Dissecting TGF-ß-induced glioblastoma invasion with engineered hyaluronic acid hydrogels.

Glioma stem cells (GSCs) contribute to rapid cellular invasion in glioblastoma (GBM). Transforming growth factor-ß (TGF-ß) has been strongly implicated in supporting key GSC functions, including stemness, immunosuppression, and resistance. Although TGF-ß is well-known as a driver of cancer invasion, how TGF-ß supports the invasion of GSCs is not well understood. Progress in understanding mechanisms of TGF-ß-driven invasion in GSC-derived tumors has been limited by an absence of three-dimensional (3D) culture systems that support TGF-ß-stimulated invasion. Here, we show that 3D hyaluronic acid (HA) matrices can address this need. We perform bioinformatic analysis of human glioma datasets, which reveals progressive enrichment of TGF-ß-related gene expression with increasingly aggressive glioma grade and GBM subtype. We then experimentally screen the invasion of a panel of human GSC spheroids through a set of 3D matrix systems, including collagen I, Matrigel, and HA, and find that only HA recapitulates TGF-ß-induced invasion. We then show that GSCs differ in their ability to invade HA in a way that can be predicted from TGF-ß receptor 2 expression and SMAD2 phosphorylation. GSC spheroid invasion depends strongly on the presence of RGD peptides on the HA backbone but is surprisingly independent of matrix metalloprotease degradability. Finally, we demonstrate that TGF-ß stimulates invasion through SMAD-dependent signaling, consistent with recent observations that TGF-ß/SMAD signals drive tumor microtube formation and invasion. Our work supports further development of HA as a matrix platform for dissecting contributions of TGF-ß and other cytokines to GBM invasion and screening of cytokine-dependent invasion in human tumors.

Eligibility for antiamyloid treatment: preparing for disease-modifying therapies for Alzheimer's disease.

BACKGROUND: Disease-modifying therapies (DMTs) for Alzheimer's disease (AD) have early evidence of efficacy. Widespread delivery of DMTs will require major service reconfiguration. Treatment pathways will need to include triaging for eligibility, regular infusions and baseline and follow-up MRI scanning. A critical step in planning is provision of real-world estimates of patients likely to be eligible for triaging, but these are challenging to obtain. METHODS: We performed a retrospective service evaluation of patients attending five memory services across North and East London and a national specialist cognitive disorders service. We examined the likely proportion of patients who would (1) be referred for triaging for DMTs and (2) potentially be suitable for treatments. RESULTS: Data from a total of 1017 patients were included, 517 of whom were seen in community memory services and 500 in a specialist clinic. In the memory services, 367/517 (71%) were diagnosed with possible AD. After exclusions of those in whom cognitive and frailty scores, MRI contraindications or anticoagulant use indicated they would be unlikely to be suitable, an estimated 32% would be eligible for triaging. In the specialist cognitive clinic, where additional investigations are available, 14% of those seen (70/500) would be potentially eligible for treatment. CONCLUSIONS: While a sizeable proportion of patients attending memory clinics may be referred for triaging for DMTs for AD, only a minority are likely to be suitable for these, as demonstrated in patients seen in specialist cognitive services. This will need to be considered when designing pathways for DMT delivery.

Improving Conversations about Parkinson's Dementia.

BACKGROUND: People with Parkinson's disease (PD) have an increased risk of dementia, yet patients and clinicians frequently avoid talking about it due to associated stigma, and the perception that "nothing can be done about it". However, open conversations about PD dementia may allow people with the condition to access treatment and support, and may increase participation in research aimed at understanding PD dementia. OBJECTIVES: To co-produce information resources for patients and healthcare professionals to improve conversations about PD dementia. METHODS: We worked with people with PD, engagement experts, artists, and a PD charity to open up these conversations. 34 participants (16 PD; 6 PD dementia; 1 Parkinsonism, 11 caregivers) attended creative workshops to examine fears about PD dementia and develop information resources. 25 PD experts contributed to the resources. RESULTS: While most people with PD (70%) and caregivers (81%) shared worries about cognitive changes prior to the workshops, only 38% and 30%, respectively, had raised these concerns with a healthcare professional. 91% of people with PD and 73% of caregivers agreed that PD clinicians should ask about cognitive changes routinely through direct questions and perform cognitive tests at clinic appointments. We used insights from the creative workshops, and input from a network of PD experts to co-develop two open-access resources: one for people with PD and their families, and one for healthcare professionals. CONCLUSION: Using artistic and creative workshops, co-learning and striving for diverse voices, we co-produced relevant resources for a wider audience to improve conversations about PD dementia.

Prospective multicenter assessment of patient preferences for properties of gadolinium-based contrast media and their potential socioeconomic impact in a screening breast MRI setting.

OBJECTIVE: It is unknown how patients prioritize gadolinium-based contrast media (GBCM) benefits (detection sensitivity) and risks (reactions, gadolinium retention, cost). The purpose of this study is to measure preferences for properties of GBCM in women at intermediate or high risk of breast cancer undergoing annual screening MRI. METHODS: An institutional reviewed board-approved prospective discrete choice conjoint survey was administered to patients at intermediate or high risk for breast cancer undergoing screening MRI at 4 institutions (July 2018-March 2020). Participants were given 15 tasks and asked to choose which of two hypothetical GBCM they would prefer. GBCMs varied by the following attributes: sensitivity for cancer detection (80-95%), intracranial gadolinium retention (1-100 molecules per 100 million administered), severe allergic-like reaction rate (1-19 per 100,000 administrations), mild allergic-like reaction rate (10-1000 per 100,000 administrations), out-of-pocket cost ($25-$100). Attribute levels were based on published values of existing GBCMs. Hierarchical Bayesian analysis was used to derive attribute "importance." Preference shares were determined by simulation. RESULTS: Response (87% [247/284]) and completion (96% [236/247]) rates were excellent. Sensitivity (importance = 44.3%, 95% confidence interval = 42.0-46.7%) was valued more than GBCM-related risks (mild allergic-like reaction risk (19.5%, 17.9-21.1%), severe allergic-like reaction risk (17.0%, 15.8-18.1%), intracranial gadolinium retention (11.6%, 10.5-12.7%), out-of-pocket expense (7.5%, 6.8-8.3%)). Lower income participants placed more importance on cost and less on sensitivity (p < 0.01). A simulator is provided that models GBCM preference shares by GBCM attributes and competition. CONCLUSIONS: Patients at intermediate or high risk for breast cancer undergoing MRI screening prioritize cancer detection over GBCM-related risks, and prioritize reaction risks over gadolinium retention. KEY POINTS: • Among women undergoing annual breast MRI screening, cancer detection sensitivity (attribute "importance," 44.3%) was valued more than GBCM-related risks (mild allergic reaction risk 19.5%, severe allergic reaction risk 17.0%, intracranial gadolinium retention 11.6%, out-of-pocket expense 7.5%). • Prospective four-center patient preference data have been incorporated into a GBCM choice simulator that allows users to input GBCM properties and calculate patient preference shares for competitor GBCMs. • Lower-income women placed more importance on out-of-pocket cost and less importance on cancer detection (p < 0.01) when prioritizing GBCM properties.

Eating pathology among adolescent girls with attention-deficit/hyperactivity disorder.

The authors investigated prospectively assessed eating pathology (body image dissatisfaction and bulimia nervosa symptoms) among an ethnically and socioeconomically diverse sample of adolescent girls with attention-deficit/hyperactivity disorder-combined type (ADHD-C; n=93), ADHD-inattentive type (ADHD-I; n=47), and a comparison group (n=88). The sample, initially ages 6-12 years, participated in a 5-year longitudinal study (92% retention rate). After statistical control of relevant covariates, girls with ADHD-C at baseline showed more eating pathology at follow-up than did comparison girls; girls with ADHD-I were intermediate between these two groups. Baseline impulsivity symptoms, as opposed to hyperactivity and inattention, best predicted adolescent eating pathology. With statistical control of ADHD, baseline peer rejection and parent- child relationship problems also predicted adolescent eating pathology. The association between punitive parenting in childhood and pathological eating behaviors in adolescence was stronger for girls with ADHD than for comparison girls. Results are discussed in terms of the expansion of longitudinal research on ADHD to include female-relevant domains of impairment, such as eating pathology.

Recency effects in HIV-associated dementia are characterized by deficient encoding.

The aim of the present study was to investigate the nature and cognitive mechanisms of serial position learning effects in HIV-associated dementia (HAD). Participants were 16 persons with HAD, 50 non-demented persons with HIV-infection, and 50 demographically comparable HIV-seronegative participants. HAD participants, relative to both comparison groups, exhibited reduced middle region (p<0.01) and elevated recency region (p<0.05) recall on the Hopkins Verbal Learning Test-Revised, but no primacy region effect (p>0.10). On recognition testing, the HAD group was impaired in discriminating targets from distractors (p<0.01) in all three serial position regions; however, they were not impaired on measures of retrieval (p>0.10) within these same regions. In sum, HAD participants relied disproportionately on recency regions of the list, indicating a passive recall style of echoing only the words within their auditory attention span. Interestingly, HAD participants did not evidence significant improvement on measures of recognition, a finding that suggests that the serial position effects are most consistent with a primary encoding deficit.

Screening for major depression in persons with HIV infection: the concurrent predictive validity of the Profile of Mood States Depression-Dejection Scale.

Major Depressive Disorder (MDD) is among the most prevalent but underdiagnosed psychiatric disorders in persons with HIV infection. Given the known adverse impact of comorbid MDD on HIV disease progression and health-related quality of life, it is important both for research and for efficient, effective clinical care, to validate existing screening measures that may discriminate between MDD and the somatic symptoms of HIV (such as fatigue). In the current study, we evaluated the concurrent predictive validity of the Profile of Mood States (POMS) Depression-Dejection scale in detecting current MDD in 310 persons with HIV infection. The Structured Clinical Interview for DSM-IV (SCID) diagnosis of MDD and the Cognitive-Affective scale from the Beck Depression Inventory (BDI-CA) served as comparative diagnostic and severity measures of depression, respectively. Results demonstrated that the POMS Depression-Dejection scale accurately classified persons with and without MDD SCID diagnoses, with an overall hit rate of 80%, sensitivity of 55%, specificity of 84%, and negative predictive power of 91% using a recommended cutpoint of 1.5 standard deviations above the normative mean. Moreover, the POMS performed comparably to the BDI-CA in classifying MDD. Findings support the predictive validity of the POMS Depression-Dejection scale as a screening instrument for MDD in persons with HIV disease.