Abstract Psychotic experiences are far more common in the population than psychotic disorder. They are associated with a number of adverse outcomes but there has been little research on associations ...with functioning and distress. We wished to investigate functioning and distress in a community sample of adolescents with psychotic experiences. Two hundred and twelve school-going adolescents were assessed for psychotic experiences, mental distress associated with these experiences, global (social/occupational) functioning on the Children's Global Assessment Scale, and a number of candidate mediator variables, including psychopathology, suicidality, trauma (physical and sexual abuse and exposure to domestic violence) and neurocognitive functioning. Seventy five percent of participants who reported psychotic experiences reported that they found these experiences distressing (mean score for severity of distress was 6.9 out of maximum 10). Participants who reported psychotic experiences had poorer functioning than participants who did not report psychotic experiences (respective means: 68.6, 81.9; OR = 0.25, 95% CI = 0.14–0.44). Similarly, participants with an Axis-1 psychiatric disorder who reported psychotic experiences had poorer functioning than participants with a disorder who did not report psychotic experiences (respective means: 61.8, 74.5; OR = 0.28, 95% CI = 0.12–0.63). Candidate mediator variables explained some but not all of the relationship between psychotic experiences and functioning (OR = 0.48, 95% CI = 0.22–1.05, P < 0.07). Young people with psychotic experiences have poorer global functioning than those who do not, even when compared with other young people with psychopathology (but who do not report psychotic experiences). A disclosure of psychotic experiences should alert treating clinicians that the individual may have significantly more functional disability than suggested by the psychopathological diagnosis alone.
The phosphoinositide 3-kinase (PI3K) pathway is targeted for frequent alteration in glioblastoma (GBM) and is one of the core GBM pathways defined by The Cancer Genome Atlas. Somatic mutations of ...PIK3R1 are observed in multiple tumor types, but the tumorigenic activity of these mutations has not been demonstrated in GBM. We show here that somatic mutations in the iSH2 domain of PIK3R1 act as oncogenic driver events. Specifically, introduction of a subset of the mutations identified in human GBM, in the nSH2 and iSH2 domains, increases signaling through the PI3K pathway and promotes tumorigenesis of primary normal human astrocytes in an orthotopic xenograft model. Furthermore, we show that cells that are dependent on mutant P85α-mediated PI3K signaling exhibit increased sensitivity to a small molecule inhibitor of AKT. Together, these results suggest that GBM patients whose tumors carry mutant PIK3R1 alleles may benefit from treatment with inhibitors of AKT.
The LUX-ZEPLIN (LZ) experiment will search for dark matter particle interactions with a detector containing a total of 10 tonnes of liquid xenon within a double-vessel cryostat. The large mass and ...proximity of the cryostat to the active detector volume demand the use of material with extremely low intrinsic radioactivity. We report on the radioassay campaign conducted to identify suitable metals, the determination of factors limiting radiopure production, and the selection of titanium for construction of the LZ cryostat and other detector components. This titanium has been measured with activities of \(^{238}\)U\(_{e}\)~\(<\)1.6~mBq/kg, \(^{238}\)U\(_{l}\)~\(<\)0.09~mBq/kg, \(^{232}\)Th\(_{e}\)~\(=0.28\pm 0.03\)~mBq/kg, \(^{232}\)Th\(_{l}\)~\(=0.25\pm 0.02\)~mBq/kg, \(^{40}\)K~\(<\)0.54~mBq/kg, and \(^{60}\)Co~\(<\)0.02~mBq/kg (68\% CL). Such low intrinsic activities, which are some of the lowest ever reported for titanium, enable its use for future dark matter and other rare event searches. Monte Carlo simulations have been performed to assess the expected background contribution from the LZ cryostat with this radioactivity. In 1,000 days of WIMP search exposure of a 5.6-tonne fiducial mass, the cryostat will contribute only a mean background of \(0.160\pm0.001\)(stat)\(\pm0.030\)(sys) counts.
The design and performance of the LUX-ZEPLIN (LZ) detector is described as of March 2015 in this Conceptual Design Report. LZ is a second-generation dark-matter detector with the potential for ...unprecedented sensitivity to weakly interacting massive particles (WIMPs) of masses from a few GeV/c2 to hundreds of TeV/c2. With total liquid xenon mass of about 10 tonnes, LZ will be the most sensitive experiment for WIMPs in this mass region by the end of the decade. This report describes in detail the design of the LZ technical systems. Expected backgrounds are quantified and the performance of the experiment is presented. The LZ detector will be located at the Sanford Underground Research Facility in South Dakota. The organization of the LZ Project and a summary of the expected cost and current schedule are given.
In this Technical Design Report (TDR) we describe the LZ detector to be built at the Sanford Underground Research Facility (SURF). The LZ dark matter experiment is designed to achieve sensitivity to ...a WIMP-nucleon spin-independent cross section of three times ten to the negative forty-eighth square centimeters.
Understanding how cancer cells resist ferroptosis is a significant problem that impacts ongoing efforts to stimulate ferroptosis as a therapeutic strategy. We reported that prominin2 is induced by ...ferroptotic stimuli and functions to resist ferroptotic death. Although this finding has significant implications for therapy, specific prominin2 inhibitors are not available. We rationalized that the mechanism by which prominin2 expression is induced by ferroptotic stress could be targeted, expanding the range of options to overcome ferroptosis resistance. Here, we show that that 4‐hydroxynonenal (4HNE), a specific lipid metabolite formed from the products of lipid peroxidation stimulates PROM2 transcription by a mechanism that involves p38 MAP kinase‐mediated activation of HSF1 and HSF1‐dependent transcription of PROM2. HSF1 inhibitors sensitize a wide variety of resistant cancer cells to drugs that induce ferroptosis. Importantly, the combination of a ferroptosis‐inducing drug and an HSF1 inhibitor causes the cytostasis of established tumors in mice, although neither treatment alone is effective. These data reveal a novel approach for the therapeutic induction of ferroptosis in cancer.
Synopsis
Stimulating ferroptosis has emerged as a potential therapeutic strategy against cancer. Some tumor cells, however, are resistant to known ferroptosis stimuli. This study identifies mechanisms that contribute to ferroptosis and develops strategies to overcome resistance.
Prominin2 expression was induced by ferroptotic stimuli and contributed to resistance.
PROM2 transcription was stimulated by the lipid metabolite 4‐hydroxynonenal (4‐HNE) via a mechanism involving p38 MAP‐kinase‐mediated activation of heat shock factor 1 (HSF1).
Resistant tumor cells were sensitized to drugs that induce ferroptosis by HSF1 inhibition.
Cytostasis of established tumors in mice was observed upon combination treatment with a ferroptosis‐inducing drug and an HSF1 inhibitor.
Stimulating ferroptosis has emerged as a potential therapeutic strategy against cancer. Some tumor cells, however, are resistant to known ferroptosis stimuli. This study identifies mechanisms that contribute to ferroptosis and develops strategies to overcome resistance.
Plasmacytoid bladder cancer is an aggressive histologic variant with a high risk of disease-specific mortality. Using whole-exome and targeted sequencing, we find that truncating somatic alterations ...in the CDH1 gene occur in 84% of plasmacytoid carcinomas and are specific to this histologic variant. Consistent with the aggressive clinical behavior of plasmacytoid carcinomas, which frequently recur locally, CRISPR/Cas9-mediated knockout of CDH1 in bladder cancer cells enhanced cell migration.
DNA-damaging agents comprise the backbone of systemic treatment for many tumor types; however, few reliable predictive biomarkers are available to guide use of these agents. In muscle-invasive ...bladder cancer (MIBC), cisplatin-based chemotherapy improves survival, yet response varies widely among patients. Here, we sought to define the role of the nucleotide excision repair (NER) gene
as a biomarker predictive of response to cisplatin in MIBC.
Somatic missense mutations in
are associated with improved response to cisplatin-based chemotherapy; however, clinically identified
mutations are distributed throughout the gene, and the impact of individual
variants on NER capacity and cisplatin sensitivity is unknown. We developed a microscopy-based NER assay to profile
mutations observed retrospectively in prior studies and prospectively within the context of an institution-wide tumor profiling initiative. In addition, we created the first
-deficient bladder cancer preclinical model for studying the impact of
loss of function.
We used our functional assay to test the NER capacity of clinically observed
mutations and found that most
helicase domain mutations cannot support NER. Furthermore, we show that introducing an
mutation into a bladder cancer cell line abrogates NER activity and is sufficient to drive cisplatin sensitivity in an orthotopic xenograft model.
Our data support a direct role for
mutations in driving cisplatin response, define the functional landscape of
mutations in bladder cancer, and provide an opportunity to apply combined genomic and functional approaches to prospectively guide therapy decisions in bladder cancer.
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Identification of pathogenic germline alterations (PGAs) has important clinical and therapeutic implications in pancreas cancer. We performed comprehensive germline testing (GT) in an unselected ...prospective cohort of patients with exocrine pancreatic neoplasms with genotype and phenotype association to facilitate identification of prognostic and/or predictive biomarkers and examine potential therapeutic implications.
Six hundred fifteen unselected patients with exocrine pancreatic neoplasms were prospectively consented for somatic tumor and matched sample profiling for 410-468 genes. GT for PGAs in 76 genes associated with cancer susceptibility was performed in an "identified" manner in 356 (57.9%) patients and in an "anonymized" manner in 259 (42.1%) patients, using an institutional review board-approved protocol. Detailed clinical and pathological features, response to platinum, and overall survival (OS) were collected for the identified cohort. OS was analyzed with Kaplan-Meier curves.
PGAs were present in 122 (19.8%) of 615 patients involving 24 different genes, including BRCA1/2, ATM, PALB2, and multiple additional genes associated with the DNA damage response pathway. Of 122 patients with germline alterations, 41.8% did not meet current guidelines for GT. The difference in median OS was not statistically significant between patients with and without PGA (50.8 months, 95% confidence interval = 34.5 to not reached, two-sided P = .94). Loss of heterozygosity was found in 60.0% of BRCA1/2.
PGAs frequently occur in pancreas exocrine neoplasms and involve multiple genes beyond those previously associated with hereditary pancreatic cancer. These PGAs are therapeutically actionable in about 5% to 10% of patients. These data support routinely offering GT in all pancreatic ductal adenocarcimona patients with a broad panel of known hereditary cancer predisposition genes.
Home Palliative Care Savings Gordon, Marvin J; Le, Tao; Lee, Emmet W ...
Journal of palliative medicine,
04/2022, Volume:
25, Issue:
4
Journal Article
Peer reviewed
Open access
The aim of this study was to evaluate an adult home palliative care (HPC) program for multiple insurance product lines using multiple vendors to determine if the annual costs of health care decreased ...for those enrolled in HPC.
Of the 506 members who were referred to and qualified for palliative care in 2019, a retroactive review was done comparing annual health care costs between the 396 members in the enrolled group and the 110 members in the group receiving usual care.
The total health care costs for the calendar year 2019 were compared between the group enrolled in HPC and those who received usual care. Cost savings were further evaluated based on whether the member was enrolled in the palliative care program for 1-5 versus 6-12 months.
Overall medical costs for these 396 enrollees for the calendar year 2019 showed a gross savings of $24,643 per member (16.7% decrease in cost). For members enrolled for 1-5 months, annual gross savings were $23,314 per member (15.8% decrease from the comparison group), and for members enrolled for 6-12 months, annual gross savings were $26,409 per member (17.9% decrease). The savings were most prominent for the commercial insurance product with a 51% decrease in annual costs.
Adult home-based palliative care delivered by multiple vendors (consisting of multiple insurance product lines) to a population is effective in decreasing total medical costs by 16.7% during a calendar year compared with a control group. The gross savings for those enrolled for 6-12 months (17.9%) were greater than the gross savings for those enrolled for 1-5 months (15.8%). The savings were most prominent for the commercial insurance product, while an increase in cost was seen for the Medicaid product.
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