RNA-Seq Analysis of Extradomain A and Extradomain B Fibronectin as Extracellular Matrix Markers for Cancer.

Alternatively spliced forms of fibronectin, called oncofetal fibronectin, are aberrantly expressed in cancer, with little to no expression in normal tissue, making them attractive biomarkers to exploit for tumor-targeted therapeutics and diagnostics. While prior studies have explored oncofetal fibronectin expression in limited cancer types and limited sample sizes, no studies have performed a large-scale pan-cancer analysis in the context of clinical diagnostics and prognostics to posit the utility of these biomarkers across multiple cancer types. In this study, RNA-Seq data sourced from the UCSC Toil Recompute project were extracted and analyzed to determine the correlation between the expression of oncofetal fibronectin, including extradomain A and extradomain B fibronectin, and patient diagnosis and prognosis. We determined that oncofetal fibronectin is significantly overexpressed in most cancer types relative to corresponding normal tissues. In addition, strong correlations exist between increasing oncofetal fibronectin expression levels and tumor stage, lymph node activity, and histological grade at the time of diagnosis. Furthermore, oncofetal fibronectin expression is shown to be significantly associated with overall patient survival within a 10-year window. Thus, the results presented in this study suggest oncofetal fibronectin as a commonly upregulated biomarker in cancer with the potential to be used for tumor-selective diagnosis and treatment applications.

Prediction of violence: Part contagious disease, part unpredictable individual: Is a public health assessment approach an additional option and at what cost?

On a population level, violence shares many similarities with communicable disease states and other public health issues. Therefore, there has been a push to apply public health interventions to the problem of societal violence and for some to even identify violence as the product of a disease state (e.g., changed brain). This conceptualization could lead to the development of new risk violence assessment tools and approaches predicated more on the public health model rather than existing instruments that have often been based on inpatient mental health populations or incarcerated populations. In this article, we will discuss aspects of legal obligation for risk violence "prediction/stratification", the application of the public health communicable disease model to violence, as well as identify why it may not always translate to the individual with whom a clinician or forensic mental health evaluator interacts.

The Therapeutic Impact of Plant-Based and Nutritional Supplements on Anxiety, Depressive Symptoms and Sleep Quality among Adults and Elderly: A Systematic Review of the Literature.

BACKGROUND: The emerging research in the literature continues to forecast a drastic and alarming increase in negative mental health and sleep health outcomes among populations, especially after the COVID-19 pandemic, which significantly influenced people's way of life. With mental health pharmaceutical interventions continuing to be stigmatized and inaccessible among populations, natural supplements provide an opportunity for intervention. OBJECTIVE: This study sought to conduct a systematic review of the literature on the most recent comprehensive evidence for which nutritional supplements have the greatest therapeutic impact on symptoms of anxiety, depression, and insomnia. METHODS: A systematic search of the literature, utilizing several databases, including PubMed and Web of Science, was conducted on 29 April 2022. We used developed keywords and MeSH terms for the search. The study eligibility criteria included (1) a randomized control trial; (2) investigating a plant-based therapeutic or natural supplement as the intervention; (3) measuring at least one health outcome of the following: anxiety symptoms, depressive symptoms, or sleep health outcomes; (4) utilizing validated measurement tools to measure the outcome of interest; (5) written in the English language; (6) peer reviewed; and (7) focused on adults and elderly populations. MAIN RESULTS: Following the PRISMA guidelines, 76 studies were included in this review. We used the revised Risk of Bias tool (RoB2) to assess the quality of all included randomized control trials. A qualitative data synthesis was conducted. Overall, we found several valuable insights from the evidence in the literature, including evidence that demonstrates the benefits of probiotics and vitamin B complexes on anxiety symptoms, depressive symptoms, and sleep quality. Implication of Key Findings: This review provides the most updated findings in the literature on the topic, including an abundance of research that was published in the past 5 years. Given the expected rise in negative mental and sleep health outcomes following the pandemic, the supplements and therapeutics identified in this study should be the target of intervention measures to increase their accessibility and affordability and allow them to be incorporated into clinical guidelines of treatment. PROSPERO registration number: CRD42022361130.

Effective gene therapy of Stargardt disease with PEG-ECO/pGRK1-ABCA4-S/MAR nanoparticles.

Stargardt disease (STGD) is the most common form of inherited retinal genetic disorders and is often caused by mutations in ABCA4. Gene therapy has the promise to effectively treat monogenic retinal disorders. However, clinically approved adeno-associated virus (AAV) vectors do not have a loading capacity for large genes, such as ABCA4. Self-assembly nanoparticles composed of (1-aminoethyl)iminobis[N-(oleoylcysteinyl-1-amino-ethyl)propionamide (ECO; a multifunctional pH-sensitive/ionizable amino lipid) and plasmid DNA produce gene transfection comparable with or better than the AAV2 capsid. Stable PEG-ECO/pGRK1-ABCA4-S/MAR nanoparticles produce specific and prolonged expression of ABCA4 in the photoreceptors of Abca4 -/- mice and significantly inhibit accumulation of toxic A2E in the eye. Multiple subretinal injections enhance gene expression and therapeutic efficacy with an approximately 69% reduction in A2E accumulation in Abca4 -/- mice after 3 doses. Very mild inflammation was observed after multiple injections of the nanoparticles. PEG-ECO/pGRK1-ABCA4-S/MAR nanoparticles are a promising non-viral mediated gene therapy modality for STGD type 1 (STGD1).

Manganese(II) EOB-Pyclen Diacetate for Liver-Specific MRI.

MRI is increasingly utilized for the diagnosis of liver disease and focal liver lesions. Although liver-targeted gadolinium-based contrast agents (GBCAs) have high efficacy, there continue to be safety concerns regarding release of toxic Gd(III) ions. Herein, Mn(EOB-PC2A) is synthesized as a nongadolinium alternative for liver-specific MRI. Mn(EOB-PC2A) has an r1 relaxivity of 2.8 mM-1 s-1 in Dulbecco's phosphate-buffered saline (DPBS) and 5.9 mM-1 s-1 in saline containing human serum albumin at 1.5 T. It has a strong uptake in hepatocytes with minimal toxicity and demonstrated robust liver-specific enhancement at a dose of 60 µmol/kg. Mn(EOB-PC2A) is a promising liver-specific contrast agent for liver MRI.

Magnetic resonance molecular imaging of extradomain B fibronectin enables detection of pancreatic ductal adenocarcinoma metastasis.

Extradomain-B Fibronectin (EDB-FN) is an oncomarker that can be visualized with magnetic resonance molecular imaging (MRMI) to detect pancreatic ductal adenocarcinoma (PDAC) metastasis. In this study, we sought to assess the expression of EDB-FN in clinical samples of PDAC and to evaluate MRMI of PDAC metastasis with an EDB-FN-specific gadolinium-based contrast agent (MT218) in an orthotopic KPC-GFP-Luc mouse model. EDB-FN expression was evaluated in PDAC tissue samples through immunohistochemistry. RNA-Seq data obtained from the GEPIA2 project was evaluated to demonstrate EDB-FN expression in large patient cohorts. FLASH-3D MRI at 3 T of the KPC-GFP-Luc metastasis model was performed following injection of MT218. Tumor enhancement in MR images was correlated to postmortem distribution of KPC-GFP-Luc tumors using fluorescent and bright-field cryo-imaging and anatomical landmarks. EDB-FN immunohistochemical staining scores of human metastatic tumor stroma, (2.17 ± 0.271), metastatic tumor parenchyma (2.08 ± 0.229), primary tumor stroma (1.61 ± 0.26), and primary tumor parenchyma (1.61 ± 0.12) were significantly (p < 0.0001) higher than normal pancreas stroma (0.14 ± 0.10) and normal pancreas parenchyma (0.14 ± 0.14). EDB-FN mRNA expression in tumors is 4.98 log2(TPM + 1) and 0.18 log2(TPM + 1) in normal tissue (p < 0.01). A mouse model of EDB-FN rich PDAC metastasis exhibited T1-weighted contrast to noise (CNR) changes of 21.80 ± 4.34 in perimetastatic regions and 8.38 ± 0.79 in metastatic regions identified through cryo-imaging, significantly higher (p < 0.05) than CNR changes found in normal liver (-6.43 ± 0.92), mesentery (2.24 ± 0.92), spleen (-3.06 ± 2.38) and intestine (1.08 ± 2.15). We conclude that EDB-FN is overexpressed in metastatic and primary PDAC tumors and MRMI with MT218 enables the detection of metastatic and perimetastatic tissues.

Efficacy of Targeted ECO/miR-200c Nanoparticles for Modulating Tumor Microenvironment and Treating Triple Negative Breast Cancer as Non-invasively Monitored by MR Molecular Imaging.

PURPOSE: To investigate the effectiveness of targeted ECO/miR-200c in modulating tumor microenvironment and treating triple negative breast cancer (TNBC) using non-invasive magnetic resonance molecular imaging (MRMI) of extradomain B fibronectin (EDB-FN) with a targeted MRI contrast agent. METHODS: MDA-MB-231 and Hs578T TNBC cells were transfected with RGD-PEG-ECO/miR-200c. Invasive and migratory potential was evaluated using transwell, scratch wound, and spheroid formation assays. Athymic nude mice bearing orthotopic MDA-MB-231 and Hs578T xenografts were treated with weekly i.v. injection of RGD-PEG-ECO/miR-200c nanoparticles at 1.0 mg/kg/week RNA for 6 weeks. MRMI of EDB-FN was performed using a targeted contrast agent MT218 [ZD2-N3-Gd(DO3A)] on a 3 T MRS 3000 scanner. T1-weighted images were acquired following intravenous injection of MT218 at dose of 0.1 mmol/kg using a fast spin echo axial sequence with respiratory gating. RESULTS: Systemic administration of RGD-PEG-ECO/miR-200c nanoparticles in mice bearing orthotopic TNBC xenografts significantly suppressed tumor progression without toxic side-effects. MRMI with MT218 revealed that the treatment significantly suppressed tumor proliferation as compared to the control. MRMI also showed that the miR-200c treatment altered tumor microenvironment by reducing EDB-FN expression, as evidenced by decreased contrast enhancement in both MDA-MB-231 and Hs578T tumors. The reduction of EDB-FN was confirmed by immunohistochemistry. CONCLUSIONS: Targeted delivery of miR-200c with RGD-PEG-ECO/miR-200c nanoparticles effectively modulates tumor microenvironment and suppresses TNBC proliferation in animal models. MRMI of tumor EDB-FN expression is effective to non-invasively monitor tumor response and therapeutic efficacy of RGD-PEG-ECO/miR-200c nanoparticles in TNBC.

Florida Law Enforcement Policies for and Experience With Tarasoff-Like Reporting.

Mandatory duty to warn law enforcement for mental health professionals in Florida took effect on July 1, 2019, as part of the recommendations from the Marjory Stoneman Douglas School (Parkland) Shooting Commission's report. Prior to this, Florida had been a permissive Tarasoff state. Although this change was intended to promote public safety, there is scant literature on the interactions between mental health providers and law enforcement related to Tarasoff situations. The objective of this study is to determine the degree to which Florida law enforcement agencies have knowledge, experience, and policies dealing with a serious threat made by a patient. An invitation to participate in a survey was distributed to police departments, sheriffs' offices, and 911 stations using email and traditional paper mail. The response rate was 11 percent (47 of 416) to an emailed questionnaire and 22 percent (82 of 369) to a paper-based follow-up survey. The surveys were completed by 31 percent (129 of 416) of potential respondents. Between 80 and 90 percent of all agencies have policies and procedures on what to do if a warning call from a mental health provider is received, which, for the majority of respondents, was the same policy as if notified about a suicidal individual.

Preclinical Assessment of the Effectiveness of Magnetic Resonance Molecular Imaging of Extradomain-B Fibronectin for Detection and Characterization of Oral Cancer.

PURPOSE: Oral squamous cell carcinoma (OSCC) has not seen a substantial improvement in patient survival despite therapeutic advances, making accurate detection and characterization of the disease a clinical priority. Here, we aim to demonstrate the effectiveness of magnetic resonance imaging (MRI) with the targeted MRI contrast agent MT218 specific to extradomain-B fibronectin (EDB-FN) in the tumor microenvironment for detection and characterization of aggressive OSCC tumors. PROCEDURES: EDB-FN expression was evaluated in human normal tongue and OSCC specimens with immunohistochemistry. Invasiveness of human CAL27, HSC3, and SCC4 OSCC cells was analyzed with spheroid formation and transwell assays. EDB-FN expression in the cells was analyzed with semiquantitative real-time PCR, western blotting, and a peptide binding study with confocal microscopy. Contrast-enhanced MRI with MT218 was performed on subcutaneous OSCC mouse models at a dose of 0.04 mmol/kg, using gadoteridol (0.1 mmol/kg) as a control. RESULTS: Strong EDB-FN expression was observed in human untreated primary and metastatic OSCC, reduced expression in treated OSCC, and little expression in normal tongue tissue. SCC4 and HSC3 cell lines demonstrated high invasive potential with high and moderate-EDB-FN expression, respectively, while CAL27 showed little invasive potential and low-EDB-FN expression. In T1-weighted MRI, MT218 produced differential contrast enhancement in the subcutaneous tumor models in correlation with EDB-FN expression in the cancer cells. Enhancement in the high-EDB-FN tumors was greater with MT218 at 0.04 mmol/kg than gadoteridol at 0.1 mmol/kg. CONCLUSIONS: The results suggest EDB-FN has strong potential as an imageable biomarker for aggressive OSCC. MRMI results demonstrate the effectiveness of MT218 and the potential for differential diagnostic imaging of oral cancer for improving the management of the disease.

Effective MR Molecular Imaging of Triple Negative Breast Cancer With an EDB-Fibronectin-Specific Contrast Agent at Reduced Doses.

MR molecular imaging (MRMI) of abundant oncogenic biomarkers in tumor microenvironment has the potential to provide precision cancer imaging in high resolution. Extradomain-B fibronectin (EDB-FN) is an oncogenic extracellular matrix protein, highly expressed in aggressive triple negative breast cancer. A targeted macrocyclic gadolinium-based contrast agent (GBCA) ZD2-N3-Gd(HP-DO3A) (MT218), specific to EDB-FN, was developed for MRMI of aggressive breast cancer. The effectiveness of different doses of MT218 for MRMI was tested in MDA-MB-231 and Hs578T human triple negative breast cancer models. At clinical dose of 0.1 and subclinical dose of 0.04 mmol Gd/kg, MT218 rapidly bound to the extracellular matrix EDB-FN and produced robust tumor contrast enhancement in both the tumor models, as early as 1-30 min post-injection. Substantial tumor enhancement was also observed in both the models with MT218 at doses as low as 0.02 mmol Gd/kg, which was significantly better than the clinical agent Gd(HP-DO3A) at 0.1 mmol Gd/kg. Little non-specific enhancement was observed in the normal tissues including liver, spleen, and brain for MT218 at all the tested doses, with renal clearance at 30 min. These results demonstrate that MRMI with reduced doses of MT218 is safe and effective for sensitive and specific imaging of aggressive breast cancers.

Prescribing for Women in Corrections.

Prescribing for women in jails and prisons requires special consideration and should be informed by extant evidence. Incarcerated women have higher rates of mental illness than both females in the community and incarcerated men. Medication administration concerns that may disproportionately affect female prisoners include drug-drug interactions with contraceptives, intermittent dosing schedules, and concerns about metabolic side effects. Further, pregnancy, lactation, and menopause may all affect medication choices. Incarcerated women frequently have comorbid mental illness, substance use disorders, and personality disorders. Finally, specific disorders, such as posttraumatic stress disorder, are more common in this population and merit special consideration for recognition and treatment.

Formulation of Biocompatible Targeted ECO/siRNA Nanoparticles with Long-Term Stability for Clinical Translation of RNAi.

Nanoparticle based siRNA formulations often suffer from aggregation and loss of function during storage. We in this study report a frozen targeted RGD-polyethylene glycol (PEG)-ECO/siß3 nanoparticle formulation with a prolonged shelf life and preserved nanoparticle functionality. The targeted RGD-PEG-ECO/siß3 nanoparticles are formed by step-wised self-assembly of RGD-PEG-maleimide, ECO, and siRNA. The nanoparticles have a diameter of 224.5 ± 9.41 nm and a zeta potential to 45.96 ± 3.67 mV in water and a size of 234.34 ± 3.01 nm and a near neutral zeta potential in saline solution. The addition of sucrose does not affect their size and zeta potential and substantially preserves the integrity and biological activities of frozen and lyophilized formulations of the targeted nanoparticles. The frozen formulation with as low as 5% sucrose retains nanoparticle integrity (90% siRNA encapsulation), size distribution (polydispersity index [PDI] ≤20%), and functionality (at least 75% silencing efficiency) at -80°C for at least 1 year. The frozen RGD-PEG-ECO/siß3 nanoparticle formulation exhibits excellent biocompatibility, with no adverse effects on hemocompatibility and minimal immunogenicity. As RNAi holds the promise in treating the previously untreatable diseases, the frozen nanoparticle formulation with the low sucrose concentration has the potential to be a delivery platform for clinical translation of RNAi therapeutics.

Professional Boundaries in Corrections.

Boundary violations occurring in corrections settings require special attention. There is a unique relationship between officers and inmates, governed by policies and procedures as well as ethics in general (e.g., the lack of ability for a person in a controlled environment to consent to a relationship due to power imbalance). Recent high-profile cases between corrections officers and inmates demonstrate the complexities inherent in these relationships. We examine several recent cases and offer analysis of the factors leading to these dangerous encounters. We discuss how a special relationship develops between a corrections employee and an inmate and how that can lead to blackmail, the introduction of contraband to the prison, or other illegal activity. It is easy to state that one should not engage in sexual encounters, but it is harder to discuss and identify feelings that develop in correctional settings, such as transference and counter-transference feelings in a therapeutic relationship. Lessons of professionalism from the doctor-patient relationship parallel the relationships between officers and inmates.

Involuntary Treatment of Psychosis in Pregnancy.

When a patient with acute psychosis refuses antipsychotic medication despite a clear need for treatment, involuntary medication is often considered. When the patient is both pregnant and acutely unwell, an additional layer of analysis enters the picture. This analysis then also includes the health of the mother and fetus, rights of the mother and fetus, and whose rights take precedence when choosing treatment options in event of a conflict. Antipsychotic agents are frequently the medications prescribed as involuntary treatment. Typical and atypical antipsychotic agents are often used in both emergent and nonemergent situations during pregnancy. Despite a lack of randomized, double-blind, controlled, prospective studies in pregnancy, available data regarding the safety of antipsychotic agents in pregnancy are relatively reassuring. At the same time, the risks of untreated psychosis, for both the mother and the fetus, are not negligible. Such cases merit ethics-related and legal analyses. Forensic psychiatrists involved in such cases need to consider the patient's capacity to make medical decisions and be able to discuss the potential risks, benefits, and alternatives with patients and in court, as part of initiation of involuntary treatment.

Challenges and Limitations to Treating ADHD in Incarcerated Populations.

An often underappreciated and hard-to-treat condition in correctional institutions is attention-deficit/hyperactivity disorder (ADHD). Although there are many effective psychopharmacologic treatments for ADHD, such as various formulations of amphetamines, many physicians are hesitant to prescribe controlled stimulants in correctional settings because of concerns about abuse and safety. Although nonstimulant alternatives are available, they are generally seen as less effective than stimulants. However, there are many unique factors regarding corrections populations and their responses to treatment, which makes it difficult to know what the ideal treatment regimen would be for this population. We review the standard treatments for ADHD, for prescribing in correctional institutions, barriers to using medications for off-label treatment of ADHD, and suggest future research that could better guide correctional treatment staff on how to approach patients with ADHD.

Pregnant Women and the Use of Corrections Restraints and Substance Use Commitment.

Recent evolving trends in the United States legal system regarding how policies and laws are applied to pregnant women include concerns over the use of restraints or shackles in pregnant inmates and forced treatment or commitment of pregnant women for substance abuse. These topics raise many questions, such as: how violent are women, particularly pregnant women; what are the informed consent and treatment implications; and who is at risk of harm? In addition, questions have been raised regarding maternal versus fetal rights, especially when the mother uses substances during a pregnancy. We review legal decisions and organizational position statements and highlight ethics-related concerns.

Psychopathology in a Galaxy Far, Far Away: the Use of Star Wars' Dark Side in Teaching.

Star Wars is well known, timeless, universal, and incorporated into shared culture. Trainees have grown up with the movies, and based on their enduring popularity, attending psychiatrists are likely to have seen them too. This article highlights psychopathology from the Dark Side of Star Wars films which can be used in teaching. These include as follows: borderline and narcissistic personality traits, psychopathy, PTSD, partner violence risk, developmental stages, and of course Oedipal conflicts.