Targeting tumour metabolism in melanoma to enhance response to immune checkpoint inhibition: A balancing act.

Immune checkpoint inhibition has transformed the treatment landscape of advanced melanoma and long-term survival of patients is now possible. However, at least half of the patients do not benefit sufficiently. Metabolic reprogramming is a hallmark of cancer cells and may contribute to both tumour growth and immune evasion by the tumour. Preclinical studies have indeed demonstrated that modulating tumour metabolism can reduce tumour growth while improving the functionality of immune cells. Since metabolic pathways are commonly shared between immune and tumour cells, it is essential to understand how modulating tumour metabolism in patients influences the intricate balance of pro-and anti-tumour immune effects in the tumour microenvironment. The key question is whether modulating tumour metabolism can inhibit tumour cell growth as well as facilitate an anti-tumour immune response. Here, we review current knowledge on the effect of tumour metabolism on the immune response in melanoma. We summarise metabolic pathways in melanoma and non-cancerous cells in the tumour microenvironment and discuss models and techniques available to study the metabolic-immune interaction. Finally, we discuss clinical use of these techniques to improve our understanding of how metabolic interventions can tip the balance towards a favourable, immune permissive microenvironment in melanoma patients.

Device Closure or Antithrombotic Therapy After Cryptogenic Stroke in Elderly Patients With a High-Risk Patent Foramen Ovale.

BACKGROUND AND PURPOSE: In young patients (aged 18-60 years) with patent foramen ovale (PFO)-associated stroke, percutaneous closure has been found to be useful for preventing recurrent ischemic stroke or transient ischemic attack (TIA). However, it remains unknown whether PFO closure is also beneficial in older patients. METHODS: Patients aged ≥60 years who had a cryptogenic stroke and PFO from ten hospitals in South Korea were included. The effect of PFO closure plus medical therapy over medical therapy alone was assessed by a propensity-score matching method in the overall cohort and in those with a high-risk PFO, characterized by the presence of an atrial septal aneurysm or a large shunt. RESULTS: Out of the 437 patients (mean age, 68.1), 303 (69%) had a high-risk PFO and 161 (37%) patients underwent PFO closure. Over a median follow-up of 3.9 years, recurrent ischemic stroke or TIA developed in 64 (14.6%) patients. In the propensity score-matched cohort of the overall patients (130 pairs), PFO closure was associated with a significantly lower risk of a composite of ischemic stroke or TIA (hazard ratio [HR]: 0.45; 95% confidence interval [CI]: 0.24-0.84; P=0.012), but not for ischemic stroke. In a subgroup analysis of confined to the high-risk PFO patients (116 pairs), PFO closure was associated with significantly lower risks of both the composite of ischemic stroke or TIA (HR: 0.40; 95% CI: 0.21-0.77; P=0.006) and ischemic stroke (HR: 0.47; 95% CI: 0.23-0.95; P=0.035). CONCLUSION: Elderly patients with cryptogenic stroke and PFO have a high recurrence rate of ischemic stroke or TIA, which may be significantly reduced by device closure.

A Multimodal Ensemble Deep Learning Model for Functional Outcome Prognosis of Stroke Patients.

BACKGROUND AND PURPOSE: The accurate prediction of functional outcomes in patients with acute ischemic stroke (AIS) is crucial for informed clinical decision-making and optimal resource utilization. As such, this study aimed to construct an ensemble deep learning model that integrates multimodal imaging and clinical data to predict the 90-day functional outcomes after AIS. METHODS: We used data from the Korean Stroke Neuroimaging Initiative database, a prospective multicenter stroke registry to construct an ensemble model integrated individual 3D convolutional neural networks for diffusion-weighted imaging and fluid-attenuated inversion recovery (FLAIR), along with a deep neural network for clinical data, to predict 90-day functional independence after AIS using a modified Rankin Scale (mRS) of 3-6. To evaluate the performance of the ensemble model, we compared the area under the curve (AUC) of the proposed method with that of individual models trained on each modality to identify patients with AIS with an mRS score of 3-6. RESULTS: Of the 2,606 patients with AIS, 993 (38.1%) achieved an mRS score of 3-6 at 90 days post-stroke. Our model achieved AUC values of 0.830 (standard cross-validation [CV]) and 0.779 (time-based CV), which significantly outperformed the other models relying on single modalities: b-value of 1,000 s/mm2 (P<0.001), apparent diffusion coefficient map (P<0.001), FLAIR (P<0.001), and clinical data (P=0.004). CONCLUSION: The integration of multimodal imaging and clinical data resulted in superior prediction of the 90-day functional outcomes in AIS patients compared to the use of a single data modality.

Patent Foramen Ovale Closure in Older Patients With Stroke: Patient Selection for Trial Feasibility.

BACKGROUND AND OBJECTIVES: Whether patent foramen ovale (PFO) closure benefits older patients with PFO and cryptogenic stroke is unknown because randomized controlled trials (RCTs) have predominantly enrolled patients younger than 60 years of age. Our objective was to estimate anticipated effects of PFO closure in older patients to predict the numbers needed to plan an RCT. METHODS: Effectiveness estimates are derived from major observational studies (Risk of Paradoxical Embolism [RoPE] Study and Oxford Vascular Study, together referred to as the "RoPE-Ox" database) and all 6 major RCTs (Systematic, Collaborative, PFO Closure Evaluation [SCOPE] Consortium). To estimate stroke recurrence risk, observed outcomes were calculated for patients older than 60 years in the age-inclusive observational databases (n = 549). To estimate the reduction in the rate of recurrent stroke associated with PFO closure vs medical therapy based on the RoPE score and the presence of high-risk PFO features, a Cox proportional hazards regression model was developed on the RCT data in the SCOPE database (n = 3,740). These estimates were used to calculate sample sizes required for a future RCT. RESULTS: Five-year risk of stroke recurrence using Kaplan-Meier estimates was 13.7 (95% CI 10.5-17.9) overall, 14.9% (95% CI 10.2-21.6) in those with high-risk PFO features. Predicted relative reduction in the event rate with PFO closure was 12.9% overall, 48.8% in those with a high-risk PFO feature. Using these estimates, enrolling all older patients with cryptogenic stroke and PFO would require much larger samples than those used for prior PFO closure trials, but selectively enrolling patients with high-risk PFO features would require totals of 630 patients for 90% power and 471 patients for 80% power, with an average of 5 years of follow-up. DISCUSSION: Based on our projections, anticipated effect sizes in older patients with high-risk features make a trial in these subjects feasible. With lengthening life expectancy in almost all regions of the world, the utility of PFO closure in older adults is increasingly important to explore.

Distal normal vessel diameter might be associated with silent brain infarcts after stenting for symptomatic carotid stenosis.

BACKGROUND: Carotid artery stenting (CAS) has been the standard treatment for carotid stenosis because it is less invasive; however, the risk of periprocedural thromboembolism is high. We investigated the predictors for silent brain infarcts (SBIs), focusing on embolic protection in CAS. METHODS: This study was single-center retrospective study, and we obtained baseline demographics and clinical, laboratory, and periprocedural variables of patients who underwent CAS. Also, methods used for embolic protection (no EPD, distal EPD, or proximal balloon guiding catheter) during CAS were obtained. Distal normal vessel diameter was defined as the diameter of cervical internal carotid artery where the artery wall becomes parallel. Diffusion-weighted imaging was performed before and after procedure to detect SBIs. The primary outcome was stented territory SBIs, and the secondary outcomes were any territories SBIs and stented territory SBIs in cases with EPD. RESULTS: A total of 196 CAS procedures with mean age 69.1 ± 9.9 years were included. After CAS, stented territory SBIs occurred in 53 (27.0 %) cases and any territories SBIs in 60 (30.6 %) cases. Univariable analyses revealed that distal normal vessel diameter (odds ratio = 1.71, 95 % confidence interval = 1.20-2.43, P = 0.003) was associated with the occurrence of stented territory SBIs after CAS. After adjusting for potential variables, larger distal normal vessel diameter (1.61 [1.10-2.36], P = 0.014) increased the occurrence of SBIs after CAS. Consistent results were obtained when the outcome was any territories SBIs or stented territory SBIs in cases with EPD. CONCLUSIONS: Distal normal vessel diameter was a predictor for the occurrence of SBI after CAS. The passable pore size of EPDs may vary depending on vessel diameter, and may impact the occurrence of SBIs.

Psychotic Symptoms in Patients With Major Neurological Diseases.

Neurological diseases often manifest with neuropsychiatric symptoms such as depression, emotional incontinence, anger, apathy and fatigue. In addition, affected patients may also experience psychotic symptoms such as hallucinations and delusions. Various factors contribute to the development of psychotic symptoms, and the mechanisms of psychosis are similar, but still differ among various neurological diseases. Although psychotic symptoms are uncommon, and have been less well investigated, they may annoy patients and their families as well as impair the patients' quality of life and increase the caregiver burden. Therefore, we need to appropriately identify and treat these psychotic symptoms in patients with neurological diseases.

Early apixaban administration considering the size of infarction and functional outcome in acute ischemic stroke.

Background and purpose: Atrial fibrillation-related stroke (AF-stroke) is associated with an adverse prognosis, characterized by a high incidence of progression, recurrence, and hemorrhagic transformation. Our study aims to investigate the potential benefits of stratified early administration of apixaban, taking into account infarct size during the acute phase, in order to enhance functional outcomes. Methods: We conducted this study at a tertiary referral stroke center, enrolling acute AF-stroke patients who received apixaban during the acute phase. Infarct size was categorized as small, medium, or large based on diffusion-weighted imaging. Patients were divided into two groups: standard initiation (apixaban initiation based on guidelines, i.e., small: 4 days, medium: 7 days, large: 14 days after stroke) and early initiation (initiation before guideline recommendations) groups. We compared favorable outcomes (modified Rankin scale score ≤ 2) at 3 months post-stroke, stroke progression, early recurrence, and symptomatic hemorrhagic transformation (sHT) between the groups. Results: Out of 299 AF-stroke patients, 170 (56.9%) were in the early initiation group. A favorable outcome was observed in 105 (61.8%) patients in the early initiation group and 62 (48.1%) patients in the standard initiation group (p = 0.019). Stroke progression or early recurrence occurred less frequently in the early initiation group (4.7% versus 13.2%, p = 0.007). Nevertheless, no difference in sHT was noted between the groups. Early initiation of apixaban was independently associated with favorable outcomes (odds ratio: 2.75, 95% confidence interval: 1.44-5.28, p = 0.002). Conclusion: Our findings suggest that early initiation of apixaban, tailored to infarct size, could serve as a viable strategy to enhance functional outcomes. This approach may potentially decrease stroke progression and early recurrence without elevating the risk of sHT.

Effect of Intravenous Thrombolysis Prior to Mechanical Thrombectomy According to the Location of M1 Occlusion.

BACKGROUND AND PURPOSE: The additive effects of intravenous thrombolysis (IVT) before mechanical thrombectomy (MT) remain unclear. We aimed to investigate the efficacy and safety of IVT prior to MT depending on the location of M1 occlusion. METHODS: We reviewed the cases of patients who underwent MT for emergent large-vessel occlusion of the M1 segment. Baseline characteristics as well as clinical and periprocedural variables were compared according to the location of M1 occlusion (i.e., proximal and distal M1 occlusion). The main outcome was the achievement of functional independence (modified Rankin Scale score, 0-2) at 3 months after stroke. The main outcomes were compared between the proximal and distal groups based on the use of IVT before MT. RESULTS: Among 271 patients (proximal occlusion, 44.6%; distal occlusion, 55.4%), 33.9% (41/121) with proximal occlusion and 24.7% (37/150) with distal occlusion underwent IVT prior to MT. Largeartery atherosclerosis was more common in patients with proximal M1 occlusion; cardioembolism was more common in those with distal M1 occlusion. In patients with proximal M1 occlusion, there was no association between IVT before MT and functional independence. In contrast, there was a significant association between the use of IVT prior to MT (odds ratio=5.30, 95% confidence interval=1.56-18.05, P=0.007) and functional independence in patients with distal M1 occlusion. CONCLUSION: IVT before MT was associated with improved functional outcomes in patients with M1 occlusion, especially in those with distal M1 occlusion but not in those with proximal M1 occlusion.

Anti-counterfeiting fiber system with near-infrared wavelength selectivity based on photothermal and thermochromic dyes.

Anti-counterfeiting (ACF) technology plays a crucial role in distinguishing genuine products from counterfeits, as well as in identity verification. Moreover, it serves as a protective measure for safeguarding the rights of individuals, companies, and governments. In this study, a high-level ACF technology was developed using a color-conversion system based on the photothermal effect of near-infrared (NIR) wavelengths. Diimonium dye (DID), which is a photothermal dye, was selected because it is an NIR absorbing dye with over 98% transparency in the visible light (vis) region. Due to the photothermal properties of DID, the temperature increased to approximately 65 °C at 1064 nm and 39 °C at 808 nm, respectively. Additionally, we employed a donor-acceptor Stenhouse adduct dye, a thermochromic dye, which exhibits reversible color change due to heat (red color) and light (colorless). Our ACF technology was applied to the brand-protecting fiber utilizing the difference in photothermal temperature according to the NIR wavelength. We successfully implemented anti-counterfeit clothing using alphabet K labels that could distinguish between genuine and counterfeit products by irradiating with specific NIR wavelengths.

Time Window for Induced Hypertension in Acute Small Vessel Occlusive Stroke With Early Neurological Deterioration.

BACKGROUND: Therapeutic-induced hypertension treatment (iHTN) is helpful for alleviating early neurological deterioration (END) in acute small vessel occlusive stroke. We examined the time parameters related to iHTN effectiveness in these patients. METHODS: We retrospectively reviewed patients with acute small vessel occlusive stroke who underwent iHTN for END, defined as an increase of ≥2 points in total National Institutes of Health Stroke Scale (NIHSS) score or ≥1 point in motor items of NIHSS. The primary outcome was an early neurological improvement (ENI; a decrease of ≥2 points in total NIHSS score or ≥1 point in motor items of NIHSS), and the secondary outcome was any neurological improvement (a decrease of ≥1 point in the total NIHSS score). We conducted a multivariable logistic regression analysis, adjusting for demographics, risk factors, baseline clinical status, and intervention-related variables. We also generated a restricted cubic spline curve for the END-to-iHTN time cutoff. RESULTS: Among the 1062 patients with small vessel occlusive stroke screened between 2017 and 2021, 136 patients who received iHTN within 24 hours from END were included. The mean age was 65.1 (±12.0) years, and 61.0% were male. Sixty-five (47.8%) patients showed ENI and 77 (56.6%) patients showed any neurological improvement. END-to-iHTN time was significantly shorter in patients with ENI (150 [49-322] versus 290 [97-545] minutes; P=0.018) or any neurological improvement (150 [50-315] versus 300 [130-573] minutes; P=0.002). A 10-minute increase in the time between END and iHTN decreased the odds of achieving ENI (odds ratio, 0.984 [95% CI, 0.970-0.997]; P=0.019) or any neurological improvement (odds ratio, 0.978 [95% CI, 0.964-0.992]; P=0.002). The restricted cubic spline curve showed that the odds ratio of ENI reached its minimum at ≈3 hours. CONCLUSIONS: Among patients with small vessel occlusive stroke with END, a shorter interval between END and the initiation of iHTN was associated with increased odds of achieving neurological improvement. The efficacy of iHTN may be limited to induction within the first 3 hours of END.

Association between arterial tortuosity and early neurological deterioration in lenticulostriate artery infarction.

Early neurological deterioration (END) in lenticulostriate artery (LSA) infarction is associated with perforating artery hypoperfusion. As middle cerebral artery (MCA) tortuosity may alter hemodynamics, we investigated the association between MCA tortuosity and END in LSA infarction. We reviewed patients with acute LSA infarction without significant MCA stenosis. END was defined as an increase of ≥ 2 or ≥ 1 in the National Institutes of Health Stroke Scale (NIHSS) total or motor score, respectively, within first 72 h. The MCA tortuosity index (actual /straight length) was measured. Stroke mechanisms were categorized as branch atheromatous disease (BAD; lesions > 10 mm and 4 axial slices) and lipohyalinotic degeneration (LD; lesion smaller than BAD). Factors associated with END in LD and BAD were investigated. END occurred in 104/390 (26.7%) patients. A high MCA tortuosity index (adjusted odds ratio, aOR 10.63, 95% confidence interval [2.57-44.08], p = 0.001) was independently associated with END. In patients with BAD, high initial NIHSS score (aOR 1.40 [1.03-1.89], p = 0.031) and presence of parental artery disease (stenosis < 50%; aOR 10.38 [1.85-58.08], p = 0.008) were associated with END. In patients with LD, high MCA tortuosity (aOR 41.78 [7.37-237.04], p < 0.001) was associated with END. The mechanism causing END in patients with LD and BAD may differ.

Generation of the iPSC line FINi002-A from a male Parkinson's disease patient carrying compound heterozygous mutations in the PRKN gene.

The most common cause of autosomal recessive familial Parkinson's disease (PD) are mutations in the PRKN/PARK2 gene encoding an E3 ubiquitin protein-ligase PARKIN. We report the generation of an iPSC cell line from the fibroblasts of a male PD patient carrying a common missense variant in exon 7 (p.Arg275Trp), and a 133 kb deletion encompassing exon 8, using transiently-present Sendai virus. The established line displays typical human primed iPSC morphology and expression of pluripotency-associated markers, normal karyotype without SNP array-detectable copy number variations and can give rise to derivatives of all three embryonic germ layers. We envisage the usefulness of this iPSC line, carrying a common and well-studied missense mutation in the RING1 domain of the PARKIN protein, for the elucidation of PARKIN-dependent mechanisms of PD using in vitro and in vivo models.

Corrected QTc interval combined with troponin value and mortality in acute ischemic stroke.

Background and Purpose: Cardiac biomarkers including, elevated troponin (ET) and prolonged heart rate-corrected QT (PQTc) interval on electrocardiography are known to frequent and have a prognostic significance in patients with acute ischemic stroke (AIS). However, it is still challenging to practically apply the results for appropriate risk stratification. This study evaluate whether combining ET and PQTc interval can better assess the long-term prognosis in AIS patients. Methods: In this prospectively registered observational study between May 2007 and December 2011, ET was defined as serum troponin-I ≥ 0.04 ng/ml and PQTc interval was defined as the highest tertile of sex-specific QTc interval (men ≥ 469 ms or women ≥ 487 ms). Results: Among the 1,668 patients [1018 (61.0%) men; mean age 66.0 ± 12.4 years], patients were stratified into four groups according to the combination of ET and PQTc intervals. During a median follow-up of 33 months, ET (hazard ratio [HR]: 4.38, 95% confidence interval [CI]: 2.94-6.53) or PQTc interval (HR: 1.53, 95% CI: 1.16-2.01) alone or both (HR: 1.77, 95% CI: 1.16-2.71) was associated with increased all-cause mortality. Furthermore, ET, PQTc interval alone or both was associated with vascular death, whereas only ET alone was associated with non-vascular death. Comorbidity burden, especially atrial fibrillation and congestive heart failure, and stroke severity gradually increased both with troponin value and QTc-interval. Conclusions: In patients with AIS, combining ET and PQTc interval on ECG enhances risk stratification for long-term mortality while facilitating the discerning ability for the burden of comorbidities and stroke severity.

Prospective analysis of video head impulse tests in patients with acute posterior circulation stroke.

Background: Video head impulse tests (vHITs), assessing the vestibulo-ocular reflex (VOR), may be helpful in the differential diagnosis of acute dizziness. We aimed to investigate vHITs in patients with acute posterior circulation stroke (PCS) to examine whether these findings could exhibit significant abnormalities based on lesion locations, and to evaluate diagnostic value of vHIT in differentiating dizziness between PCS and vestibular neuritis (VN). Methods: We prospectively recruited consecutive 80 patients with acute PCS and analyzed vHIT findings according to the presence of dorsal brainstem stroke (DBS). We also compared vHIT findings between PCS patients with dizziness and a previously studied VN group (n = 29). Receiver operating characteristic (ROC) analysis was performed to assess the performance of VOR gain and its asymmetry in distinguishing dizziness between PCS and VN. Results: Patients with PCS underwent vHIT within a median of 2 days from stroke onset. Mean horizontal VOR gain was 0.97, and there was no significant difference between PCS patients with DBS (n = 15) and without (n = 65). None exhibited pathologic overt corrective saccades. When comparing the PCS group with dizziness (n = 40) to the VN group (n = 29), patients with VN demonstrated significantly lower mean VOR gains in the ipsilesional horizontal canals (1.00 vs. 0.57, p < 0.001). VOR gain and their asymmetry effectively differentiated dizziness in the PCS from VN groups, with an area under the ROC curve of 0.86 (95% CI 0.74-0.98) and 0.91 (95% CI 0.83-0.99, p < 0.001), respectively. Conclusion: Significantly abnormal vHIT results were rare in patients with acute PCS, even in the presence of DBS. Moreover, vHIT effectively differentiated dizziness between PCS and VN, highlighting its potential for aiding differential diagnosis of acute dizziness.

Generation of an iPSC line (FINi001-A) from a girl with developmental and epileptic encephalopathy due to a heterozygous gain-of-function p.R1882Q variant in the voltage-gated sodium channel Nav1.2 protein encoded by the SCN2A gene.

A range of epilepsies, including the most severe group of developmental and epileptic encephalopathies (DEEs), are caused by gain-of-function variants in voltage-gated channels. Here we report the generation and characterisation of an iPSC cell line from the fibroblasts of a girl with early infantile DEE carrying heterozygous missense gain-of-function mutation (R1882Q) in Nav1.2(SCN2A) protein, using transient transfection with a single mRNA molecule. The established iPSC line displays typical human primed pluripotent stem cell characteristics: typical colony morphology and robust expression of pluripotency-associated marker genes, ability to give rise to derivatives of all three embryonic germ layers, and normal karyotype without any SNP array-detectable copy number variations. We anticipate that this iPSC line will be useful for the development of neuronal hyperactivity-caused human stem cell-based DEE models, advancing both understanding and potential therapy development for this debilitating condition.

More Than 50 Percent Reduction in LDL Cholesterol in Patients With Target LDL <70 mg/dL After a Stroke.

BACKGROUND: Whether a strategy to target an LDL (low-density lipoprotein) cholesterol <70 mg/dL is more effective when LDL is reduced >50% from baseline rather than <50% from baseline has not been investigated. METHODS: The Treat Stroke to Target trial was conducted in France and South Korea in 61 sites between March 2010 and December 2018. Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned to a target LDL cholesterol of <70 mg/dL or 100±10 mg/dL, using statin and/or ezetimibe as needed. We used the results of repeated LDL measurements (median, 5 [2-6] per patient) during 3.9 years (interquartile range, 2.1-6.8) of follow-up. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization, and vascular death. Cox regression model including lipid-lowering therapy as a time-varying variable, after adjustment for randomization strategy, age, sex, index event (stroke or transient ischemic attack), and time since the index event. RESULTS: Among 2860 patients enrolled, patients in the lower target group who had >50% LDL cholesterol reduction from baseline during the trial had a higher baseline LDL cholesterol and a lower LDL cholesterol achieved as compared to patients who had <50% LDL cholesterol reduction (155±32 and 62 mg/dL versus 121±34 and 74 mg/dL, respectively, P<0.001 for both). In the <70 mg/dL target group, patients with >50% LDL reduction had a significant reduction in the primary outcome as compared to the higher target group (hazard ratio, 0.61 [95% CI, 0.43-0.88]; P=0.007) and patients with <50% LDL reduction from baseline had little reduction (hazard ratio, 0.96 [95% CI, 0.73-1.26]; P=0.75). CONCLUSIONS: In this post hoc analysis of the TST trial, targeting an LDL cholesterol of <70 mg/dL reduced the risk of primary outcome compared with 100±10 mg/dL provided LDL cholesterol reduction from baseline was superior to 50%, thereby suggesting that the magnitude of LDL cholesterol reduction was as important to consider as the target level to achieve. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01252875. URL: https://clinicaltrialsregister.eu; Unique identifier: EUDRACT2009-A01280-57.

[Shared decision making in involuntary treatment: four case studies from court ordered psychiatric treatment]. / Gedeelde besluitvorming in het gedwongen kader: vier casestudies uit de tbs.

BACKGROUND: Shared decision making (SDM) can result in better treatment outcomes. Little is known about the practice of SDM in forensic psychiatry; a context in which not only psychiatric problems are present, but also freedom restrictions and involuntary hospitalisation. AIM: To explore the current degree of SDM in a forensic psychiatric setting and to identify factors that influence SDM. METHOD: Semi-structured interviews (n = 4 triads: treatment coordinator, sociotherapeutic mentor and patient) combined with scores on questionnaires (SDM-Q-Doc and SDM-Q-9). RESULTS: The SDM-Q showed a relatively high degree of SDM. Themes like cognitive and executive functions of the patient, subcultural differences, insight into the disease and reciprocal cooperation appeared to influence the SDM. In addition, SDM in forensic psychiatry appeared to be more of a means of improving communication about the decisions of the treatment team than truly ‘shared’ decision making. CONCLUSION: This first exploration shows that SDM is applied in forensic psychiatry, however operationalised differently than the theory behind SDM prescribes.

Glycogen synthase 1 targeting reveals a metabolic vulnerability in triple-negative breast cancer.

BACKGROUND: Hypoxia-induced glycogen turnover is implicated in cancer proliferation and therapy resistance. Triple-negative breast cancers (TNBCs), characterized by a hypoxic tumor microenvironment, respond poorly to therapy. We studied the expression of glycogen synthase 1 (GYS1), the key regulator of glycogenesis, and other glycogen-related enzymes in primary tumors of patients with breast cancer and evaluated the impact of GYS1 downregulation in preclinical models. METHODS: mRNA expression of GYS1 and other glycogen-related enzymes in primary breast tumors and the correlation with patient survival were studied in the METABRIC dataset (n = 1904). Immunohistochemical staining of GYS1 and glycogen was performed on a tissue microarray of primary breast cancers (n = 337). In four breast cancer cell lines and a mouse xenograft model of triple-negative breast cancer, GYS1 was downregulated using small-interfering or stably expressed short-hairpin RNAs to study the effect of downregulation on breast cancer cell proliferation, glycogen content and sensitivity to various metabolically targeted drugs. RESULTS: High GYS1 mRNA expression was associated with poor patient overall survival (HR 1.20, P = 0.009), especially in the TNBC subgroup (HR 1.52, P = 0.014). Immunohistochemical GYS1 expression in primary breast tumors was highest in TNBCs (median H-score 80, IQR 53-121) and other Ki67-high tumors (median H-score 85, IQR 57-124) (P < 0.0001). Knockdown of GYS1 impaired proliferation of breast cancer cells, depleted glycogen stores and delayed growth of MDA-MB-231 xenografts. Knockdown of GYS1 made breast cancer cells more vulnerable to inhibition of mitochondrial proteostasis. CONCLUSIONS: Our findings highlight GYS1 as potential therapeutic target in breast cancer, especially in TNBC and other highly proliferative subsets.