Associations Between Adverse Childhood Experiences and Tobacco, Alcohol, and Drug Use Among Individuals with Serious Mental Illnesses in Public-Sector Treatment Settings.

Adverse childhood experiences (ACEs) increase risk of substance use disorders (SUDs). Little research has focused on individuals with serious mental illnesses (SMI), despite their high prevalence of both ACEs and SUDs. We combined two datasets from prior studies (n = 299 and n = 240, total n = 539) that measured ACEs and made research diagnoses for SUDs. When controlling for other variables-age, gender, race, diagnostic category (psychotic disorder versus mood disorder), and study site (Washington, DC-area versus southeast Georgia)- in logistic regression models, ACE score was associated with tobacco use, presence of any SUD, alcohol use disorder, cannabis use disorder, and cocaine use disorder. Each one-unit increase in the ACE score increased the odds of SUD-related outcomes by 9-18%. Clinicians, program planners, and researchers should be aware of the powerful and long-lasting impact of ACEs, and the need for thorough screening and assessment of both SUDs and ACEs among patients with SMI.

Sex-dependent role of Pannexin 1 in regulating skeletal muscle and satellite cell function.

The development and regeneration of skeletal muscle are mediated by satellite cells (SCs), which ensure the efficient formation of myofibers while repopulating the niche that allows muscle repair following injuries. Pannexin 1 (Panx1) channels are expressed in SCs and their levels increase during differentiation in vitro, as well as during skeletal muscle development and regeneration in vivo. Panx1 has recently been shown to regulate muscle regeneration by promoting bleb-based myoblast migration and fusion. While skeletal muscle is largely influenced in a sex-specific way, the sex-dependent roles of Panx1 in regulating skeletal muscle and SC function remain to be investigated. Here, using global Panx1 knockout (KO) mice, we demonstrate that Panx1 loss reduces muscle fiber size and strength, decreases SC number, and alters early SC differentiation and myoblast fusion in male, but not in female mice. Interestingly, while both male and female Panx1 KO mice display an increase in the number of regenerating fibers following acute injury, the newly formed fibers in male Panx1 KO mice are smaller. Overall, our results demonstrate that Panx1 plays a significant role in regulating muscle development, regeneration, and SC number and function in male mice and reveal distinct sex-dependent functions of Panx1 in skeletal muscle.

Expression of Pannexin 1 and Pannexin 3 during skeletal muscle development, regeneration, and Duchenne muscular dystrophy.

Pannexin 1 (Panx1) and Pannexin 3 (Panx3) are single membrane channels recently implicated in myogenic commitment, as well as myoblast proliferation and differentiation in vitro. However, their expression patterns during skeletal muscle development and regeneration had yet to be investigated. Here, we show that Panx1 levels increase during skeletal muscle development becoming highly expressed together with Panx3 in adult skeletal muscle. In adult mice, Panx1 and Panx3 were differentially expressed in fast- and slow-twitch muscles. We also report that Panx1/PANX1 and Panx3/PANX3 are co-expressed in mouse and human satellite cells, which play crucial roles in skeletal muscle regeneration. Interestingly, Panx1 and Panx3 levels were modulated in muscle degeneration/regeneration, similar to the pattern seen during skeletal muscle development. As Duchenne muscular dystrophy is characterized by skeletal muscle degeneration and impaired regeneration, we next used mild and severe mouse models of this disease and found a significant dysregulation of Panx1 and Panx3 levels in dystrophic skeletal muscles. Together, our results are the first demonstration that Panx1 and Panx3 are differentially expressed amongst skeletal muscle types with their levels being highly modulated during skeletal muscle development, regeneration, and dystrophy. These findings suggest that Panx1 and Panx3 channels may play important and distinct roles in healthy and diseased skeletal muscles.

Regulation of Skeletal Muscle Myoblast Differentiation and Proliferation by Pannexins.

Pannexins are newly discovered channels that are now recognized as mediators of adenosine triphosphate release from several cell types allowing communication with the extracellular environment. Pannexins have been associated with various physiological and pathological processes including apoptosis, inflammation, and cancer. However, it is only recently that our work has unveiled a role for Pannexin 1 and Pannexin 3 as novel regulators of skeletal muscle myoblast proliferation and differentiation. Myoblast differentiation is an ordered multistep process that includes withdrawal from the cell cycle and the expression of key myogenic factors leading to myoblast differentiation and fusion into multinucleated myotubes. Eventually, myotubes will give rise to the diverse muscle fiber types that build the complex skeletal muscle architecture essential for body movement, postural behavior, and breathing. Skeletal muscle cell proliferation and differentiation are crucial processes required for proper skeletal muscle development during embryogenesis, as well as for the postnatal skeletal muscle regeneration that is necessary for muscle repair after injury or exercise. However, defects in skeletal muscle cell differentiation and/or deregulation of cell proliferation are involved in various skeletal muscle pathologies. In this review, we will discuss the expression of pannexins and their post-translational modifications in skeletal muscle, their known functions in various steps of myogenesis, including myoblast proliferation and differentiation, as well as their possible roles in skeletal muscle development, regeneration, and diseases such as Duchenne muscular dystrophy.

Pannexin 1 and pannexin 3 channels regulate skeletal muscle myoblast proliferation and differentiation.

Pannexins constitute a family of three glycoproteins (Panx1, -2, and -3) forming single membrane channels. Recent work demonstrated that Panx1 is expressed in skeletal muscle and involved in the potentiation of contraction. However, Panxs functions in skeletal muscle cell differentiation, and proliferation had yet to be assessed. We show here that Panx1 and Panx3, but not Panx2, are present in human and rodent skeletal muscle, and their various species are differentially expressed in fetal versus adult human skeletal muscle tissue. Panx1 levels were very low in undifferentiated human primary skeletal muscle cells and myoblasts (HSMM) but increased drastically during differentiation and became the main Panx expressed in differentiated cells. Using HSMM, we found that Panx1 expression promotes this process, whereas it was impaired in the presence of probenecid or carbenoxolone. As for Panx3, its lower molecular weight species were prominent in adult skeletal muscle but very low in the fetal tissue and in undifferentiated skeletal muscle cells and myoblasts. Its overexpression (∼43-kDa species) induced HSMM differentiation and also inhibited their proliferation. On the other hand, a ∼70-kDa immunoreactive species of Panx3, likely glycosylated, sialylated, and phosphorylated, was highly expressed in proliferative myoblasts but strikingly down-regulated during their differentiation. Reduction of its endogenous expression using two Panx3 shRNAs significantly inhibited HSMM proliferation without triggering their differentiation. In summary, our results demonstrate that Panx1 and Panx3 are co-expressed in human skeletal muscle myoblasts and play a pivotal role in dictating the proliferation and differentiation status of these cells.

Increased Elastase and Matrix Metalloproteinase Levels in the Pulmonary Arteries of Infants With Congenital Diaphragmatic Hernia.

BACKGROUND: Pulmonary vascular disease (PVD) complicated with pulmonary hypertension (PH) is a leading cause of mortality in congenital diaphragmatic hernia (CDH). Unfortunately, CDH patients are often resistant to PH therapy. Using the nitrogen CDH rat model, we previously demonstrated that CDH-associated PVD involves an induction of elastase and matrix metalloproteinase (MMP) activities, increased osteopontin and epidermal growth factor (EGF) levels, and enhanced smooth muscle cell (SMC) proliferation. Here, we aimed to determine whether the levels of the key members of this proteinase-induced pathway are also elevated in the pulmonary arteries (PAs) of CDH patients. METHODS: Neutrophil elastase (NE), matrix metalloproteinase-2 (MMP-2), epidermal growth factor (EGF), tenascin-C, and osteopontin levels were assessed by immunohistochemistry in the PAs from the lungs of 11 CDH patients and 5 normal age-matched controls. Markers of proliferation (proliferating cell nuclear antigen (PCNA)) and apoptosis (cleaved (active) caspase-3) were also used. RESULTS: While expressed by both control and CDH lungs, the levels of NE, MMP-2, EGF, as well as tenascin-C and osteopontin were significantly increased in the PAs from CDH patients. The percentage of PCNA-positive PA SMCs were also enhanced, while those positive for caspase-3 were slightly decreased. CONCLUSIONS: These results suggest that increased elastase and MMPs, together with elevated tenascin-C and osteopontin levels in an EGF-rich environment may contribute to the PVD in CDH infants. The next step of this study is to expand our analysis to a larger cohort, and determine the potential of targeting this pathway for the treatment of CDH-associated PVD and PH. TYPE OF STUDY: Therapeutic. LEVEL OF EVIDENCE: LEVEL III.

Pannexin 1 dysregulation in Duchenne muscular dystrophy and its exacerbation of dystrophic features in mdx mice.

BACKGROUND: Duchenne muscular dystrophy (DMD) is associated with impaired muscle regeneration, progressive muscle weakness, damage, and wasting. While the cause of DMD is an X-linked loss of function mutation in the gene encoding dystrophin, the exact mechanisms that perpetuate the disease progression are unknown. Our laboratory has demonstrated that pannexin 1 (Panx1 in rodents; PANX1 in humans) is critical for the development, strength, and regeneration of male skeletal muscle. In normal skeletal muscle, Panx1 is part of a multiprotein complex with dystrophin. We and others have previously shown that Panx1 levels and channel activity are dysregulated in various mouse models of DMD. METHODS: We utilized myoblast cell lines derived from DMD patients to assess PANX1 expression and function. To investigate how Panx1 dysregulation contributes to DMD, we generated a dystrophic (mdx) mouse model that lacks Panx1 (Panx1-/-/mdx). In depth characterization of this model included histological analysis, as well as locomotor, and physiological tests such as muscle force and grip strength assessments. RESULTS: Here, we demonstrate that PANX1 levels and channel function are reduced in patient-derived DMD myoblast cell lines. Panx1-/-/mdx mice have a significantly reduced lifespan, and decreased body weight due to lean mass loss. Their tibialis anterior were more affected than their soleus muscles and displayed reduced mass, myofiber loss, increased centrally nucleated myofibers, and a lower number of muscle stem cells compared to that of Panx1+/+/mdx mice. These detrimental effects were associated with muscle and locomotor functional impairments. In vitro, PANX1 overexpression in patient-derived DMD myoblasts improved their differentiation and fusion. CONCLUSIONS: Collectively, our findings suggest that PANX1/Panx1 dysregulation in DMD exacerbates several aspects of the disease. Moreover, our results suggest a potential therapeutic benefit to increasing PANX1 levels in dystrophic muscles.

Adverse Childhood Experiences and Arrest Rates among Individuals with Serious Mental Illnesses.

Adverse childhood experiences (ACEs) are linked to both poor mental health and adverse social outcomes, including arrest and incarceration. Furthermore, individuals with serious mental illnesses (SMI) are known to have high rates of childhood adversity and are overrepresented in all facets of the criminal justice system. Few studies have examined the associations between ACEs and arrests among individuals with SMI. We examined the impact of ACEs on arrest among individuals with SMI while controlling for age, gender, race, and educational attainment. In a combined sample from two separate studies in different settings (N = 539), we hypothesized that ACE scores would be associated with prior arrest, as well as rate of arrests. The prevalence of prior arrest was very high (415, 77.3%) and was predicted by male gender, African American race, lower educational attainment, and mood disorder diagnosis. Arrest rate (number of arrests per decade, which thus accounted for age) was predicted by lower educational attainment and higher ACE score. Diverse clinical and policy implications include improving educational outcomes for individuals with SMI, reducing and addressing childhood maltreatment and other forms of childhood or adolescent adversity, and clinical approaches that help clients reduce the likelihood of arrest while addressing trauma histories.

Inhibition of PANX1 Channels Reduces the Malignant Properties of Human High-Risk Neuroblastoma.

Pannexin 1 (PANX1) is expressed in many tissue types including tissues of neural origin. Neuroblastoma (NB) is a neural crest-derived malignancy mainly occurring in children. The majority of NB patients present with high-risk disease for which current therapies are ineffective. Here, we show that while PANX1 is expressed in NB of all stages, high PANX1 expression in high-risk NB is associated with a reduced survival probability. PANX1 channel inhibition using probenecid (PBN) or carbenoxolone (CBX) reduced the proliferation of our panel of high-risk NB cell lines. We show that expression of the Y10F PANX1 mutant, which cannot be phosphorylated on tyrosine 10 and acts in a dominant-negative manner, curtailed NB cell proliferation. Furthermore, PBN and CBX treatment halted the growth of NB spheroids and in some cases triggered the regression of established NB spheroids. Finally, both drugs reduced the progression of high-risk NB in vivo. Together our data indicate that PANX1 channels regulate human NB malignant properties and that the use of PBN or CBX may provide a new therapeutic approach for high-risk NB.

Comparing safety and adequacy between surgical biopsy versus core needle biopsy in diagnosing neuroblastoma.

BACKGROUND: Adequate tissue biopsy is essential for diagnosis and risk stratification of neuroblastoma (NB). Historically, NB diagnosis has relied on tissue obtained via surgical biopsy. However, core needle biopsy may provide a safe and adequate method of obtaining tissue in pediatric patients. AIM: The aim of this study is to compare the adequacy and safety between core needle biopsy and surgical biopsy for the diagnosis of NB in children at our institution. METHODS: Institutional approval was obtained. Medical records of patients diagnosed with NB from 2004 - 2019 were retrospectively reviewed. Patients had either core needle biopsy (CNB) or surgical biopsy (SB) including open/minimally invasive biopsy. Data included patient demographics, tumor location and size, sample adequacy for diagnosis and risk stratification, post-biopsy complications, length of hospital stay, and need for repeat biopsy. Statistical analysis was conducted using the Mann-Whitney U test or Student's t-test. RESULTS: Thirty-eight patients were included; 53 biopsies were performed including 41 SB and 12 CNB. Patient and tumor characteristics were similar in both groups, as well as the biopsy adequacy for diagnosis and risk stratification. In all cases, there was no need for repeat biopsy. The CNB group demonstrated reduced length of stay (2 ± 0.4 days vs 5 ± 0.5 days; P < 0.0001) and fewer complications (8%) than the SB group (44%) (P = 0.038). CONCLUSION: Core needle biopsy is an acceptable modality for diagnosis and risk stratification in the pediatric population. Advantages include decreased length of stay and fewer post-procedure complications.

Quercetin induces pannexin 1 expression via an alternative transcript with a translationally active 5' leader in rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a deadly cancer of skeletal muscle origin. Pannexin 1 (PANX1) is down-regulated in RMS and increasing its levels drastically inhibits RMS progression. PANX1 upregulation thus represents a prospective new treatment strategy for this malignancy. However, the mechanisms regulating PANX1 expression, in RMS and other contexts, remain largely unknown. Here we show that both RMS and normal skeletal muscle express a comparable amount of PANX1 mRNAs, but surprisingly the canonical 5' untranslated region (5' UTR) or 5' leader of the transcript is completely lost in RMS. We uncover that quercetin, a natural plant flavonoid, increases PANX1 protein levels in RMS by inducing re-expression of a 5' leader-containing PANX1 transcript variant that is efficiently translated. This particular PANX1 mRNA variant is also present in differentiated human skeletal muscle myoblasts (HSMM) that highly express PANX1. Mechanistically, abolishing ETV4 transcription factor binding sites in the PANX1 promoter significantly reduced the luciferase reporter activities and PANX1 5' UTR levels, and both quercetin treatment in RMS cells and induction of differentiation in HSMM enriched the binding of ETV4 to its consensus element in the PANX1 promoter. Notably, quercetin treatment promoted RMS differentiation in a PANX1-dependent manner. Further showing its therapeutic potential, quercetin treatment prevented RMS in vitro tumor formation while inducing complete regression of established spheroids. Collectively, our results demonstrate the tumor-suppressive effects of quercetin in RMS and present a hitherto undescribed mechanism of PANX1 regulation via ETV4-mediated transcription of a translationally functional 5' leader-containing PANX1 mRNA.

Information sharing across mental health service providers and criminal legal system stakeholders: Perspectives of people with serious mental illnesses and their family members.

OBJECTIVE: The overrepresentation of people with serious mental illnesses in the criminal legal system has spurred information-sharing initiatives to transmit information between mental health service providers and criminal legal system stakeholders with the goal of improving resources and streamlining access to care. However, no research to date has examined the perspectives of people with mental illnesses who have their information shared across these systems or the perspectives of their family members. This study examined the perspectives on mental health-criminal legal system information sharing among people with serious mental illnesses and a history of arrest, as well as their family members. METHODS: Researchers interviewed 24 clients with serious mental illnesses and a history of arrest who are enrolled in a randomized, controlled trial of a police-mental health Linkage System as well as 11 of their family members. Participants were recruited and interviewed between November 2020 and February 2021. A thematic analysis was used to code and analyze all interview transcripts. RESULTS: Study participants articulated perceived benefits and concerns around cross-system information sharing. There was strong support for information sharing in both directions, with the anticipation that such information sharing can prevent unnecessary arrest and/or incarceration, promote positive and safe interactions with criminal legal system professionals, and foster greater understanding and access to treatment. Concerns were more limited and largely related to perceived stigma around mental illnesses and the potential consequences of such stigma. CONCLUSIONS: While concerns about information sharing should be considered, study participants overwhelmingly perceived the sharing of information between mental health providers and criminal legal stakeholders as a positive intervention. Such perspectives can be understood as a pragmatic choice in the face of criminal legal system contact and additional research could guide programmatic and policy changes.

Characterizing Arrests and Charges Among Individuals With Serious Mental Illnesses in Public-Sector Treatment Settings.

Objective: Individuals with serious mental illnesses are overrepresented in all facets of the legal system. State-level criminal histories of patients with serious mental illnesses were analyzed to determine the proportion who had been arrested and number of lifetime arrests and charges, associations of six variables with number of arrests, and the most common charges from individuals' first two arrests and most recent two arrests. Methods: A total of 240 patients were recruited at three inpatient psychiatric facilities and gave consent to access their criminal history. Information was extracted from Record of Arrest and Prosecution (RAP) sheets for lifetime arrests in Georgia. Results: A total of 171 (71%) had been arrested. Their mean±SD lifetime arrests were 8.6±10.1, and mean lifetime charges were 12.6±14.6. In a Poisson regression, number of arrests was associated with lower educational attainment, Black or African American race, the presence of a substance use disorder, the presence of a mood disorder, and female sex. Common early charges included marijuana possession, driving under the influence of alcohol, and burglary and shoplifting. Common recent charges included probation violations, failure to appear in court, officer obstruction­related charges, and disorderly conduct. Conclusions: Findings point to a need for policy and program development in the legal system (e.g., pertaining to charges such as willful obstruction of an officer), the mental health community (e.g., to ensure that professionals know about clients' legal involvement and can partner in strategies to reduce arrests), and social services sectors (to address charges, such as shoplifting, often related to material disadvantage).

The potency of the fs260 connexin43 mutant to impair keratinocyte differentiation is distinct from other disease-linked connexin43 mutants.

Although there are currently 62 mutants of Cx43 (connexin43) that can cause ODDD (oculodentodigital dysplasia), only two mutants have also been reported to cause palmar plantar hyperkeratosis. To determine how mutants of Cx43 can lead to this skin disease, REKs (rat epidermal keratinocytes) were engineered to express an ODDD-associated Cx43 mutant always linked to skin disease (fs260), an ODDD-linked Cx43 mutant which has been reported to sometimes cause skin disease (fs230), Cx43 mutants which cause ODDD only (G21R, G138R), a mouse Cx43 mutant linked to ODDD (G60S), a non-disease-linked truncated Cx43 mutant that is trapped in the endoplasmic reticulum (Delta244*) or full-length Cx43. When grown in organotypic cultures, of all the mutants investigated, only the fs260-expressing REKs consistently developed a thinner stratum corneum and expressed lower levels of Cx43, Cx26 and loricrin in comparison with REKs overexpressing wild-type Cx43. REKs expressing the fs260 mutant also developed a larger organotypic vital layer after acetone-induced injury and exhibited characteristics of parakeratosis. Collectively, our results suggest that the increased skin disease burden exhibited in ODDD patients harbouring the fs260 mutant is probably due to multiple additive effects cause by the mutant during epidermal differentiation.

Adversity in childhood/adolescence and premorbid tobacco, alcohol, and cannabis use among first-episode psychosis patients.

AIM: Premorbid substance use is widely recognized as a crucial factor in early psychosis. We explored the effects of childhood/adolescent adversity on premorbid tobacco, alcohol, and cannabis use. We hypothesized that adversity in childhood would be associated with an increased likelihood of use, and amount of intake, of tobacco, alcohol, and cannabis. We analysed which domains of adversity have the greatest impact. METHODS: First-episode psychosis patients were enrolled from six inpatient psychiatric units in Atlanta, Georgia and Washington, D.C. Premorbid substance use was thoroughly measured, and childhood/adolescent adversity was rated using 14 scales/subscales. Factor analysis was used to reduce these scales/subscales to the three domains of adversity (termed Violence and Environmental Adversity, Interpersonal Abuse, and Neglect and Lack of Connectedness). Regression analyses determined associations between adversity domains and premorbid substance use. RESULTS: Our sample (n = 247) primarily consisted of African Americans (86.2%) and males (74.5%). Violence and Environmental Adversity was significantly associated with five of six substance use variables and marginally associated with the sixth. Interpersonal Abuse was unassociated with substance use, and Neglect and Lack of Connectedness was associated only with a lower likelihood cannabis use. When Violence and Environmental Adversity results were stratified by gender, effects on tobacco use and amount of tobacco use were stronger among females. CONCLUSIONS: Childhood/adolescent trauma and adversity have meaningful associations with premorbid substance use in first-episode psychosis patients. First-episode psychosis and clinical high-risk treatment settings may benefit from expanding the assessment of childhood/adolescent adversity to include factors pertaining to violence exposure and adversities beyond abuse and neglect.

Identification of pannexin 1-regulated genes, interactome, and pathways in rhabdomyosarcoma and its tumor inhibitory interaction with AHNAK.

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, is an aggressive cancer with a poor prognosis. Despite current management, the 5-year survival rate for patients with metastatic RMS is ∼30%; underscoring the need to develop better treatment strategies. We have recently reported that pannexin 1 (PANX1) levels are downregulated in RMS and that restoring its expression inhibits RMS progression. Here, we have surveyed and characterized the molecular changes induced by PANX1 re-expression in RMS. We cataloged transcriptomic changes in this context by RNA sequencing. At the protein level, we unveiled PANX1 interactors using BioID, complemented by co-immunoprecipitation coupled to high-performance liquid chromatography/electrospray ionization tandem mass spectrometry performed in PANX1-enriched fractions. Using these data, we generated searchable public databases for the PANX1 interactome and changes to the RMS transcriptome occurring when PANX1 expression is restored. STRING network analyses revealed a PANX1 interactome involving plasma membrane and cytoskeleton-associated proteins including the previously undescribed interactor AHNAK. Indeed, AHNAK knockdown abrogated the PANX1-mediated reduction in RMS cell viability and migration. Using these unbiased approaches, we bring insight to the mechanisms by which PANX1 inhibits RMS progression, identifying the cell migration protein AHNAK as a key modifier of PANX1-mediated changes in RMS malignant properties.

Subjective social status, objective social status, and substance use among individuals with serious mental illnesses.

Subjective social status (SSS) and objective socioeconomic status (OSS) may appear to be similar social determinants of mental health, but are actually independently associated with diverse health outcomes including substance use and substance use disorders (SUDs). Such associations have not been examined among individuals with serious mental illnesses (SMI) despite their high prevalence of comorbid substance use; frequent treatment and recovery complications associated with such use; and high levels of economic disadvantage, discrimination, and inequities in this marginalized population. These psychosocial adversities manifest as poor mental illness outcomes, poor physical health, and early mortality in populations with SMI. We hypothesized that both SSS and OSS would predict substance use severity and SUD diagnoses in 240 patients with SMI. SSS, measured by the MacArthur Scale of Subjective Social Status, was unassociated with a composite measure of income and education used to operationalize OSS. Additionally, SSS and OSS were differentially associated with various types of substance use disorders. Only OSS was associated with whether individuals smoked cigarettes, or the level of nicotine dependence. Conversely, only SSS was associated with drug use severity. Our results shed light on the potential for differential impacts of SSS and OSS among persons with SMI.

Effects of perceived social status and discrimination on hope and empowerment among individuals with serious mental illnesses.

Hope and empowerment are key elements of recovery in the context of serious mental illnesses (SMI). We examined predictors of hope among individuals with SMI and tested a hypothesized path model in which perceived social status and perceived discrimination adversely impact hope, directly and through their impacts on depressive symptoms. Data from 232 individuals with SMI receiving care in public-sector settings were used in both a multiple linear regression (predicting Herth Hope Scale scores), and in path analyses examining both direct and indirect effects of perceived social status (Social Status Ladder) and perceived discrimination (Everyday Discrimination Scale). Depressive symptoms, perceived social status, and perceived discrimination were predictive of hope. Path analyses revealed that perceived social status has a direct effect on hope and empowerment but also impacts hope through its effects on depression. Similarly, perceived everyday discrimination affects hope and empowerment, though this effect is mediated through its effects on depression. Two alternative models and a trimmed hypothesized model did not fit the data or improve fit. These social determinants of mental health should provoke program and policy change to improve mental health and enhance recovery among persons with SMI.

Membrane-type 1 matrix metalloproteinase stimulates cell migration through epidermal growth factor receptor transactivation.

Proteolysis of extracellular matrix proteins by membrane-type 1 matrix metalloproteinase (MT1-MMP) plays a pivotal role in tumor and endothelial cell migration. In addition to its proteolytic activity, several studies indicate that the proinvasive properties of MT1-MMP also involve its short cytoplasmic domain, but the specific mechanisms mediating this function have yet to be fully elucidated. Having previously shown that the serum factor sphingosine 1-phosphate stimulates MT1-MMP promigratory function through a process that involves its cytoplasmic domain, we now extend these findings to show that this cooperative interaction is permissive to cellular migration through MT1-MMP-dependent transactivation of the epidermal growth factor receptor (EGFR). In the presence of sphingosine 1-phosphate, MT1-MMP stimulates EGFR transactivation through a process that is dependent upon the cytoplasmic domain of the enzyme but not its catalytic activity. The MT1-MMP-induced EGFR transactivation also involves G(i) protein signaling and Src activities and leads to enhanced cellular migration through downstream extracellular signal-regulated kinase activation. The present study, thus, elucidates a novel role of MT1-MMP in signaling events mediating EGFR transactivation and provides the first evidence of a crucial role of this receptor activity in MT1-MMP promigratory function. Taken together, our results suggest that the inhibition of EGFR may represent a novel target to inhibit MT1-MMP-dependent processes associated with tumor cell invasion and angiogenesis.

Connexins act as tumor suppressors in three-dimensional mammary cell organoids by regulating differentiation and angiogenesis.

Connexins are tumor suppressors, and human breast connexin 26 (Cx26) and connexin 43 (Cx43) gap junctions are often down-regulated in breast cancer. We previously showed that Cx26 and Cx43 overexpressed in MDA-MB-231 breast cancer cells inhibited tumor growth in vivo but not in two-dimensional cultures. In the current study, we show that overexpression of Cx26 or Cx43 has tumor-suppressive properties in a three-dimensional environment such that they reduced anchorage-independent cell growth and induced partial redifferentiation of three-dimensional organoids of MDA-MB-231 cells. Importantly, the majority of exogenous connexins did not localize to the cell-cell interface or rescue gap junctional intercellular communication (GJIC) as assessed by dye transfer, providing evidence of a GJIC-independent mechanism of mammary tumor suppression. To further elucidate the mechanisms involved in connexin-induced three-dimensional redifferentiation of tumor cells, we examined whether connexin expression has a role in epithelial to mesenchymal transition (EMT). Cx26 and Cx43 reduced cell migration, increased cytokeratin 18 expression, and decreased vimentin levels, indicating a shift from a mesenchymal towards an epithelial phenotype. In addition, we examined the role of connexins in angiogenesis by probing an angiogenesis antibody array with conditioned media from three-dimensional MDA-MB-231 cultures. This revealed that connexin overexpression regulated various angiogenesis-linked proteins. Furthermore, secreted factors from connexin overexpressing cells inhibited endothelial cell tubulogenesis and migration, and xenografts of Cx43 overexpressing MDA-MB-231 cells showed reduced tumor angiogenesis. In summary, Cx26 and Cx43 inhibit the malignant properties of MDA-MB-231 cells via GJIC-independent mechanisms, including regulation of EMT and angiogenesis.