on Health Behaviors among Older Adults.

Objectives: Previous research on cognitive impairment and health behaviors has focused largely on how health behaviors affect cognition; rarely has it examined whether cognitive impairment affects health behaviors. The purpose of this study was to examine the impact of cognitive impairment on engagement in health behaviors among older adults. Methods: The study sample included 19,644 adults aged 50 or older from the Health and Retirement Study 1995-2012 surveys. We used mixed-effects logistic regression to analyze the influence of cognitive impairment, measured using the Telephone Interview for Cognitive Status, on the engagement of health behaviors including physical activity, smoking, and drinking. Results: Cognitive impairment without dementia [CIND] (OR = .84, 95% CI = .80-.89) and dementia (OR = .68, 95% CI = .61-.75) were associated with a lower likelihood of engaging in regular vigorous physical activity during longitudinal follow-up, after adjusting for covariates. CIND or dementia was not significantly associated with the likelihood of smoking or alcohol consumption. Conclusions: CIND and dementia are risk factors for physical inactivity among older adults. Promotion of regular physical activity should be an essential component of health promotion programs for persons with cognitive impairment.

Disability type, depression, and antidepressants use among older adults in the United States.

Objectives: The study aimed to estimate the prevalence of depression and antidepressant use among older adults with different types of disability.Methods: The study sample consisted of 32,193 adults 50 years and older who participated in the Adult Functioning and Disability supplement of the National Health Interview Survey from 2010-2014. Logistic regression was used to estimate depressive symptoms and self-reported antidepressant use by disability type.Results: One in ten participants reported feeling depressed daily or weekly, and less than half of them reported using antidepressants. Adults with a disability in cognition (odds ratio [OR] = 5.55), mobility (OR = 1.92), vision (OR = 1.91), hearing (OR = 1.88), and self-care (OR = 1.66) were more likely to often feel depressed. Antidepressant use was higher among those with cognition and self-care disability compared with no disabilities. A dose-response association existed between the number of disabilities and depression (AOR = 2.3) and antidepressant use (AOR = 1.39).Conclusions: Various forms of disability are strongly associated with depression in older adults. Antidepressants may be underutilized among older adults with certain impairments, including vision, hearing, and mobility. Future research needs should elucidate the mechanisms linking different disabilities to depression and aim to develop treatments tailored to the needs of older adults with disabilities.

Contextualizing acculturative stress among Latino immigrants in the United States: a systematic review.

Purpose: This systematic review of the literature informed of (a) the relationship between acculturation and acculturative stress, (b) examined the determinants of acculturative stress among Latino immigrants in the U.S., and (c) provided a conceptual framework that can be used to specify the interactive effect of various factors on acculturative stress. Methods: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), this review synthesized the results of thirty studies published between 2000 and 2015 that investigated the influence of several socio-demographic and cultural contexts on acculturative stress among Latino immigrants categorized using Family Stress Management (FSM) theory as a framework. Results: Studied highlighted several protectors from and risks to acculturative stress. Historical context protective factors included having a choice over the decision to migrate and social support; risks included discrimination, family left abroad, and fear of deportation. Economic context protective factors included higher income. The development context protective factors included English skills, years in the U.S., and being married; risks included being female. Cultural context protective factors included being culturally competent and acculturation; risks included family-cultural conflict and ethnic enclave pressures. Internal context protectors included post-immigration religious coping, church attendance, and family values. Implications: The results highlighted incorporating cultural aspects (i.e. family values and social support) in mental health practice with Latino immigrants. A less stressful integration experience can be achieved if age-related stressors and experiences of discrimination are acknowledged and the need for social support and harmonious family dynamics was prioritized in service plans.

Loss of PKM2 in Lgr5+ intestinal stem cells promotes colitis-associated colorectal cancer.

The regulatory properties of pyruvate kinase M2 isoform (PKM2), the key glycolytic enzyme, influence altered energy metabolism including glycolysis in cancer. In this study, we found that PKM2 was highly expressed in patients with ulcerative colitis or colorectal cancer (CRC). We then investigated the effectiveness of conditionally ablating PKM2 in Lgr5+ intestinal stem cells (ISC) using a mouse model of colitis-associated CRC (AOM plus DSS). Tamoxifen-inducible Lgr5-driven deletion of PKM2 in ISC (PKM2ΔLgr5-Tx) significantly promoted tumor incidence and size in the colon and lower body weight compared with findings in vehicle-treated mice (PKM2ΔLgr5-Veh). Histopathologic analysis revealed considerable high-grade dysplasia and adenocarcinoma in the colon of PKM2ΔLgr5-Tx mice while PKM2ΔLgr5-Veh mice had low- and high-grade dysplasia. Loss of PKM2 was associated with dominant expression of PKM1 in Lgr5+ ISC and their progeny cells. Further, the organoid-forming efficiency of whole cancer cells or Lgr5+ cells obtained from colon polyps of PKM2ΔLgr5-Tx mice was significantly increased when compared with PKM2ΔLgr5-Veh mice. Cancer organoids from PKM2ΔLgr5-Tx mice exhibited increased mitochondrial oxygen consumption and a shift of metabolites involved in energy metabolism. These findings suggest that loss of PKM2 function in ISC promotes colitis-associated CRC.

Microbiota-Derived Lactate Accelerates Intestinal Stem-Cell-Mediated Epithelial Development.

Symbionts play an indispensable role in gut homeostasis, but underlying mechanisms remain elusive. To clarify the role of lactic-acid-producing bacteria (LAB) on intestinal stem-cell (ISC)-mediated epithelial development, we fed mice with LAB-type symbionts such as Bifidobacterium and Lactobacillus spp. Here we show that administration of LAB-type symbionts significantly increased expansion of ISCs, Paneth cells, and goblet cells. Lactate stimulated ISC proliferation through Wnt/ß-catenin signals of Paneth cells and intestinal stromal cells. Moreover, Lactobacillus plantarum strains lacking lactate dehydrogenase activity, which are deficient in lactate production, elicited less ISC proliferation. Pre-treatment with LAB-type symbionts or lactate protected mice in response to gut injury provoked by combined treatments with radiation and a chemotherapy drug. Impaired ISC-mediated epithelial development was found in mice deficient of the lactate G-protein-coupled receptor, Gpr81. Our results demonstrate that LAB-type symbiont-derived lactate plays a pivotal role in promoting ISC-mediated epithelial development in a Gpr81-dependent manner.

Physical activity and health services utilization and costs among U.S. adults.

The objective of this study was to examine the relationship between physical activity and health services utilization and costs among adults aged 18 or older in the U.S. Data came from the Medical Expenditure Panel Survey-Household component from 2007 through 2011 (n=117,361). Regular physical activity was defined as spending half an hour or more in moderate or vigorous physical activity at least three times a week. The following categories of self-reported health services utilization and costs were examined: preventive, office-based, outpatient, inpatient, emergency department, home health, and prescription medicines. The association of physical activity and health services utilization and costs was estimated using two-part models. Adults who engaged in regular physical activity were more likely to use preventive (ORs ranged from 1.06 to 1.34, p<0.05) and office-based services (OR=1.05, 95% CI=1.01-1.10, p<0.05). Combining results from both parts of the two-part models, physically active adults incurred significantly lower utilization of inpatient (0.09 vs 0.12 visit per person), emergency room (0.18 vs 0.19 visit per person), home health care (1.21 vs 1.92 visit per person), and prescription medicines (12.66 vs 13.75 number of prescriptions per person) and spent $27 less per capita expenditures for office-based visits, $351 less for inpatient visits, and $52 less for home health care visits. Promoting regular physical activity may reduce health care costs through decreasing demand for secondary and tertiary care services.

Serious psychological distress as a barrier to dental care in community-dwelling adults in the United States.

OBJECTIVES: To examine whether serious psychological distress (SPD), a nonspecific indicator of past year mental health problems, was associated with subsequent dental care utilization, dental expenditures, and unmet dental needs. METHODS: We analyzed data from panel 13 thru 15 of the Medical Expenditure Panel Survey -Household Component (n=31,056). SPD was defined as a score of 13 or higher on the Kessler Psychological Distress Scale (K6). Logistic regression, zero-inflated negative binomial model, and generalized linear model (GLM) with a gamma distribution were used to test the study hypotheses. RESULTS: Adults with SPD had, in the subsequent year, 35 percent lower odds of adhering to annual dental checkups and a twofold increase in the odds of having unmet dental needs. Although adults with SPD did not have significantly more dental visits than those without SPD, they spent 20 percent more on dental care. CONCLUSIONS: SPD was a modest independent risk factor for lack of subsequent preventive dental care, greater unmet dental needs, and greater dental expenditures. In addition to expanding adult dental coverage, it is important to develop and evaluate interventions to increase the utilization of dental care particularly preventive dental services among people with mental illness in order to improve oral health and reduce dental expenditures among this vulnerable population.