Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer.

ABTRACT: Forkhead box A1 (FOXA1) is a pioneer transcription factor that is essential for the normal development of several endoderm-derived organs, including the prostate gland1,2. FOXA1 is frequently mutated in hormone-receptor-driven prostate, breast, bladder and salivary-gland tumours3-8. However, it is unclear how FOXA1 alterations affect the development of cancer, and FOXA1 has previously been ascribed both tumour-suppressive9-11 and oncogenic12-14 roles. Here we assemble an aggregate cohort of 1,546 prostate cancers and show that FOXA1 alterations fall into three structural classes that diverge in clinical incidence and genetic co-alteration profiles, with a collective prevalence of 35%. Class-1 activating mutations originate in early prostate cancer without alterations in ETS or SPOP, selectively recur within the wing-2 region of the DNA-binding forkhead domain, enable enhanced chromatin mobility and binding frequency, and strongly transactivate a luminal androgen-receptor program of prostate oncogenesis. By contrast, class-2 activating mutations are acquired in metastatic prostate cancers, truncate the C-terminal domain of FOXA1, enable dominant chromatin binding by increasing DNA affinity and-through TLE3 inactivation-promote metastasis driven by the WNT pathway. Finally, class-3 genomic rearrangements are enriched in metastatic prostate cancers, consist of duplications and translocations within the FOXA1 locus, and structurally reposition a conserved regulatory element-herein denoted FOXA1 mastermind (FOXMIND)-to drive overexpression of FOXA1 or other oncogenes. Our study reaffirms the central role of FOXA1 in mediating oncogenesis driven by the androgen receptor, and provides mechanistic insights into how the classes of FOXA1 alteration promote the initiation and/or metastatic progression of prostate cancer. These results have direct implications for understanding the pathobiology of other hormone-receptor-driven cancers and rationalize the co-targeting of FOXA1 activity in therapeutic strategies.

Left Ventricular Vertical Run-Length Nonuniformity MRI Adds Prognostic Value to MACE in Patients with End-Stage Renal Disease.

BACKGROUND: Vertical run-length nonuniformity (VRLN) is a texture feature representing heterogeneity within native T1 images and reflects the extent of cardiac fibrosis. In uremic cardiomyopathy, interstitial fibrosis was the major histological alteration. The prognostic value of VRLN in patients with end-stage renal disease (ESRD) remains unclear. PURPOSE: To evaluate the prognostic value of VRLN MRI in patients with ESRD. STUDY TYPE: Prospective. POPULATION: A total of 127 ESRD patients (30 participants in the major adverse cardiac events, MACE group). FIELD STRENGTH/SEQUENCE: 3.0 T/steady-state free precession sequence, modified Look-Locker imaging. ASSESSMENT: MRI image qualities were assessed by three independent radiologists. VRLN values were measured in the myocardium on the mid-ventricular short-axis slice of T1 mapping. Left ventricular (LV) mass, LV end-diastolic and end-systolic volume, as well as LV global strain cardiac parameters were measured. STATISTICAL TESTS: The primary endpoint was the incident of MACE from enrollment time to January 2023. MACE is a composite endpoint consisting of all-cause mortality, acute myocardial infarction, stroke, heart failure hospitalization, and life-threatening arrhythmia. Cox proportional-hazards regression was performed to test whether VRLN independently correlated with MACE. The intraclass correlation coefficients of VRLN were calculated to evaluate intraobserver and interobserver reproducibility. The C-index was computed to examine the prognostic value of VRLN. P-value <0.05 were considered statistically significant. RESULTS: Participants were followed for a median of 26 months. VRLN, age, LV end-systolic volume index, and global longitudinal strain remained significantly associated with MACE in the multivariable model. Adding VRLN to a baseline model containing clinical and conventional cardiac MRI parameters significantly improved the accuracy of the predictive model (C-index of the baseline model: 0.781 vs. the model added VRLN: 0.814). DATA CONCLUSION: VRLN is a novel marker for risk stratification toward MACE in patients with ESRD, superior to native T1 mapping and LV ejection fraction. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY STAGE: 2.

Myocardial extracellular volume quantified by cardiac magnetic resonance predicts left ventricular aneurysm following acute myocardial infarction.

OBJECTIVE: This study aimed to investigate the correlation between increased extracellular matrix estimated by cardiac magnetic resonance (CMR) and left ventricular aneurysm after acute myocardial infarction. METHODS: A total of 175 patients from 3 centers with an isolated left anterior descending culprit vessel underwent CMR examinations within 1 week and at a 6-month follow-up. Of these, 92 were identified to have left ventricular aneurysms (LVAs): 74 with functional aneurysm and 18 with anatomical aneurysm. The predictive significance of acute extracellular volume (ECV), left gadolinium enhancement (LGE), and other characteristics were analyzed using binary logistic regression analysis. RESULTS: Patients with LVA were more likely to present with left ventricular adverse remodeling (LVAR) than those without (p = 0.009). With optimal cutoff values of 30.90% for LGE and 33% for ECV to discriminate LVA from non-LVA, the area under the curve (AUC) by receiver operator characteristic curve (ROC) analysis was 0.92 (95% CI: 0.87-0.96; p < 0.001) and 0.93 (95% CI: 0.88-0.96; p < 0.001), respectively. ECV was significantly better than LGE at discriminating between functional and anatomical LVA (p < 0.001). Both acute LGE and ECV were predictors of LVA, with an odds ratio of 1.35 (95% CI: 1.21-1.52, p < 0.001) and 1.23 (95% CI: 1.13-1.33, p < 0.001), respectively, by multivariable logistic regression analysis. CONCLUSIONS: Acute LGE and ECV of the myocardium provided predictive significance for LVA. The discriminative significance of ECV for functional versus anatomical LVA was better than the discriminative significance of LGE. KEY POINTS: • Patients with LVA were more likely to present with LVAR. • Acute LGE and ECV of the myocardium provided the strongest predictive significance for LVA. • The discriminative significance of ECV for functional versus anatomical LVA was better than that of LGE.

Improvement in Intraoperative Image Quality in Transcranial Magnetic Resonance-Guided Focused Ultrasound Surgery Using Transmitter Gain Adjustment.

INTRODUCTION: Transcranial magnetic resonance-guided focused ultrasound surgery (TcMRgFUS) has the advantage of allowing immediate evaluation of therapeutic effects after each sonication and intraoperative magnetic resonance imaging (MRI) to visualize the lesion. When the image shows that the lesion has missed the planned target and the therapeutic effects are insufficient, the target of the subsequent ablation can be finely adjusted based on the image. The precision of this adjustment is determined by the image quality. However, the current intraoperative image quality with a 3.0T MRI system is insufficient for precisely detecting the lesion. Thus, we developed and validated a method for improving intraoperative image quality. METHODS: Because intraoperative image quality is affected by transmitter gain (TG), we acquired T2-weighted images (T2WIs) with two types of TG: the automatically adjusted TG (auto TG) and the manually adjusted TG (manual TG). To evaluate the character of images with 2 TGs, the actual flip angle (FA), the image uniformity, and the signal-to-noise ratio (SNR) were measured using a phantom. Then, to assess the quality of intraoperative images, T2WIs with both TGs were acquired during TcMRgFUS for 5 patients. The contrast-to-noise ratio (CNR) of the lesion was retrospectively estimated. RESULTS: The images of the phantom with the auto TG showed substantial variations between the preset and actual FAs (p < 0.01), whereas on the images with the manual TG, there were no variations between the two FAs (p > 0.05). The total image uniformity was considerably lower with the manual TG than with the auto TG (p < 0.01), indicating that the image's signal values with the manual TG were more uniform. The manual TG produced significantly higher SNRs than the auto TG (p < 0.01). In the clinical study, the lesions were clearly detected in intraoperative images with the manual TG, but they were difficult to identify in images with the auto TG. The CNR of lesions in images with manual TG was considerably higher than in images with auto TG (p < 0.01). CONCLUSION: Regarding intraoperative T2WIs using a 3.0T MRI system during TcMRgFUS, the manual TG method improved image quality and delineated the ablative lesion more clearly than the current method with auto TG.

Translational Research Techniques for the Facial Plastic Surgeon: An Overview.

The field of facial plastic and reconstructive surgery (FPRS) is an incredibly diverse, multispecialty field that seeks innovative and novel solutions for the management of physical defects on the head and neck. To aid in the advancement of medical and surgical treatments for these defects, there has been a recent emphasis on the importance of translational research. With recent technological advancements, there are now a myriad of research techniques that are widely accessible for physician and scientist use in translational research. Such techniques include integrated multiomics, advanced cell culture and microfluidic tissue models, established animal models, and emerging computer models generated using bioinformatics. This study discusses these various research techniques and how they have and can be used for research in the context of various important diseases within the field of FPRS.

Thrombolysis, Complete Recanalization, Diffusion Reversal, and Luxury Perfusion in Hyperacute Stroke.

A 59-year old man was admitted to our stroke care unit 1.8 hours after onset of cardioembolic stroke. Administration of issue-plasminogen activator achieved complete recanalization, and his lesion on diffusion-weighted imaging (DWI) disappeared and single photon emission computed tomography showed luxury perfusion. DWI reversal and luxury perfusion were sometimes observed in hyperacute stroke patients, especially timely reperfusion was achieved. However, the relationships between DWI reversal and luxury perfusion were not well known. Transient DWI reversal may be associated with luxury perfusion in patients treated with t-PA, via early complete recanalization achieved by thrombolysis.

Sonographically Determined Fecal Width: An Objective Indicator of Management of Bladder and Bowel Dysfunction in Children.

OBJECTIVE: To test whether sonographically determined fecal width (SDFW) correlates with symptom improvement in a population of children with bladder and bowel dysfunction (BBD) managed with standard urotherapy (SU), even for those patients lacking initial bowel complaints. METHODS: We retrospectively analyzed 200 pediatric BBD patients managed with SU for at least 3 months. Self-reported symptom improvement (complete, partial, no response) following International Children's Continence Society guidelines was tabulated. Patients with complex urologic diagnoses other than vesicoureteral reflux (VUR) were excluded. Pharmacotherapy choice, physical therapy (PT), urinary tract infection (UTI) occurrence, and VUR status were tabulated. SDFW was recorded. Non-parametric analysis of variants (ANOVA) and parametric/non-parametric t testing were used for analysis. RESULTS: Patients had a mean age of 9.5 years (4-12). Forty-eight patients had no gastrointestinal complaints at presentation. Urotherapy yielded complete, partial, and no responses in 14% (n = 27), 33% (n = 67), and 53% (n = 106) of patients, respectively. The average SDFW for those patients with complete response (2.6 cm) was smaller than the SDFW of those with a partial response (3.1 cm) or no response (3.3 cm) (P = .0001). Non-compliance led to greater SDFW compared to compliant patients (3.7 cm and 3.1 cm, respectively, P = .0001). Fecal width was unaffected by VUR, UTI, PT, or pharmacotherapy. CONCLUSION: SDFW correlates well with symptom improvement in pediatric patients managed for BBD, confirming our hypothesis. SDFW is reasonable as single objective parameter to identify successful management in patients with BBD, extending to those without bowel complaints at presentation.

Early Identification and Intervention in Malignant Transformation of Respiratory Papillomatosis.

BACKGROUND Human papilloma virus is a ubiquitous and preventable disease with the potential to cause recurrent respiratory papillomatosis. These papillomas affect the mucosal surface of the airways and may lead to airway obstruction. The papillomas require excision when breathing is compromised, and may be fatal if untreated. Rarely, these papillomas progress to cancer. CASE REPORT We report the case of a 21-year-old woman with a history of HPV 11- and 16-positive recurrent laryngeal and respiratory papillomatosis (RRP) since the age of 7 months, requiring multiple local resections in her respiratory tract. Chest CT demonstrated multiple cavitary lesions throughout both lungs with a rapidly growing mass that occupied most of her right lung. Imaging supported a diagnosis of malignant transformation to squamous cell carcinoma of the lung. Bilateral involvement of the lungs indicated stage IVa squamous cell lung cancer, which is not curable. CONCLUSIONS Clinicians should suspect malignant transformation in patients with HPV type 11, especially if they have required multiple excisions. Earlier age at onset and number of excisions may be predictors for severity of the disease course. These patients need continued surveillance imaging to allow early interventions if malignant transformation occurs. We present the case of a 21-year-old being diagnosed with an incurable disease that may have been avoided with adequate preventive care.

Robotic versus laparoscopic surgery for hiatal hernia repair: a systematic literature review and meta-analysis.

The number of robotic hiatal hernia repairs (RHHR) is increasing. However, the superiority of this minimally invasive approach remains controversial. The aim of this study was to evaluate the available literature reporting on outcomes of RHHR compared with laparoscopic hiatal hernia repair (LHHR) in adult patients. The design of this systematic review was developed using the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Web of Science, PubMed, the Cochrane Library, and ClinicalTrials.gov databases were searched. Identified publications were reviewed independently by two authors. High heterogeneity was further explored through sensitivity analysis. The primary endpoint was the development of postoperative complications. Secondary endpoints included operation time, intraoperative complications, 30 day readmission rates and length of stay. The analysis was performed using Stata 17.0 software. A total of 7 studies totaling 10078 patients met the inclusion criteria. Five studies included postoperative complications. The postoperative complications rate was 4.25% (302/7111) in the LHHR group, and 3.49% (38/1088) in the RHHR group. Postoperative complications significantly decreased after RHHR compared with LHHR (OR 0.52; 95% CI 0.36 to 0.75, P = 0.000). Three studies involving 2176 patients reported length of hospital stay. In the three studies, the mean Length of hospital stay was 3.2 days in the RHHR group, and 4.2 days in the LHHR group. Length of hospital stay was decreased by a mean of 0.68 days for RHHR compared with LHHR (WMD, - 0.68 days; 95% CI - 1.32 to - 0.03, P = 0.02). There was no significant difference between the RHHR group and the LHHR group regarding operative time, intraoperative complications, and 30 day readmission (P > 0.05). Our research shows that RHHR may be the better option, as the approach decreases postoperative complications and length of hospital stay.

Cervical Transverse Myelitis Following COVID-19 Vaccination.

Various COVID-19 vaccines are associated with numerous adverse side effects. Associations between vaccinations and neurological disorders, such as transverse myelitis, stroke, Bell's palsy, acute disseminated encephalomyelitis, and Guillain-Barré syndrome, have been reported. A 27-year-old Japanese woman presented with paresthesia four days after receiving a second dose of the COVID-19 vaccine. One month after vaccination, she started to feel left lower limb weakness, and her symptoms almost improved after two steroid pulse therapies. Spinal cord tumor biopsy could potentially help make a definitive diagnosis in clinical situations. However, it is very important to review the patient's medical history, including vaccinations received, before performing a direct spinal cord biopsy, which is invasive and does not guarantee a definitive diagnosis.

Predictors of thermal increase in magnetic resonance-guided focused ultrasound treatment for essential tremor: histogram analysis of skull density ratio values for 1024 elements.

OBJECTIVE: Sufficient thermal increase capable of generating thermocoagulation is indispensable for an effective clinical outcome in patients undergoing magnetic resonance-guided focused ultrasound (MRgFUS). The skull density ratio (SDR) is one of the most dominant predictors of thermal increase prior to treatment. However, users currently rely only on the average SDR value (SDRmean) as a screening criterion, although some patients with low SDRmean values can achieve sufficient thermal increase. The present study aimed to examine the numerical distribution of SDR values across 1024 elements to identify more precise predictors of thermal increase during MRgFUS. METHODS: The authors retrospectively analyzed the correlations between the skull parameters and the maximum temperature achieved during unilateral ventral intermediate nucleus thalamotomy with MRgFUS in a cohort of 55 patients. In addition, the numerical distribution of SDR values was quantified across 1024 elements by using the skewness, kurtosis, entropy, and uniformity of the SDR histogram. Next, the authors evaluated the correlation between the aforementioned indices and a peak temperature > 55°C by using univariate and multivariate logistic regression analyses. Receiver operating characteristic curve analysis was performed to compare the predictive ability of the indices. The diagnostic performance of significant factors was also assessed. RESULTS: The SDR skewness (SDRskewness) was identified as a significant predictor of thermal increase in the univariate and multivariate logistic regression analyses (p < 0.001, p = 0.013). Moreover, the receiver operating characteristic curve analysis indicated that the SDRskewness exhibited a better predictive ability than the SDRmean, with area under the curve values of 0.847 and 0.784, respectively. CONCLUSIONS: The SDRskewness is a more accurate predictor of thermal increase than the conventional SDRmean. The authors suggest setting the SDRskewness cutoff value to 0.68. SDRskewness may allow for the inclusion of treatable patients with essential tremor who would have been screened out based on the SDRmean exclusion criterion.

Correction of the skull density ratio for transcranial MRI-guided focused ultrasound thalamotomy: clinical significance of predicting therapeutic temperature.

OBJECTIVE: In transcranial magnetic resonance imaging-guided focused ultrasound (TcMRgFUS), a high skull density ratio (SDR) is advantageous to achieve a sufficiently high temperature at the target. However, it is not easy to estimate the temperature rise because the SDR shows different values depending on the reconstruction filter used. The resolution characteristic of a computed tomography (CT) image depends on a modulation transfer function (MTF) defined by the reconstruction filter. Differences in MTF induce unstable SDRs. The purpose of this study was both to standardize SDR by developing a method to correct the MTF and to enable effective patient screening prior to TcMRgFUS treatment and more accurate predictions of focal temperature. METHODS: CT images of a skull phantom and five subjects were obtained using eight different reconstruction filters. A frequency filter (FF) was calculated using the MTF of each reconstruction filter, and the validity of SDR standardization was evaluated by comparing the variation in SDR before and after FF correction. Subsequently, FF processing was similarly performed using the CT images of 18 patients who had undergone TcMRgFUS, and statistical analyses were performed comparing the relationship between the SDRs before and after correction and the maximum temperature in the target during TcMRgFUS treatment. RESULTS: The FF was calculated for each reconstruction filter based on one manufacturer's BONE filter. In the CT images of the skull phantom, the SDR before FF correction with five of the other seven reconstruction filters was significantly smaller than that with the BONE filter (p < 0.01). After FF correction, however, a significant difference was recognized under only one condition. In the CT images of the five subjects, variation of the SDR due to imaging conditions was significantly improved after the FF correction. In 18 cases treated with TcMRgFUS, there was no correlation between SDR before FF correction and maximum temperature (rs = 0.31, p > 0.05); however, a strong positive correlation was observed after FF correction (rs = 0.71, p < 0.01). CONCLUSIONS: After FF correction, the difference in SDR due to the reconstruction filter used is smaller, and the correlation with temperature is stronger. Therefore, the SDR can be standardized by applying the FF, and the maximum temperature during treatment may be predicted more accurately.

[Two Cases of Parkinson's Disease Accompanied with Nasogastric Tube Syndrome].

We report 2 cases of patients with Parkinson's disease who exhibited bilateral vocal cord paralysis induced by an indwelling nasogastric tube (N-G tube). Both patients showed abrupt inspiratory stridor after N-G tube placement. A fiberoptic laryngeal examination revealed bilateral vocal cord abductor paralysis (VCAP). After N-G tube removal, patient symptoms improved. Nasogastric tube syndrome (NGTS) is an uncommon but life-threatening syndrome that causes sore throat and bilateral VCAP following N-G tube insertion. Throat pain is considered an important early manifestation of NGTS. However, in cases of advanced Parkinson's disease, subjective symptoms of NGTS, such as throat pain, may be difficult to recognize. We here report 2 patients with parkinson's disease accompanied by NGTS with literature review and proposed that inspiratory strider is a useful objective symptom in early diagnosing of NGTS. (Received March 25, 2020; Accepted May 18, 2020; Published September 1, 2020).

Atypical type of familial Mediterranean fever: An underdiagnosed cause of chronic aseptic meningitis.

We report an atypical case of familial Mediterranean fever (FMF) concomitant with chronic aseptic meningitis. The patient experienced fever, abdominal and back pain because of serositis, and headache because of aseptic meningitis for 4 weeks. Blood examinations revealed increased white blood cells and serum amyloid A level. Medications, including steroids, did not improve his symptoms. However, the patient experienced immediate relief after the administration of colchicine. We diagnosed him as having atypical FMF based on the symptoms, especially positive response to colchicine, and heterozygous mutations on exon2 and 5 (E148Q/S503C) in MEFV gene. Unlike typical FMF, a cause of recurrent aseptic meningitis, atypical FMF might be an underdiagnosed cause of chronic aseptic meningitis.

Prevalence and clinical characteristics of cortical superficial siderosis in patients with acute stroke.

Cortical superficial siderosis (cSS) is a pathologic and radiologic diagnosis of hemosiderin deposition in subpial brain layers. However, cSS has not been fully studied in patients with acute stroke. Here, we investigated the prevalence of cSS in patients with acute stroke and analyzed the relationship between cSS and different clinical and neuroimaging characteristics. From September 2014 through June 2016, consecutive patients with acute stroke who were admitted to our department were retrospectively investigated. We analyzed the prevalence of cSS and the associations between cSS and risk factors, the topographic distribution of cerebral microbleeds (CMBs), and the severity of white matter lesions (WMLs). In total, 739 patients (589 patients with ischemic stroke/transient ischemic stroke [IS/TIA] and 150 with intracerebral hemorrhage [ICH]; mean age, 71.4 years) were enrolled. We identified cSS in six (1.0%) patients with IS/TIA and seven (4.7%) patients with ICH. The presence of cSS was associated with ICH (P < 0.0001), WMLs (P = 0.0105), and lobar and non-lobar CMBs (both P < 0.0001); no associations between cSS and age, sex, cardiovascular risk factors, IS subtype classification, or antiplatelet and anticoagulant therapy were found. In a multivariable logistic regression analysis, high numbers of lobar CMBs (≥ 2; odds ratio, 11.03; 95% confidence interval, 2.03-205.40; P = 0.0029) were independently associated with cSS. Furthermore, cSS was often located near lobar CMBs. Our results suggest that cSS is prevalent in ICH and is independently associated with lobar CMBs; however, no associations between cSS and other risk factors or comorbidities were observed.

Current Scaling and Dirac Fermion Heating in Multi-Layer Graphene.

We have performed transport measurements on a multi-layer graphene device fabricated by conventional mechanical exfoliation. By using the zero-field resistance of our graphene device as a self-thermometer, we are able to determine the effective Dirac fermion temperature TDF at various driving currents I while keeping the lattice constant fixed. Interesting, it is found that TDF is proportional to Ia where a ~ 1. According to theoretical and experimental studies, the exponent a is given by 2/(2+p) where the charge-phonon scattering rate 1/τph is proportional to TP. Therefore our results yield p ~ 0, suggesting that there is little Dirac fermion-phonon scattering, a great advantage for applications in nanoelectronics.

Experimental evidence for direct insulator-quantum Hall transition in multi-layer graphene.

We have performed magnetotransport measurements on a multi-layer graphene flake. At the crossing magnetic field Bc, an approximately temperature-independent point in the measured longitudinal resistivity ρxx, which is ascribed to the direct insulator-quantum Hall (I-QH) transition, is observed. By analyzing the amplitudes of the magnetoresistivity oscillations, we are able to measure the quantum mobility µq of our device. It is found that at the direct I-QH transition, µqBc ≈ 0.37 which is considerably smaller than 1. In contrast, at Bc, ρxx is close to the Hall resistivity ρxy, i.e., the classical mobility µBc is ≈ 1. Therefore, our results suggest that different mobilities need to be introduced for the direct I-QH transition observed in multi-layered graphene. Combined with existing experimental results obtained in various material systems, our data obtained on graphene suggest that the direct I-QH transition is a universal effect in 2D.

GR-FET application for high-frequency detection device.

A small forbidden gap matched to low-energy photons (meV) and a quasi-Dirac electron system are both definitive characteristics of bilayer graphene (GR) that has gained it considerable interest in realizing a broadly tunable sensor for application in the microwave region around gigahertz (GHz) and terahertz (THz) regimes. In this work, a systematic study is presented which explores the GHz/THz detection limit of both bilayer and single-layer graphene field-effect transistor (GR-FET) devices. Several major improvements to the wiring setup, insulation architecture, graphite source, and bolometric heating of the GR-FET sensor were made in order to extend microwave photoresponse past previous reports of 40 GHz and to further improve THz detection.