Cdk5 inhibition in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis suppresses neurodegeneration and extends survival.

Deregulated cyclin-dependent kinase 5 (Cdk5) activity closely correlates with hyperphosphorylated tau, a common pathology found in neurodegenerative diseases. Previous postmortem studies had revealed increased Cdk5 immunoreactivity in amyotrophic lateral sclerosis (ALS); hence, we investigated the effects of Cdk5 inhibition on ALS model mice and neurons in this study. For the in vitro study, motor neuron cell lines with wild-type superoxide dismutase 1 (SOD1) or SOD1G93A and primary neuronal cultures from SOD1G93A transgenic (TG) mice or non-TG mice were compared for the expression of proteins involved in tau pathology, neuroinflammation, apoptosis, and neuritic outgrowth by applying Cdk5-small interfering RNA or Cdk5-short hairpin RNA (shRNA). For the in vivo study, SOD1G93A mice and non-TG mice were intrathecally injected with adeno-associated virus 9 (AAV9)-scramble (SCR)-shRNA or AAV9-Cdk5-shRNA at the age of 5 weeks. Weight and motor function were measured three times per week from 60 days of age, longevity was evaluated, and the tissues were collected from 90-day-old or 120-day-old mice. Neurons with SOD1G93A showed increased phosphorylated tau, attenuated neuritic growth, mislocalization of SOD1, and enhanced neuroinflammation and apoptosis, all of which were reversed by Cdk5 inhibition. Weights did not show significant differences among non-TG and SOD1G93A mice with or without Cdk5 silencing. SOD1G93A mice treated with AAV9-Cdk5-shRNA showed significantly delayed disease onset, delayed rotarod failure, and prolonged survival compared with those treated with AAV9-SCR-shRNA. The brain and spinal cord of SOD1G93A mice intrathecally injected with AAV9-Cdk5-shRNA exhibited suppressed tau pathology, neuroinflammation, apoptosis, and an increased number of motor neurons compared to those of SOD1G93A mice injected with AAV9-SCR-shRNA. Cdk5 inhibition could be an important mechanism in the development of a new therapeutic strategy for ALS.

Dual effects of TGF-ß inhibitor in ALS - inhibit contracture and neurodegeneration.

As persistent elevation of transforming growth factor-ß (TGF-ß) promotes fibrosis of muscles and joints and accelerates disease progression in amyotrophic lateral sclerosis (ALS), we investigated whether inhibition of TGF-ß would be effective against both exacerbations. The effects of TGF-ß and its inhibitor on myoblasts and fibroblasts were tested in vitro and confirmed in vivo, and the dual action of a TGF-ß inhibitor in ameliorating the pathogenic role of TGF-ß in ALS mice was identified. In the peripheral neuromuscular system, fibrosis in the muscles and joint cavities induced by excessive TGF-ß causes joint contracture and muscular degeneration, which leads to motor dysfunction. In an ALS mouse model, an increase in TGF-ß in the central nervous system (CNS), consistent with astrocyte activity, was associated with M1 microglial activity and pro-inflammatory conditions, as well as with neuronal cell death. Treatment with the TGF-ß inhibitor halofuginone could prevent musculoskeletal fibrosis, resulting in the alleviation of joint contracture and delay of motor deterioration in ALS mice. Halofuginone could also reduce glial cell-induced neuroinflammation and neuronal apoptosis. These dual therapeutic effects on both the neuromuscular system and the CNS were observed from the beginning to the end stages of ALS; as a result, treatment with a TGF-ß inhibitor from the early stage of disease delayed the time of symptom exacerbation in ALS mice, which led to prolonged survival.

Watching (De)Intercalation of 2D Metals in Epitaxial Graphene: Insight into the Role of Defects.

Intercalation forms heterostructures, and over 25 elements and compounds are intercalated into graphene, but the mechanism for this process is not well understood. Here, the de-intercalation of 2D Ag and Ga metals sandwiched between bilayer graphene and SiC are followed using photoemission electron microscopy (PEEM) and atomistic-scale reactive molecular dynamics simulations. By PEEM, de-intercalation "windows" (or defects) are observed in both systems, but the processes follow distinctly different dynamics. Reversible de- and re-intercalation of Ag is observed through a circular defect where the intercalation velocity front is 0.5 nm s-1 ± 0.2 nm s.-1 In contrast, the de-intercalation of Ga is irreversible with faster kinetics that are influenced by the non-circular shape of the defect. Molecular dynamics simulations support these pronounced differences and complexities between the two Ag and Ga systems. In the de-intercalating Ga model, Ga atoms first pile up between graphene layers until ultimately moving to the graphene surface. The simulations, supported by density functional theory, indicate that the Ga atoms exhibit larger binding strength to graphene, which agrees with the faster and irreversible diffusion kinetics observed. Thus, both the thermophysical properties of the metal intercalant and its interaction with defective graphene play a key role in intercalation.

Association Between Fat Depletion and Prognosis of Amyotrophic Lateral Sclerosis: CT-Based Body Composition Analysis.

OBJECTIVE: The purpose of this study was to present the results of our investigation of the prognostic value of adipopenia and sarcopenia in patients with amyotrophic lateral sclerosis (ALS). METHODS: Consecutive patients with ALS with abdominal computed tomography (CT) were retrospectively identified at a single tertiary hospital between January 2010 and July 2021. Deep learning-based volumetric CT body composition analysis software was used to obtain abdominal waist fat volume, fat attenuation, and skeletal muscle area at the L3 level, then normalized to the fat volume index (FVI) and skeletal muscle index (SMI). Adipopenia and sarcopenia were defined as the sex-specific lowest quartile and SMI reference values, respectively. The associations of CT-derived body composition parameters with clinical variables, such as body mass index (BMI) and creatinine, were evaluated by Pearson correlation analyses, and associations with survival were assessed using the multivariable Cox regression analysis. RESULTS: Eighty subjects (40 men, 65.5 ± 9.4 years of age) were investigated (median interval between disease onset and CT examination = 25 months). The mean BMI at the CT examination was 20.3 ± 4.3 kg/m2 . The BMI showed a positive correlation with both FVI (R = 0.70, p < 0.001) and SMI (R = 0.63, p < 0.001), and the serum creatinine level was associated with SMI (R = 0.68, p < 0.001). After adjusting for sex, age, King's stage, BMI, creatinine, progression rate, and sarcopenia, adipopenia was associated with shorter survival (hazard ratio [HR] = 5.94, 95% confidence interval [CI] = 1.01, 35.0, p = 0.049). In a subgroup analysis for subjects with nutritional failure (stage 4a), the HR of adipopenia was 15.1 (95% CI = 2.45, 93.4, p = 0.003). INTERPRETATION: Deep learning-based CT-derived adipopenia in patients with ALS is an independent poor prognostic factor for survival. ANN NEUROL 2023;94:1116-1125.

Prognostic factors of first-onset optic neuritis based on diagnostic criteria and antibody status: a multicentre analysis of 427 eyes.

BACKGROUND: Optic neuritis (ON) prognosis is influenced by various factors including attack severity, underlying aetiologies, treatments and consequences of previous episodes. This study, conducted on a large cohort of first ON episodes, aimed to identify unique prognostic factors for each ON subtype, while excluding any potential influence from pre-existing sequelae. METHODS: Patients experiencing their first ON episodes, with complete aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibody testing, and clinical data for applying multiple sclerosis (MS) diagnostic criteria, were enrolled. 427 eyes from 355 patients from 10 hospitals were categorised into four subgroups: neuromyelitis optica with AQP4 IgG (NMOSD-ON), MOG antibody-associated disease (MOGAD-ON), ON in MS (MS-ON) or idiopathic ON (ION). Prognostic factors linked to complete recovery (regaining 20/20 visual acuity (VA)) or moderate recovery (regaining 20/40 VA) were assessed through multivariable Cox regression analysis. RESULTS: VA at nadir emerged as a robust prognostic factor for both complete and moderate recovery, spanning all ON subtypes. Early intravenous methylprednisolone (IVMP) was associated with enhanced complete recovery in NMOSD-ON and MOGAD-ON, but not in MS-ON or ION. Interestingly, in NMOSD-ON, even a slight IVMP delay in IVMP by >3 days had a significant negative impact, whereas a moderate delay up to 7-9 days was permissible in MOGAD-ON. Female sex predicted poor recovery in MOGAD-ON, while older age hindered moderate recovery in NMOSD-ON and ION. CONCLUSION: This comprehensive multicentre analysis on first-onset ON unveils subtype-specific prognostic factors. These insights will assist tailored treatment strategies and patient counselling for ON.

Burden and preparedness of care partners of people living with amyotrophic lateral sclerosis at home in Korea: A care partner survey.

INTRODUCTION/AIMS: The care burden of people living with amyotrophic lateral sclerosis (pALS) increases with disease progression. This study aimed to investigate the home care status and preparedness of care partners of pALS (cALS) in Korea. METHODS: An online survey was conducted with family care partners of patients diagnosed with ALS for over 1 year in 2022. The data collected included care time, depression evaluated using the patient health questionnaire-9 (PHQ-9), preparedness for caregiving scale (PCS), and caregiver competence scale (CCS). Results were compared based on whether the pALS underwent a tracheostomy or not. RESULTS: Ninety-eight cALS of 98 pALS participated in the study, of whom 59 pALS had undergone tracheostomy. Among the cALS, 60.2% were spouses, and 34.7% were children. The cALS took care of the patients for 13 (8-20) hours/day (median, interquartile range [IQR]) on weekdays and 15 (10-24) h/day on weekends. Among the cALS, 91.8% were depressed, and 28.6% had severe depression. The median (IQR) PCS and CCS scores were low (11/32 (8-15) and 8/20 (8-11), respectively), and both were lower in those caring for patients without than with tracheostomy (p < .001 and p < .02, respectively). Most cALS (77.6%) wished to continue caring for their pALS at home. DISCUSSION: Family care partners of pALS spend more than half of each day caring for patients and are often depressed. Most cALS preferred providing care at home, but felt ill-prepared. Designing home-based medical care is necessary for pALS to thrive at home.

Baseline Serum neutrophil-to-lymphocyte ratio in acral melanoma compared with nonacral melanoma and its prognostic significance.

BACKGROUND: Acral lentiginous melanoma (ALM), a cutaneous melanoma subtype, exhibits a poorer prognosis than nonacral cutaneous melanoma (NACM). The neutrophil-to-lymphocyte ratio (NLR) is emerging as a prognostic indicator across diverse cancers. OBJECTIVE: We explored the baseline NLR disparities between ALM and NACM, and the NLR's prognostic significance in patients with ALM. METHODS: We reviewed records of patients with ALM and NACM diagnosed between 1997 and 2022, analyzing medical data. RESULTS: Among 327 and 159 patients with ALM and NACM, respectively, baseline NLR varied based on distinct clinicopathologic factors between ALM and NACM. In stage 3 to 4 melanomas, the median NLR for ALM (2.18; IQR, 1.70-3.08) significantly surpassed NACM (1.74; IQR, 1.33-2.53) (P = .029). In patients with ALM, high NLR (hazard ratio, 1.64; 95% CI, 1.02-2.66; P = .043) was independently correlated with poor progression-free survival when adjusting for ulceration, Breslow thickness of ≥2 mm, and nodal invasion. LIMITATIONS: Single-center, retrospective design. CONCLUSION: Advanced-stage ALM exhibited a significantly higher baseline NLR compared with that of NACM. Evaluating baseline NLR could provide valuable prognostic insights for patients with ALM.

Spontaneous Recovery of Pathological Fracture Caused by Medication-Related Osteonecrosis of the Jaw.

Pathological fracture is one of the most serious complications in medication-related osteonecrosis of the jaw (MRONJ). This case is a report of an 87-year-old woman who had been diagnosed with pathological fracture due to MRONJ. The authors performed minimally invasive and conservative treatment, such as intraoral dressing, antibiotic therapy, and simple debridement, for patients with pathologic fractures due to MRONJ. After 1 year, the inflammatory symptoms disappeared and pathological fractures spontaneously recovered.

The effect of training to target cognitive biases towards social rejection in eating disorders.

OBJECTIVE: This study examined the effect of cognitive bias modification for interpretation (CBM-I) training in Korean women with eating disorders (EDs). METHOD: Sixty-three women with EDs participated in the study. Participants were randomly assigned to the intervention group where they received six sessions of CBM-I training (n = 31) in addition to treatment-as-usual or were put on a waiting list (n = 32). Participants' interpretation and attention biases, emotion regulation, affect, and ED psychopathology were assessed at baseline, end-of-intervention (4 weeks), and follow-up (8 weeks). RESULTS: Participants who completed the CBM-I training displayed greater reductions in negative interpretation bias (Δη2 = 0.107) and emotion dysregulation (Δη2 = 0.085) with medium to large effect sizes compared to the control group, which were maintained from baseline to follow-up. Disengagement from negative faces and a focus on positive faces was found in the intervention group with a moderate effect size at the end-of-intervention (Δη2 = 0.090). Both intervention and control groups showed improvements in ED psychopathology. Baseline neuroticism was positively correlated with CBM-I effect. DISCUSSION: The results suggest that modifying interpretation bias towards ambiguous social stimuli might be an effective adjuvant treatment to reduce negative expectations of social situations and improve emotion regulation in women with bulimia nervosa and anorexia nervosa.

Morphological characteristics of facial scars: A retrospective analysis according to scar location, onset, age, and cause.

The morphology of facial scars shows a wide variation in terms of texture and colour. To date, there are no reliable predictors of aberrant scarring. We conducted a retrospective analysis to identify factors associated with specific scar features and types. Photographs and medical records of 428 patients with facial scars were retrospectively reviewed. Patients with keloids were excluded. The mean age of the patients was 45.43 ± 23.13 years with a male-to-female ratio of 1:1.36. Atrophic scars were the most common (42.8%), followed by flat scars (38.7%) and hypertrophic scars (18.5%). Scars on the forehead were more likely to be atrophic, whereas scars on the chin/jaw and around the mouth were more likely to be hypertrophic. Hypopigmentation was significantly more common in scars located on the forehead. Redness (erythema) was significantly more common in scars located on the chin/jaw. Old scars were less likely to be erythematous, and hypertrophic. Atrophic scars were more common in younger patients. Scars caused by dermatologic conditions, such as acne, were more likely to be atrophic, whereas surgical scars had the lowest risk of being atrophic or hypertrophic. In conclusion, the location, onset, and cause of facial scars were associated with specific features of scars.

AXL+SIGLEC6+ dendritic cells in cerebrospinal fluid and brain tissues of patients with autoimmune inflammatory demyelinating disease of CNS.

Inflammatory demyelinating disease of the CNS (IDD) is a heterogeneous group of autoimmune diseases, and multiple sclerosis is the most common type. Dendritic cells (DCs), major antigen-presenting cells, have been proposed to play a central role in the pathogenesis of IDD. The AXL+SIGLEC6+ DC (ASDC) has been only recently identified in humans and has a high capability of T cell activation. Nevertheless, its contribution to CNS autoimmunity remains still obscure. Here, we aimed to identify the ASDC in diverse sample types from IDD patients and experimental autoimmune encephalomyelitis (EAE). A detailed analysis of DC subpopulations using single-cell transcriptomics for the paired cerebrospinal fluid (CSF) and blood samples of IDD patients (total n = 9) revealed that three subtypes of DCs (ASDCs, ACY3+ DCs, and LAMP3+ DCs) were overrepresented in CSF compared with their paired blood. Among these DCs, ASDCs were also more abundant in CSF of IDD patients than in controls, manifesting poly-adhesional and stimulatory characteristics. In the brain biopsied tissues of IDD patients, obtained at the acute attack of disease, ASDC were also frequently found in close contact with T cells. Lastly, the frequency of ASDC was found to be temporally more abundant in acute attack of disease both in CSF samples of IDD patients and in tissues of EAE, an animal model for CNS autoimmunity. Our analysis suggests that the ASDC might be involved in the pathogenesis of CNS autoimmunity.

Development of a Semiquantitative Whole-Body MRI Scoring System for Multiple Myeloma.

Background In patients with multiple myeloma (MM), the serum marker ß2-microglobulin does not always accurately reflect tumor load. In contrast, whole-body (WB) MRI has shown high sensitivity for detecting bone lesions. Purpose To develop and validate a semiquantitative WB MRI scoring system for newly diagnosed MM and to compare it with the International Staging System (ISS) and Revised ISS (R-ISS). Materials and Methods This study included two retrospective groups (group 1, July 2015 to September 2021; group 2, February 2020 to September 2021) and one prospective group (group 3, October 2021 to February 2022) of patients with newly diagnosed MM. A new scoring system for MM was developed using spine MRI scans in group 1 and WB MRI scans in group 2 that integrated three features: (a) background marrow pattern, (b) number of focal bone lesions, and (c) presence of extramedullary or paramedullary lesions. The summed total score ranged from zero to nine. The interobserver agreement for each feature was assessed using Fleiss or Cohen weighted κ. WB MRI total scores in group 3 were compared across ISS and R-ISS stages using two-way analysis of variance. Results Groups 1, 2, and 3 included 103 patients (mean age, 62.1 years ± 9.1 [SD]; 60 men), 36 patients (mean age 65.4 years ± 11.3 [SD]; 19 women), and 39 participants (mean age, 62.0 years ± 11.7 [SD]; 20 men), respectively. The interobserver agreements for the three features composing the scoring system were substantial (κ range, 0.69-0.80). WB MRI total score increased with increasing ISS stage (mean score for ISS 1, 2, and 3 was 2.2, 4.2, and 5.8, respectively; P = .009) and R-ISS stage (mean score for R-ISS 1, 2, and 3 was 2.1, 3.8, and 5.9, respectively; P = .005). Conclusion The developed WB MRI scoring system for MM demonstrated substantial observer agreement and corresponded well with ISS and R-ISS stages. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Dragan and Messiou in this issue.

Effect of rosuvastatin 20 mg versus rosuvastatin 5 mg plus ezetimibe on statin side-effects in elderly patients with atherosclerotic cardiovascular disease: Rationale and design of a randomized, controlled SaveSAMS trial.

BACKGROUND: Current guidelines recommend that patients with established atherosclerotic cardiovascular disease (ASCVD) use high-intensity statin therapy to lower low-density lipoprotein (LDL)-cholesterol levels by at least 50%, irrespective of age. However, in real-world practice, there is reluctance to maintain statin use in response to side-effects, particularly statin-associated muscle symptoms (SAMS). Moreover, no randomized trial has been conducted on the safety of statin therapy in elderly patients. TRIAL DESIGN: This investigator-initiated, multicenter, randomized clinical trial aimed to investigate the incidence of SAMS and its effect on LDL-cholesterol levels in elderly patients with established ASCVD. Eligible patients were aged 70 years or older with established ASCVD. Consecutive patients who met the inclusion criteria were randomized in a 1:1 fashion to receive either intensive statin monotherapy (rosuvastatin 20 mg) or combination therapy (rosuvastatin/ezetimibe, 5/10 mg). The primary endpoint of the study is SAMS at 6 months with regard to treatment strategy. Positive SAMS results are defined as patients with a proposed statin myalgia index score of 7 or higher. The key secondary end-points are target LDL-cholesterol achievement (LDL < 70 mg/dL), incidence of myopathy, rhabdomyolysis, frequency of drug discontinuation, and creatinine kinase, aspartate transaminase, alanine transaminase, total cholesterol, LDL-cholesterol, high-density lipoprotein-cholesterol, triglyceride, and highly sensitive C-reactive protein levels at 6 months. CONCLUSIONS: The SaveSAMS study is a multicenter, randomized trial that will compare the incidence of SAMS in patients with established ASCVD who are 70 years or older on intensive statin monotherapy to that combination therapy.

MOG antibody-associated encephalitis in adult: clinical phenotypes and outcomes.

BACKGROUND: We investigated the clinical characteristics and outcomes of myelin oligodendrocyte glycoprotein (MOG) antibody-associated autoimmune encephalitis (MOGAE) in adult patients. METHODS: From an institutional cohort, we analysed adult patients with MOGAE followed-up for more than 1 year. Disease severity was assessed using the modified Rankin scale (mRS) and Clinical Assessment Scale in Autoimmune Encephalitis scores. Immunotherapy profiles, outcomes and disease relapses were evaluated along with serial brain MRI data. RESULTS: A total of 40 patients were enrolled and categorised into cortical encephalitis (18 patients), limbic encephalitis (LE, 5 patients) and acute disseminated encephalomyelitis (ADEM, 17 patients). 80.0% of patients achieved good clinical outcomes (mRS 0‒2) and 40.0% relapsed. The LE subtype was associated with an older onset age (p=0.004) and poor clinical outcomes (p=0.014) than the other subtypes but with a low rate of relapse (0.0%). 21/25 (84.0%) relapse attacks were associated with an absence or short (≤6 months) immunotherapy maintenance. On MRI, the development of either diffuse cerebral or medial temporal atrophy within the first 6 month was correlated with poor outcomes. MOG-antibody (MOG-Ab) was copresent with anti-N-methyl-D-aspartate receptor (NMDAR)-antibody in 13 patients, in whom atypical clinical presentation (cortical encephalitis or ADEM, p<0.001) and disease relapse (46.2% vs 0.0%, p<0.001) were more frequent compared with conventional NMDAR encephalitis without MOG-Ab. CONCLUSIONS: Outcomes are different according to the three phenotypes in MOGAE. Short immunotherapy maintenance is associated with relapse, and brain atrophy was associated with poor outcomes. Patients with dual antibodies of NMDAR and MOG have a high relapse rate.

Early rituximab treatment reduces long-term disability in aquaporin-4 antibody-positive neuromyelitis optica spectrum.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) causes relapsing inflammatory attacks in the central nervous system, leading to disability. As rituximab, a B-lymphocyte-depleting monoclonal antibody, is an effective in preventing NMOSD relapses, we hypothesised that earlier initiation of rituximab can also reduce long-term disability of patients with NMOSD. METHODS: This multicentre retrospective study involving 19 South Korean referral centres included patients with NMOSD with aquaporin-4 antibodies receiving rituximab treatment. Factors associated with the long-term Expanded Disability Status Scale (EDSS) were assessed using multivariable regression analysis. RESULTS: In total, 145 patients with rituximab treatment (mean age of onset, 39.5 years; 88.3% female; 98.6% on immunosuppressants/oral steroids before rituximab treatment; mean disease duration of 121 months) were included. Multivariable analysis revealed that the EDSS at the last follow-up was associated with time to rituximab initiation (interval from first symptom onset to initiation of rituximab treatment). EDSS at the last follow-up was also associated with maximum EDSS before rituximab treatment. In subgroup analysis, the time to initiation of rituximab was associated with EDSS at last follow-up in patients aged less than 50 years, female and those with a maximum EDSS score ≥6 before rituximab treatment. CONCLUSIONS: Earlier initiation of rituximab treatment may prevent long-term disability worsening in patients with NMOSD, especially among those with early to middle-age onset, female sex and severe attacks.

Diagnosis of Marginal Infiltration in Soft Tissue Sarcoma by Radiomics Approach Using T2-Weighted Dixon Sequence.

BACKGROUND: Determination of preoperative soft tissue sarcoma (STS) margin is crucial for patient prognosis. PURPOSE: To evaluate diagnostic performance of radiomics model using T2-weighted Dixon sequence for infiltration degree of STS margin. STUDY TYPE: Retrospective. POPULATION: Seventy-two STS patients consisted of training (n = 58) and test (n = 14) sets. FIELD STRENGTH/SEQUENCE: A 3.0 T; T2-weighted Dixon images. ASSESSMENT: Pathologic result of marginal infiltration in STS (circumscribed margin; n = 27, group 1, focally infiltrative margin; n = 31, group 2-A, diffusely infiltrative margin; n = 14, group 2-B) was the reference standard. Radiomic volume and shape (VS) and other (T2) features were extracted from entire tumor volume and margin, respectively. Twelve radiomics models were generated using four combinations of classifier algorithms (R, SR, LR, LSR) and three different inputs (VS, T2, VS + T2 [VST2] features) to differentiate the three groups. Three radiologists (reader 1, 2, 3) analyzed the marginal infiltration with 6-scale confidence score. STATISTICAL TESTS: Area under the receiver operating characteristic curve (AUC) and concordance rate. RESULTS: Averaged AUCs of R, SR, LR, LSR models were 0.438, 0.466, 0.438, 0.466 using VS features, 0.596, 0.584, 0.814, 0.815 using T2 features, and 0.581, 0.587, 0.821, 0.821 using VST2 features, respectively. The LR and LSR models constructed with T2 or VST2 features showed higher AUC and concordance rate compared to radiologists' analysis (AUC; 0.730, 0.675, 0.706, concordance rate; 0.46, 0.43, 0.47 in reader 1, 2, 3). DATA CONCLUSION: Radiomics model constructed with features from tumor margin on T2-weighted Dixon sequence is a promising method for differentiating infiltration degree of STS margin. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Synthesis and evaluation of 18F-labeled procainamide as a PET imaging agent for malignant melanoma.

Malignant melanoma has an aggressive nature and a high metastatic propensity resulting in the highest mortality rate of any skin cancer. In this study, we synthesized 18F-labeled procainamide (PCA) for detection of melanoma using positron emission tomography (PET), and evaluated its biological characteristics. The non-decay-corrected radiochemical yield of 18F-PCA was 10-15% and its in vitro stability was over 98% for 2 h. At 1 h, cellular uptake of 18F-PCA was 3.8-fold higher in a group with the presence of l-tyrosine than in a non-l-tyrosine-treated group. Furthermore, 18F-PCA permitted visualization of B16F10 (mouse melanoma) xenografts on microPET after intravenous injection, and was retained in the tumor for 60 min, with a high tumor-to-liver uptake ratio. 18F-PCA showed specific melanoma uptake in primary lesions with a high melanin targeting ability in small animal models. 18F-PCA may have potential as a PET imaging agent for direct melanoma detection.

CRISPR-Cas9 mediated genome editing of Huntington's disease neurospheres.

BACKGROUND: Huntington's disease (HD) is a fatal genetic disease caused by polyglutamine aggregation encoded by an expanded CAG repeat in the huntingtin gene (HTT). In this study, we cultured neurospheres derived from R6/2 mice, a representative animal model of HD, as an in vitro model. GuideRNAs were designed to induce large deletion or frameshift indel mutation of CAG expansion. These gRNAs and Cas9 were delivered to the R6/2 neurospheres and disease-related phenotypes were observed. METHODS AND RESULTS: Deletion or indel mutation of the CAG repeat was confirmed by PCR, T7E1 assay and sequencing of the edited neurospheres. Edited neurospheres showed decreased polyglutamine aggregation compared with control HD neurospheres. In the edited neurosphere, we confirmed the upregulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and brain-derived neurotrophic factor (BDNF), whose reduced expressions are closely involved in the disease progression. In addition, flow cytometry result showed an increase in cell viability with an overall decrease in necrotic and apoptotic populations among edited R6/2 neurospheres. Additional siRNA experiments confirmed that the increased viability was decreased through inhibition of PGC-1α or BDNF. CONCLUSION: Our study confirmed that CAG repeat of R6/2 mouse-derived neurospheres can be edited through CRISPR-Cas9. Editing of CAG repeat sequence decreases polyglutamine aggregation and cellular apoptosis of HD neurospheres, which may be related to the increased expressions of PGC-1α and BDNF. Our data provide the evidence that CRISPR-Cas9 mediated genome editing has therapeutic potential on HD neuronal cells.

Targeting of pancreatic cancer cells and stromal cells using engineered oncolytic Salmonella typhimurium.

Pancreatic cancer is resistant to conventional therapeutic interventions, mainly due to abundant cancer stromal cells and poor immune cell infiltration. Here, we used a targeted cancer therapy approach based on attenuated Salmonella typhimurium engineered to express cytolysin A (ClyA) to target cancer stromal cells and cancer cells and treat pancreatic cancer in mice. Nude mice bearing subcutaneous or orthotopic human pancreatic cancers were treated with engineered S. typhimurium expressing ClyA. The tumor microenvironment was monitored to analyze stromal cell numbers, stromal cell marker expression, and immune cell infiltration. The attenuated bacteria accumulated and proliferated specifically in tumor tissues after intravenous injection. The bacteria secreted ClyA into the tumor microenvironment. A single dose of ClyA-expressing Salmonella markedly inhibited growth of pancreatic cancer both in subcutaneous xenograft- and orthotopic tumor-bearing nude mice. Histological analysis revealed a marked decrease in expression of stromal cell markers and increased immune cell (neutrophils and macrophages) infiltration into tumors after colonization by ClyA-expressing bacteria. ClyA-expressing S. typhimurium destroyed cancer stromal cells and cancer cells in mouse models of human pancreatic cancer. This approach provides a novel strategy for combining anticancer and anti-stromal therapy to treat pancreatic cancer.

Performance of PRAME immunohistochemistry compared with that of c-Kit, c-Myc, or cyclin D1 for the diagnosis of acral melanocytic tumors.

The diagnostic role of preferentially expressed antigen in melanoma (PRAME) immunohistochemistry has not been thoroughly evaluated for acral melanocytic tumors. The objective of this study was to evaluate the utility of this modality for the diagnosis of acral melanocytic tumors compared with other potential markers. Melanocytic tumors were classified as either acral nevi, challenging melanocytic tumors (superficial atypical melanocytic proliferation of uncertain significance (SAMPUS)-favor benign (SAMPUS-FB), SAMPUS-favor malignant (SAMPUS-FM)) or acral melanomas. A total of 106 acral melanocytic tumors including acral nevi (n = 32), SAMPUS-FB (n = 17), SAMPUS-FM (n = 20), and acral melanomas (n = 37) were included. Diagnostic power, assessed using an area under the receiver operating characteristic curve (AUC) for distinguishing acral melanomas and acral nevi, was highest for PRAME (AUC = 0.997), followed by c-Myc (AUC = 0.755), cyclin D1 (AUC = 0.652), and c-Kit (AUC = 0.573). At a PRAME expression level ≥30% as a positive test for acral melanoma, the sensitivity and specificity of this marker for discriminating acral melanoma from acral nevus were 100% and 96.9%, respectively. PRAME immunohistochemistry also discriminated SAMPUS-FM from SAMPUS-FB with a sensitivity and specificity of 90.0% and 76.5%, respectively. In conclusion, PRAME immunohistochemistry can be used effectively to distinguish between various spectra of acral melanocytic neoplasms.