An intra-tumoral niche maintains and differentiates stem-like CD8 T cells.

Tumour-infiltrating lymphocytes are associated with a survival benefit in several tumour types and with the response to immunotherapy1-8. However, the reason some tumours have high CD8 T cell infiltration while others do not remains unclear. Here we investigate the requirements for maintaining a CD8 T cell response against human cancer. We find that CD8 T cells within tumours consist of distinct populations of terminally differentiated and stem-like cells. On proliferation, stem-like CD8 T cells give rise to more terminally differentiated, effector-molecule-expressing daughter cells. For many T cells to infiltrate the tumour, it is critical that this effector differentiation process occur. In addition, we show that these stem-like T cells reside in dense antigen-presenting-cell niches within the tumour, and that tumours that fail to form these structures are not extensively infiltrated by T cells. Patients with progressive disease lack these immune niches, suggesting that niche breakdown may be a key mechanism of immune escape.

Applications of Modified Mesenchymal Stem Cells as Targeted Systems against Tumor Cells.

Combined gene and cell therapy are promising strategies for cancer treatment. Given the complexity of cancer, several approaches are actively studied to fight this disease. Using mesenchymal stem cells (MSCs) has demonstrated dual antitumor and protumor effects as they exert massive immune/regulatory effects on the tissue microenvironment. MSCs have been widely investigated to exploit their antitumor target delivery system. They can be genetically modified to overexpress genes and selectively or more efficiently eliminate tumor cells. Current approaches tend to produce more effective and safer therapies using MSCs or derivatives; however, the effect achieved by engineered MSCs in solid tumors is still limited and depends on several factors such as the cell source, transgene, and tumor target. This review describes the progress of gene and cell therapy focused on MSCs as a cornerstone against solid tumors, addressing the different MSC-engineering methods that have been approached over decades of research. Furthermore, we summarize the main objectives of engineered MSCs against the most common cancers and discuss the challenges, limitations, risks, and advantages of targeted treatments combined with conventional ones.

Disease severity and mortality in Alzheimer's disease: an analysis using the U.S. National Alzheimer's Coordinating Center Uniform Data Set.

BACKGROUND: Evidence on the relative risk of death across all stages of Alzheimer's disease (AD) is lacking but greatly needed for the evaluation of new interventions. We used data from the Uniform Data Set (UDS) of the National Alzheimer's Coordinating Center (NACC) to assess the expected survival of a person progressing to a particular stage of AD and the relative risk of death for a person in a particular stage of AD compared with cognitively normal (CN) people. METHODS: This was a retrospective observational cohort study of mortality and its determinants in participants with incident mild cognitive impairment (MCI) due to AD or AD dementia compared with CN participants. Overall survival and hazard ratios of all-cause mortality in participants ≥ 50 years of age with clinically assessed or diagnosed MCI due to AD, or mild, moderate, or severe AD dementia, confirmed by Clinical Dementia Rating scores, versus CN participants were estimated, using NACC UDS data. Participants were followed until death, censoring, or until information to determine disease stage was missing. RESULTS: Aged between 50 and 104 years, 12,414 participants met the eligibility criteria for the study. Participants progressing to MCI due to AD or AD dementia survived a median of 3-12 years, with higher mortality observed in more severe stages. Risk of death increased with the severity of AD dementia, with the increase significantly higher at younger ages. Participants with MCI due to AD and CN participants had a similar risk of death after controlling for confounding factors. CONCLUSIONS: Relative all-cause mortality risk increases with AD severity, more so at younger ages. Mortality does not seem to be higher for those remaining in MCI due to AD. Findings might imply potential benefit of lower mortality if preventing or delaying the progression of AD is successful, and importantly, this potential benefit might be greater in relatively younger people. Future research should replicate our study in other samples more representative of the general US population as well as other populations around the world.

Optofluidic control of rodent learning using cloaked caged glutamate.

Glutamate is the major excitatory neurotransmitter in the brain, and photochemical release of glutamate (or uncaging) is a chemical technique widely used by biologists to interrogate its physiology. A basic prerequisite of these optical probes is bio-inertness before photolysis. However, all caged glutamates are known to have strong antagonism toward receptors of γ-aminobutyric acid, the major inhibitory transmitter. We have developed a caged glutamate probe that is inert toward these receptors at concentrations that are effective for photolysis with violet light. Pharmacological tests in vitro revealed that attachment of a fifth-generation (G5) dendrimer (i.e., cloaking) to the widely used 4-methoxy-7-nitro-indolinyl(MNI)-Glu probe prevented such off-target effects while not changing the photochemical properties of MNI-Glu significantly. G5-MNI-Glu was used with optofluidic delivery to stimulate dopamine neurons of the ventral tegmental area of freely moving mice in a conditioned place-preference protocol so as to mediate Pavlovian conditioning.

Cell Therapy as Target Therapy against Colon Cancer Stem Cells.

Cancer stem cells (CSCs) are a small subpopulation of cells within tumors with properties, such as self-renewal, differentiation, and tumorigenicity. CSCs have been proposed as a plausible therapeutic target as they are responsible for tumor recurrence, metastasis, and conventional therapy resistance. Selectively targeting CSCs is a promising strategy to eliminate the propagation of tumor cells and impair overall tumor development. Recent research shows that several immune cells play a crucial role in regulating tumor cell proliferation by regulating different CSC maintenance or proliferation pathways. There have been great advances in cellular immunotherapy using T cells, natural killer (NK) cells, macrophages, or stem cells for the selective targeting of tumor cells or CSCs in colorectal cancer (CRC). This review summarizes the CRC molecular profiles that may benefit from said therapy and the main vehicles used in cell therapy against CSCs. We also discuss the challenges, limitations, and advantages of combining conventional and/or current targeted treatments in the late stages of CRC.

Intergenerational support and retirement timing among older men and women by race/ethnicity.

Retirement timing is associated with health and economic outcomes for older adults. However, it is unclear how the pressures of supporting older parents and young adult children are associated with retirement. This study uses a life course perspective to consider how the linked lives of working older adults and their support of adult children and parents are associated with retirement. Cox proportional hazard models are estimated using the Health and Retirement Study (1992-2014) to assess the relationship between intergenerational support exchanges and retirement timing by gender and race/ethnicity. Providing most types of intergenerational support and especially providing time support are associated with an increased risk of retirement. Unlike all other respondents, Hispanic women providing intergenerational time support have similar retirement risks as those not providing any intergenerational support. These differing patterns by race/ethnicity suggest that earlier life course trajectories may shape older adults' ability to respond to family needs.

Selenite Downregulates STAT3 Expression and Provokes Lymphocytosis in the Liver of Chronically Exposed Syrian Golden Hamsters.

Arsenic is considered a worldwide pollutant that can be present in drinking water. Arsenic exposure is associated with various diseases, including cancer. Antioxidants as selenite and α-tocopherol-succinate have been shown to modulate arsenic toxic effects. Since changes in STAT3 and PSMD10 gene expression have been associated with carcinogenesis, the aim of this study was to evaluate the effect of arsenic exposure and co-treatments with selenite or α-tocopherol-succinate on the expression of these genes, in the livers of chronically exposed Syrian golden hamsters. Animals were divided into six groups: (i) control, (ii) chronically treated with 100 ppm arsenic, (iii) treated with 6 ppm α-tocopherol-succinate (α-TOS), (iv) treated with 8.5 ppm selenite, (v) treated with arsenic + α-TOS, and (vi) treated with arsenic + selenite. Urine samples and livers were collected after 20 weeks of continuous exposure. The urine samples were analyzed for arsenic species by atomic absorption spectrophotometry, and real-time RT-qPCR analysis was performed for gene expression evaluation. A reduction in STAT3 expression was observed in the selenite-treated group. No differences in PSMD10 expression were found among groups. Histopathological analysis revealed hepatic lymphocytosis in selenite-treated animals. As a conclusion, long-term exposure to arsenic does not significantly alter the expression of STAT3 and PSMD10 oncogenes in the livers of hamsters; however, selenite down-regulates STAT3 expression and provokes lymphocytosis.

National estimates of kinship size and composition among adults with activity limitations in the United States.

BACKGROUND: The number of adults living with limitations in daily activities in the United States is large, and projected to increase. Families, which are becoming more complex, are critical to the wellbeing of this population. OBJECTIVE: We present national estimates of the size and composition of kin networks for adults with activity limitations. METHODS: We use the 2013 Panel Study of Income Dynamics to assess kin relationships of adults aged 40 and older with an activity limitation. We assess kin relations up and down one generation and horizontally, including spouses, adult children, parents, siblings, step-kin, parent-in-laws, children-in-law, and sibling-in-laws. We estimate kinship size and differences across race/ethnicity, education, and marital status. We also estimate the number of helpers. RESULTS: Adults with activity limitations have a substantial number of adult kin: 9.1 on average, while only 12% have fewer than four kin. Spouses and adult biological children, the most common caregivers, account for less than one-third of these kin. Kin networks are much larger among those who report their background as Hispanic rather than non-Hispanic white or Black, married rather than unmarried, and less-than-college rather than college-educated. CONCLUSIONS: Despite concerns about increasing family complexity, we find that 88% of individuals with a limitation have four or more family members, and as kin size increases the average number of kin helping increases from one to two. CONTRIBUTION: We provide estimates of kinship size and composition for adults with disabilities, assessing the number of kin, types of kin, and sociodemographic differences.

Evaluating the clinical effectiveness and safety of various HER2-targeted regimens after prior taxane/trastuzumab in patients with previously treated, unresectable, or metastatic HER2-positive breast cancer: a systematic review and network meta-analysis.

PURPOSE: In the absence of head-to-head trial data, network meta-analysis (NMA) was used to compare trastuzumab emtansine (T-DM1) with other approved treatments for previously treated patients with unresectable or metastatic HER2-positive breast cancer (BC). METHODS: Systematic reviews were conducted of published controlled trials of treatments for unresectable or metastatic HER2-positive BC with early relapse (≤ 6 months) following adjuvant therapy or progression after trastuzumab (Tras) + taxane published from January 1998 to January 2018. Random-effects NMA was conducted for overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety endpoints. RESULTS: The NMA included regimens from seven randomized controlled trials: T-DM1 and combinations of Tras, capecitabine (Cap), lapatinib (Lap), neratinib, or pertuzumab (Per; unapproved). OS results favored T-DM1 over approved comparators: hazard ratio (HR) (95% credible interval [95% CrI]) vs Cap 0.68 (0.39, 1.10), LapCap 0.76 (0.51, 1.07), TrasCap 0.78 (0.44, 1.19). PFS trends favored T-DM1 over all other treatments: HR (95% CrI) vs Cap 0.38 (0.19, 0.74), LapCap 0.65 (0.40, 1.10), TrasCap 0.62 (0.34, 1.18); ORR with T-DM1 was more favorable than with all approved treatments. In surface under cumulative ranking curve (SUCRA) analysis T-DM1 ranked highest for all efficacy outcomes. Discontinuation due to adverse events was less likely with T-DM1 than with all comparators except neratinib. In general, gastrointestinal side effects were less likely and elevated liver transaminases and thrombocytopenia more likely with T-DM1 than with comparators. CONCLUSIONS: The efficacy and tolerability profiles of T-DM1 are generally favorable compared with other treatments for unresectable or metastatic HER2-positive BC.

Dillapiole in Piper holtonii as an Inhibitor of the Symbiotic Fungus Leucoagaricus gongylophorus of Leaf-Cutting Ants.

Plants of the Piperaceae family are studied for their diverse secondary metabolism with a vast array of compounds that act as chemical defense agents against herbivores. Of all the agricultural pests, the management of insects is a highly significant challenge in the Neotropics, and ants of the Attini tribe pose a major problem. Due to their symbiotic association with the fungus Leucoagaricus gongylophorus (Möller) Singer (Agaricaceae), the species of Atta and Acromyrmex have exhaustive foraging activity which has intensified as deforestation and monoculture farming have increased. The control of leaf-cutting ants is still carried out with synthetic products with negative consequences to the environment and human health. In search for natural and sustainable alternatives to synthetic pesticides, Piper holtonii C. DC. was selected among other plant species after field observations of the foraging activity of Atta cephalotes, which revealed that P. holtonii was never chosen by ants. In vitro evaluation of an ethanol extract of the leaves of P. holtonii resulted in promising inhibitory activity (IC50 102 ppm) against L. gongylophorus. Subsequently, bioassay-guided fractionation led to the isolation of the phenylpropanoid dillapiole, which was also detected in the essential oil. This compound demonstrated inhibition of the fungus with an IC50 of 38 ppm. Considering the symbiotic relationship between the Attini ants and L. gongylophorus, the negative effect on the survival of one of the organisms will affect the survival of the other, so dillapiole or standardized essential oil extracts of P. holtonii containing this active principle could be a unique and useful source as a control agent for leaf cutting-ants.

Mitigating Poverty through the Formation of Extended Family Households: Race and Ethnic Differences.

In times of hardship, moving in with family is one strategy for alleviating economic deprivation and uncertainty. The ability of the family to buffer against poverty may vary by the resources available to and the economic needs of individuals. I assess how the formation of extended-family households is associated with a move into or out of poverty and how this association varies by race and ethnicity, since economic resources and norms around extended-family households differ. Using longitudinal data that span four years, I estimate linear fixed effects regression models to assess how changes in living arrangements are related to changes in poverty. I find that moving into an extended-family household reduces poverty, especially for the joining family unit. Most of this poverty reduction occurs through a family safety net, with a non-poor family taking in poor family units.

Reports of self-rated health by citizenship and homeownership, United States 2000-2010.

Citizenship facilitates home ownership, which promotes access to additional resources and structures social context, factors that improve the health of individuals and communities. The objective of this study was to examine whether citizenship moderated the association between homeownership and self-rated health. We used multivariate logistic regression models and propensity score matching techniques to examine this association using pooled years 2000-2010 of the Medical Expenditure Panel Survey data linked with the National Health Interview Survey to examine U.S. adults aged 18 and older (N=170,429). Rates of fair/poor health among homeowners vs. non-homeowners were comparable for foreign-born non-citizens. However, native- and foreign-born citizen non-homeowners showed significantly higher rates of reporting fair/poor health, with native-born citizens having the highest rates of poor health. While homeownership is protective for self-rated health, not meeting the "American Dream" of home ownership may be embodied more in the health of native-born citizens as "failure" and translate into poorer self-rated health. However, the economic privileges of homeownership and its association with better self-rated health are limited to citizens. Non-citizens may be disadvantaged despite socioeconomic position, particularly wealth as considered by homeownership, placing citizenship at the forefront as the most proximate and important burden besides socioeconomic status that needs further investigation as a fundamental health determinant.

Ogg1 genetic background determines the genotoxic potential of environmentally relevant arsenic exposures.

Inorganic arsenic (i-As) is a well-established human carcinogen to which millions of people are exposed worldwide. It is generally accepted that the genotoxic effects of i-As after an acute exposure are partially linked to the i-As-induced production of reactive oxygen species, but it is necessary to better determine whether chronic sub-toxic i-As doses are able to induce biologically significant levels of oxidative DNA damage (ODD). To fill in this gap, we have tested the genotoxic and oxidative effects of environmentally relevant arsenic exposures using mouse embryonic fibroblast MEF mutant Ogg1 cells and their wild-type counterparts. Effects were examined by using the comet assay complemented with the use of FPG enzyme. Our findings indicate that MEF Ogg1-/- cells are more sensitive to arsenite-induced acute toxicity, genotoxicity and ODD. Long-term exposure to sub-toxic doses of arsenite generates a detectable increase in ODD and genotoxic DNA damage only in MEF Ogg1-deficient cells. Altogether, the data presented here point out the relevance of ODD and Ogg1 genetic background on the genotoxic risk of i-As at environmentally plausible doses. The persistent accumulation of DNA 8-OH-dG lesions in Ogg1-/- cells during the complete course of the exposure suggests a relevant role in arsenic-associated carcinogenic risk in turn.

Variant prostate carcinoma and elevated serum CA-125.

INTRODUCTION: About 10% of tumors derived from nongynecologic, noncoelomic tissues react with the OC125 antibody. Some patients with advanced prostate cancer were found to have elevated serum CA-125 level. MATERIALS AND METHODS: We examined the clinical history of 11 patients with castration resistant prostate cancer and an elevated serum CA-125 level. Pathological review and immunohistochemical staining were performed on tumors from eight of these patients. RESULTS: Patients with advanced prostate cancer and an elevated serum CA-125 level responded to androgen ablative therapy (median duration, 27 months). They were predisposed to develop persistent or recurrent urinary symptoms and visceral metastases. Eight of 11 patients had a low or undetectable serum prostate-specific antigen level (≤ 4 ng/mL) or an elevated serum carcinoembryonic antigen level (> 6 ng/mL). In 3 of 7 patients whose specimens were available for further review, the tumors contained histologic features compatible with a diagnosis of ductal or endometrioid adenocarcinoma of the prostate. CONCLUSIONS: Patients with prostate cancer and an elevated serum CA-125 level have unique clinical and pathologic characteristics. Some of these patients possess tumors compatible with a subtype of prostate cancer known as ductal adenocarcinoma. Additional studies need to be performed to elucidate the biologic basis of the various subtypes of prostate cancer.

The impact of local black residents' socioeconomic status on white residents' racial views.

This paper extends the study of contextual influences on racial attitudes by asking how the SES of the local black community shapes the racial attitudes of local whites. Using responses to the 1998-2002 General Social Surveys merged with year 2000 census data, we compare the influences of black educational and economic composition on white residents' attitudes. Finally, the independence of these effects from the impact of white contextual SES is assessed. Across three dimensions of racial attitudes, white residents' views are more positive in localities where the black population contains more college graduates. However, such localities tend also to have highly educated white populations, as well as higher incomes among blacks and whites, and the multiple influences are inseparable. In contrast, many racial attitude measures show an independent effect of black economic composition, white residents reporting more negative views where the local African American community is poorer.

Another health insurance gap: gaining and losing coverage among natives and immigrants at older ages.

As the immigrant population grows older and larger, limitations on access to health insurance may create a new subgroup of people who remain outside or on the margin of coverage. Using the Survey of Income and Program Participation (SIPP) data from the 2004 and 2008 panels, we address the health insurance gap between foreign-born and native-born adults among those aged 50-64 and the 65 and older, two sub-populations that have received relatively little attention in past research. We argue that current practices leave a significant minority of older foreign-born residents inconsistently covered or without any insurance. We find that health insurance coverage for older immigrants is both less likely and more episodic even when compositional differences in SES and assimilation are controlled.

Hitting closer to home: State policies' impacts on health by race and legal status.

While the proliferation of inclusionary and exclusionary state policies has led to an increasingly heterogeneous patchwork of state climates, state policy and the climates they create have become increasingly important for health outcomes. We leverage the heterogeneity across state policy climates to test the relationship between state-level policies and health inequality across the US. We include 24 state policies related to public health and safety, immigration enforcement, integration, and healthcare to capture the state climate. Using the Survey of Income and Program Participation (SIPP), a nationally representative study of households in the U.S., we estimate multilevel regression models to assess the relationship between state policy climate and healthcare utilization. We further examine differential effects of the policy climate across various vulnerable groups, by examining differences by citizenship status and race. We find that more exclusionary policies may be detrimental to healthcare utilization for all residents regardless of race and legal status- but ultimately racial minorities and noncitizens see the greatest benefits from inclusive policy climates.

Geographic Relocation in Response to Parents' Health Shocks: Who Moves and How Close?

Objective: This article examines how parent-child geographic proximity changes around the onset of parental health shocks in the United States. Differences in the likelihood of moving closer across social groups are also investigated. Background: Adult children often care for older parents with health problems, but this requires relatively close proximity. As families are becoming smaller and many adult children live away from their parents, it is unclear how responsive families will be to older adults' health problems. Method: We estimate a series of fixed effects and event study models on data from the Health and Retirement Study (2004-2018) to assess changes in parent-child proximity after parents' first onset of cognitive impairment and functional limitations. Results: We find robust evidence that parents and children tend to stay close or move closer to each other in response to parent's health declines. Moves occur immediately and in subsequent waves after the onset of health shocks. Reductions in parent-child distance are consistently larger among mother-daughter dyads, dyads without spouses or multiple children, and non-Hispanic white families. Conclusion: The geographic availability of adult children to provide care is responsive to parents' needs. After the onset of a serious health condition, most older adults have a spouse or child living close enough to provide care. Parents' and children's lives are dynamically linked, and either or both may relocate to facilitate care.

Racial and ethnic diversity in global neuroscience clinical trials.

Background: Despite efforts to increase diversity in neuroscience trials, racial and ethnic minority groups remain underrepresented. Disparities in clinical trial participation could reflect unequal opportunities to participate and may contribute to decreased generalizability of findings and failure to identify important differences in efficacy and safety outcomes. Methods: We retrospectively reviewed the F. Hoffmann-La Roche database for global, multicenter, neuroscience clinical trials from February 2016 to February 2021 and summarized and stratified race and ethnicity distributions by clinical trial therapeutic area and by country. These data were then compared to national population data for each study's targeted age group (available for studies conducted in the US, Canada, and the UK). The underrepresentation or overrepresentation of each racial and ethnic group was summarized. Results: The analysis population included 8015 participants from 47 countries. Globally, 85.6 % of participants were White, 7.1 % were Asian, 1.6 % were Black, 1.3 % were American Indian or Alaska Native, less than 0.1 % were Native Hawaiian or other Pacific Islander, 0.7 % were of multiple races, and 3.6 % were of other/unknown race. White individuals predominated in all but one trial. Black individuals were underrepresented in all trials but one. Asian individuals were overrepresented in approximately 20 % of trials. In the US, 7.3 % of participants were of Hispanic or Latino ethnicity vs 16.4 % of the US population. Conclusion: The findings and learnings from this summary and analysis demonstrate the need for continued awareness and new approaches in designing studies that reflect population diversity.

Safety and Efficacy of Endovascular Coils and Non-Flow-Diverting Stents for Management of Unruptured Intracranial Aneurysms: A Location-Specific Outcomes Analysis.

INTRODUCTION: The relationship between the anatomical location of an unruptured saccular aneurysm, the efficacy, and the potential complications associated with coil and non-flow-diverting stents remains poorly documented. Therefore, the aim of this study is to evaluate the efficacy and safety of endovascular treatment based on the anatomical position of the unruptured intracranial aneurysm (UIA). METHODS: A retrospective cohort study was conducted using an anonymized database of patients who underwent endovascular therapy for UIAs between 2014 and 2021. RESULTS: A total of 138 patients with 147 UIAs were included. Immediate Raymond-Roy occlusion class I or II was achieved in 99.2% of patients in all anatomical locations, with a 96.2% occlusion rate at the 12-month follow-up. Complications occurred more frequently in the anterior cerebral artery (35%) and internal carotid artery in its ophthalmic segment (25%). However, the difference was not statistically significant. CONCLUSIONS: Our study shows that endovascular treatment with stents and coils is effective and safe for managing UIAs in various anatomical locations. The incidence of thromboembolic complications was significantly higher for UIAs located in the anterior cerebral artery.