A population-based study comparing comorbid conditions and mental distress among Hispanic Adolescent and Young Adult cancer survivors to propensity score matched controls

https://openworks.mdanderson.org/sumexp22/1073/thumbnail.jp

Cavin-1/PTRF alters prostate cancer cell-derived extracellular vesicle content and internalization to attenuate extracellular vesicle-mediated osteoclastogenesis and osteoblast proliferation

Background: Tumour-derived extracellular vesicles (EVs) play a role in tumour progression; however, the spectrum of molecular mechanisms regulating EV secretion and cargo selection remain to be fully elucidated. We have reported that cavin-1 expression in prostate cancer PC3 cells reduced the abundance of a subset of EV proteins, concomitant with reduced xenograft tumour growth and metastasis. Methods: We examined the functional outcomes and mechanisms of cavin-1 expression on PC3-derived EVs (PC3-EVs). Results: PC3-EVs were internalized by osteoclast precursor RAW264.7 cells and primary human osteoblasts (hOBs) in vitro, stimulating osteoclastogenesis 37-fold and hOB proliferation 1.5-fold, respectively. Strikingly, EVs derived from cavin-1-expressing PC3 cells (cavin-1-PC3-EVs) failed to induce multinucleate osteoblasts or hOB proliferation. Cavin-1 was not detected in EVs, indicating an indirect mechanism of action. EV morphology, size and quantity were also not affected by cavin-1 expression, suggesting that cavin-1 modulated EV cargo recruitment rather than release. While cavin-1-EVs had no osteoclastogenic function, they were internalized by RAW264.7 cells but at a reduced efficiency compared to control EVs. EV surface proteins are required for internalization of PC3-EVs by RAW264.7 cells, as proteinase K treatment abolished uptake of both control and cavin-1-PC3-EVs. Removal of sialic acid modifications by neuraminidase treatment increased the amount of control PC3-EVs internalized by RAW264.7 cells, without affecting cavin-1-PC3-EVs. This suggests that cavin-1 expression altered the glycosylation modifications on PC3-EV surface. Finally, cavin-1 expression did not affect EV in vivo tissue targeting as both control and cavin-1-PC3-EVs were predominantly retained in the lung and bone 24 hours after injection into mice. Discussion: Taken together, our results reveal a novel pathway for EV cargo sorting, and highlight the potential of utilizing cavin-1-mediated pathways to attenuate metastatic prostate cancer

Prefoldin 6 mediates longevity response from heat shock factor 1 to FOXO in C-elegans

Heat shock factor 1 (HSF-1) and forkhead box O (FOXO) are key transcription factors that protect cells from various stresses. In Caenorhabditis elegans, HSF-1 and FOXO together promote a long life span when insulin/IGF-1 signaling (IIS) is reduced. However, it remains poorly understood how HSF-1 and FOXO cooperate to confer IIS-mediated longevity. Here, we show that prefoldin 6 (PFD-6), a component of the molecular chaperone prefoldin-like complex, relays longevity response from HSF-1 to FOXO under reduced IIS. We found that PFD-6 was specifically required for reduced IIS-mediated longevity by acting in the intestine and hypodermis. We showed that HSF-1 increased the levels of PFD-6 proteins, which in turn directly bound FOXO and enhanced its transcriptional activity. Our work suggests that the prefoldin-like chaperone complex mediates longevity response from HSF-1 to FOXO to increase the life span in animals with reduced IIS.11Ysciescopu

Gateway RFP-fusion vectors for high-throughput functional analysis of genes

There is an increasing demand for high throughput (HTP) methods for gene analysis on a genome-wide scale. However, the current repertoire of HTP detection methodologies allows only a limited range of cellular phenotypes to be studied. We have constructed two HTP-optimized expression vectors generated from the red fluorescent reporter protein (RFP) gene. These vectors produce RFP-tagged target proteins in a multiple expression system using gateway cloning technology (GCT). The RFP tag was fused with the cloned genes, thereby allowing us localize the expressed proteins in mammalian cells. The effectiveness of the vectors was evaluated using an HTP-screening system. Sixty representative human C2 domains were tagged with RFP and overexpressed in HiB5 neuronal progenitor cells, and we studied in detail two C2 domains that promoted the neuronal differentiation of HiB5 cells. Our results show that the two vectors developed in this study are useful for functional gene analysis using an HTP-screening system on a genome-wide scale.We appreciate the helpful advice of Dr. Tobias Meyer and Dr. Won Do Heo of Stanford University in the construction of the set of entry clones of human C2 domains. This work was supported by a grant from the Basic Research Program of the Korea Science and Engineering Foundation (R01-2002- 000-00128-0), and a Korea Research Foundation Grant (KRF- 2006-005-J04204)

Motivational and Behavioral Activation as an Adjunct to Psychiatric Rehabilitation for Mild to Moderate Negative Symptoms in Individuals with Schizophrenia: A Proof-of-Concept Pilot Study

Few psychosocial approaches address the negative symptoms of schizophrenia, which shares common features with depression and anxiety. Behavioral activation (BA) is effective for addressing depression and anxiety in adults with various mental disorders. Motivational Interviewing (MI) has been successfully applied to address ambivalence or lack of motivation towards treatment. Motivational and behavioral activation (mBA) has been developed by incorporating the core principles from BA and MI with recent findings on the negative symptoms of schizophrenia. In this study, we aimed to examine the feasibility and preliminary efficacy of mBA in a non-randomized controlled pilot study that included individuals with schizophrenia with mild to moderate negative symptoms receiving psychiatric rehabilitation. A total of 73 individuals with schizophrenia were recruited. Forty-seven of the participants who met the study inclusion and exclusion criteria were assigned to either an mBA + usual psychiatric rehabilitation group (mBA) or a usual psychiatric rehabilitation only group (treatment as usual, TAU). Administering mBA to individuals with schizophrenia with mild to moderate negative symptoms was feasible in a community mental health setting. Relative to TAU, mBA was associated with large effects in reducing negative symptoms measured using the Positive and Negative Syndrome Scale (PANSS) and the Brief Negative Symptom Scale (BNSS). However, after considering PANSS cognitive deficits and marital status as covariates due to significant differences in their baseline levels, the treatment effects on the BNSS were partially observed. In addition, participants in the mBA group showed improved verbal learning and memory compared with those in the TAU group. In individuals with schizophrenia receiving the usual forms of psychiatric rehabilitation in a community mental health setting, mBA appears to offer a promising adjunctive approach for addressing mild to moderate negative symptoms. Further investigations are needed to replicate the current findings in a randomized controlled trial