Added Value of FDG PET/MRI in Gynecologic Oncology: A Pictorial Review.

Fluorine 18-fluorodeoxyglucose (FDG) PET and MRI independently play a valuable role in the management of patients with gynecologic malignancies, particularly endometrial and cervical cancer. The PET/MRI hybrid imaging technique combines the metabolic information obtained from PET with the excellent soft-tissue resolution and anatomic details provided by MRI in a single examination. MRI is the modality of choice for assessment of local tumor extent in the pelvis, whereas PET is used to assess for local-regional spread and distant metastases. The authors discuss the added value of FDG PET/MRI in imaging gynecologic malignancies of the pelvis, with a focus on the role of FDG PET/MRI in diagnosis, staging, assessing treatment response, and characterizing complications. PET/MRI allows better localization and demarcation of the extent of disease, characterization of lesions and involvement of adjacent organs and lymph nodes, and improved differentiation of benign from malignant tissues, as well as detection of the presence of distant metastasis. It also has the advantages of decreased radiation dose and a higher signal-to-noise ratio of a prolonged PET examination of the pelvis contemporaneous with MRI. The authors provide a brief technical overview of PET/MRI, highlight how simultaneously performed PET/MRI can improve stand-alone MRI and PET/CT in gynecologic malignancies, provide an image-rich review to illustrate practical and clinically relevant applications of this imaging technique, and review common pitfalls encountered in clinical practice. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

Nucleotide-dependent farnesyl switch orchestrates polymerization and membrane binding of human guanylate-binding protein 1.

Dynamin-like proteins (DLPs) mediate various membrane fusion and fission processes within the cell, which often require the polymerization of DLPs. An IFN-inducible family of DLPs, the guanylate-binding proteins (GBPs), is involved in antimicrobial and antiviral responses within the cell. Human guanylate-binding protein 1 (hGBP1), the founding member of GBPs, is also engaged in the regulation of cell adhesion and migration. Here, we show how the GTPase cycle of farnesylated hGBP1 (hGBP1F) regulates its self-assembly and membrane interaction. Using vesicles of various sizes as a lipid bilayer model, we show GTP-dependent membrane binding of hGBP1F In addition, we demonstrate nucleotide-dependent tethering ability of hGBP1F Furthermore, we report nucleotide-dependent polymerization of hGBP1F, which competes with membrane binding of the protein. Our results show that hGBP1F acts as a nucleotide-controlled molecular switch by modulating the accessibility of its farnesyl moiety, which does not require any supportive proteins.

Prognostic risk factors for rare oncocytic variantin 101 cases of papillary thyroid carcinoma.

OBJECTIVE: Oncocytic variant (OV) is an unusual subtype of papillary thyroid cancer whose histopathologic diagnostic criteria, clinicopathologic features and biological behavior are different and have not been comprehensively studied, characterized in literature. Previous studies present conflicting results upon its prognosis. We investigated demographic and clinicopathologic risk factors affecting its prognosis while presenting our clinical experience. SUBJECTS AND METHODS: This is a retrospective cohort study reviewing 101 patients of OV from an archive of 4500 well-differentiated thyroid cancer patients treated with iodine-131 (131I) between 1991 and 2017. Predefined parameters of age, gender, tumor size (TS), total 131I dose, time to recurrent disease, overall survival, extrathyroidal extension, multifocality, vascular invasion, accompanying other variants, capsular status of thyroid gland, initial cervical lymph node (LN) metastases, preablation stimulated thyroglobulin level, background thyroiditis and stage were evaluated by statistical comparison between metastatic and nonmetastatic groups. RESULTS: Seventeen cases (17%) developed metastases/recurrence, 70% of the recurrences occured before 24 months. Four patients (4%) died during the follow-up. Metastatic sites were usually cervical LN, local recurrence in thyroid bed and lungs. Multivariate analysis revealed stage (IV) and TS were the main parameters impacting recurrence/metastases. In the follow-up, isolated cervical LN metastases were found in 41% of metastatic cases, while 12% had sole recurrence in thyroid bed. Eighty eight percent of the metastatic disease included locoregional (cervical) and/or remote LN. The recurrences were associated with initial thyroid masses greater than 3.5cm in diameter. CONCLUSION: We found that the prognosis of OV is not poor in our series. Stage (IV) and tumor size are the main risk factors in metastatic development.

Evaluation of predictor variables of diagnostic [18F] FDG-PET/CT in fever of unknown origin.

BACKGROUND: Fever of unknown origin (FUO) is defined as an illness having fever which lasts at least 3 weeks of duration and is higher than 38.3 ºC on several measurements. The causes are infections, malignancies, noninfectious inflammatory diseases and miscellaneous. If [18F]FDG-PET/CT helps the final diagnosis, it is called contributory. The aim of the study is to evaluate the predictor variables effecting a contributory PET/CT for the diagnosis. METHODS: This is a retrospective cohort study conducted between June 2006 and May 2015 including 76 patients. The evaluated predictor variables are age, sex, ESR, CRP, fibrinogen, ferritin, albumin, haemoglobin level, platelet count, total leukocyte count, neutrophil percentage, lymphocyte percentage, ALP, LDH, ALAT, ASAT, GGT, total bilirubin, CK, RF, ANA, urinanalysis, chest radiography, abdominal US, lymphadenopathy, duration of fever, comorbid diseases and previous therapies. RESULTS: ESR (P=0.001), CRP (P=0.001), fibrinogen (P=0.009), lymphopenia (P<0.001), neutrophilia (P<0.001), ferritin (P<0.001), leukocytosis (P=0.003), duration of fever before PET/CT (<3 months) were found to be statistically significant for positive contribution of PET/CT results to the diagnosis. CONCLUSIONS: [18F]FDG-PET/CT is helpful and contributory for the diagnosis of FUO in patients having higher levels of CRP, ESR, ferritin, fibrinogen, leukocytosis, neutrophilia and shorter durations of fever (<3 months).

Impact of tall cell variant histology on predicting relapse and changing the management of papillary thyroid carcinoma patients.

OBJECTIVE: There has been much discussion recently about the risk category of tall cell variant (TVC) histology and its effects on the management of papillary thyroid carcinoma (PTC). We, therefore, undertook a retrospective study to compare stage-matched risk factors and recurrence rates between classical PTC (cPTC) patients and patients with TCV histology. SUBJECTS AND METHODS: A total of 3128 well-differentiated thyroid carcinoma patients who were treated and followed-up for more than 5 years in our clinic from 1995 to 2016 were included in this study. There were 2783 PTC (89%) patients, 1113 (40%) of them were cPTC and 56 (2%) of them were TCV patients. RESULTS: In all stages, the stage-matched incidence of extrathyroidal extension (ETE), lymphovascular invasion and initial lymph node metastases were significantly higher in TCV patients than in cPTC patients (P<0.001). Recurrence was in 10 of 27 patients (37%) with TCV and in 91 of 890 (10%) patients with cPTC diagnosed in stage I (odds ratio (OR)=5.16); in 4 of 6 patients with TCV and 18 of 84 (21%) patients with cPTC in stage II (OR=7.33); in 5 of 6 patients with TCV and 11 of 46 (23%) patients with cPTC in stage III (OR=15.90); and in 13 of 17 patients with TCV and 31 of 93 (33%) patients with cPTC in stage IV (OR=6.50). Stage-matched recurrence rates were found significantly higher in all stages of TCV patients than in cPTC patients (OR=8.49, P<0.001). Recurrence with distant metastases was seen more frequently in TCV patients than in cPTC patients (P<0.001) and treatment of metastatic disease was more difficult in TCV patients. CONCLUSION: Tall cell variant was an independent poor prognostic factor in papillary thyroid carcinoma patients even if they were diagnosed at early stages of the disease. Patients with tall cell variant histology required more aggressive therapeutic approach and closer follow-up than classical patients.

Clinical Significance of Fluorine-18-fluorodeoxyglucose Positron Emission Tomography/computed Tomography in the Follow-up of Colorectal Cancer: Searching off Approaches Increasing Specificity for Detection of Recurrence.

BACKGROUND: Nearly 40% of colorectal cancer (CRC) recurs within 2 years after resection of primary tumor. Imaging with fluorine-18-fluorodeoxyglucose (l8F-FDG) positron emission tomography/computed tomography (PET/CT) is the most recent modality and often applied for the evaluation of metastatic spread during the follow-up period. Our goal was to study the diagnostic importance of 18F-FDG-PET/CT data of maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG) and the difference of SUVmax on dual-time imaging in CRC. PATIENTS AND METHODS: We examined the SUVmax value of lesions on control or restaging 18F-FDG-PET/CT of 53 CRC patients. All lesions with increased SUVmax values were confirmed by colonoscopy or histopathology. We compared PET/CT results with conventional imaging modalities (CT, MRI) and tumor markers (carbohydrate antigen 19-9 [Ca 19-9], carcinoembryonic antigen [CEA]). RESULTS: Mean SUVmax was 6.9 ± 5.6 in benign group, 12.7 ± 6.1 in malignant group. Mean TLG values of malignant group and benign group were 401 and 148, respectively. 18F-FDG-PET/CT was truely positive in 48% of patients with normal Ca 19-9 or CEA levels and truely negative in 10% of cases with elevated Ca 19-9 or CEA. CT or MRI detected suspicious malignancy in 32% of the patients and 18F-FDG-PET/CT was truely negative in 35% of these cases. We found the most important and striking statistical difference of TLG value between the groups with benign and recurrent disease. CONCLUSIONS: Although SUVmax is a strong metabolic parameter (p = 0.008), TLG seems to be the best predictor in recurrence of CRC (p = 0.001); both are increasing the specificity of 18F-FDG-PET/CT.

Risk factors and stratification for recurrence of patients with differentiated thyroid cancer, elevated thyroglobulin and negative I-131 whole-body scan, by restaging 18F-FDG PET/CT.

OBJECTIVE: In nearly 20%-30% of patients with differentiated thyroid carcinoma (DTC) relapse and 7% of them die during the next 10 years after initial diagnosis. In 10%-30% of patients with DTC after ablation therapy during the follow-up show a negative iodine-131 (131I) whole-body screening test (131I WBS) and increased serum thyroglobulin (Tg) level. Loss of ability of DTC metastatic lesions to trap 131I is associated with pure survival and often aggressive disease. Several studies have shown that in DTC cases non trapping 131I, fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) can detect recurrence or metastases with high sensitivity (80%-90%). The purpose of this study was to investigate the clinicopathologic features and other related risk factors of patients with DTC having elevated Tg levels and negative 131I WBS in which recurrence was detected by 18F-FDG PET/CT. We tried to study and stratify patients in this grey zone who could benefit from 18F-FDG PET/CT for the detection of metastases/recurrence according to predefined risk factors not investigated by other researchers. SUBJECTS AND METHODS: We studied retrospectively 165 DTC patients with elevated Tg levels and a negative 131I WBS during their follow-up between 2004-2015. Metastases/recurrence was found in 49% of the patients on restaging with 18F-FDG PET/CT and were compared with nonmetastatic group according to predefined risk factors. These factors were also evaluated in true positive and false negative cases. RESULTS: The sensitivity and specificity of 18F-FDG PET/CT for detecting recurrent/metastatic disease were 90% and 98.5%, respectively. No apparent predefined risk factor impacting a false negative 18F-FDG PET/CT was found. Findings in follicular carcinoma, Hürtle cell carcinoma and papillary carcinoma were not different from positive PET findings. The variants of papillary carcinoma also had no statistically difference with regard to 18F-FDG results. CONCLUSION: The most important factors affecting a true positive 18F-FDG PET/CT study were: ETE, high total 131I dose and the SUVmax values over 4.5.

Prognosis estimation under the light of metabolic tumor parameters on initial FDG-PET/CT in patients with primary extranodal lymphoma.

BACKGROUND: Non-Hodgkin's lymphomas arising from the tissues other than primary lymphatic organs are named primary extranodal lymphoma. Most of the studies evaluated metabolic tumor parameters in different organs and histopathologic variants of this disease generally for treatment response. We aimed to evaluate the prognostic value of metabolic tumor parameters derived from initial FDG-PET/CT in patients with a medley of primary extranodal lymphoma in this study. PATIENTS AND METHODS: There were 67 patients with primary extranodal lymphoma for whom FDG-PET/CT was requested for primary staging. Quantitative PET/CT parameters: maximum standardized uptake value (SUVmax), average standardized uptake value (SUVmean), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were used to estimate disease-free survival and overall survival. RESULTS: SUVmean, MTV and TLG were found statistically significant after multivariate analysis. SUVmean remained significant after ROC curve analysis. Sensitivity and specificity were calculated as 88% and 64%, respectively, when the cut-off value of SUVmean was chosen as 5.15. After the investigation of primary presentation sites and histo-pathological variants according to recurrence, there is no difference amongst the variants. Primary site of extranodal lymphomas however, is statistically important (p = 0.014). Testis and central nervous system lymphomas have higher recurrence rate (62.5%, 73%, respectively). CONCLUSIONS: High SUVmean, MTV and TLG values obtained from primary staging FDG-PET/CT are potential risk factors for both disease-free survival and overall survival in primary extranodal lymphoma. SUVmean is the most significant one amongst them for estimating recurrence/metastasis.

18F-FDG PET/CT findings in a case of a semantic variant of primary progressive aphasia.

UNLABELLED: Progressive speech and language disorders are commonly referred to as primary progressive aphasia (PPA), which is a clinical syndrome eroding both speech and language. Functional imaging may reveal the cause of this disorder even if structural imaging is absent. Fluorine-18- fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) allows the assessment of neuronal activity by semi-quantitatively measuring glucose metabolism in the brain. In medical literature, (18)F-FDG PET/CT studies show hypometabolic areas in different regions of the brain which are special clues for differentiating the subgroups of PPA. CONCLUSION: This case was reported to demonstrate the characteristic (18)F-FDG PET CT findings for a semantic variant of PPA.

Evaluation of radiographic and metabolic changes in bone metastases in response to systemic therapy with (18)FDG-PET/CT.

BACKGROUND: The aim of the study was to retrospectively evaluate radiographic and metabolic changes in bone metastases in response to systemic therapy with (18)FDG-PET/CT and determine their roles on the evaluation of therapy response. PATIENTS AND METHODS: We retrospectively evaluated radiographic and metabolic characteristics of bone metastases in 30 patients who were referred for the evaluation of response to systemic therapy with (18)FDG-PET/CT. All patients underwent integrated (18)FDG-PET/CT before and after treatment. RESULTS: The baseline radiographic patterns of the target lesions in responders group were lytic, sclerotic, mixed and CT negative; after treatment the radiographic patterns of all target lesions changed to a sclerotic pattern and attenuation increased (p = 0.012) and metabolic activity decreased (p = 0.012). A correlation was found between decreasing metabolic activity and increasing attenuation of the target lesions (r = -0.55) (p = 0.026). However, in nonresponders group, the baseline radiologic patterns of the target lesions were lytic, blastic, mixed and CT negative; after treatment all lytic target lesions remained the same and one CT negative lesion turned to lytic pattern and the attenuation of the target lesions decreased (p ± 0.12) and metabolic activity increased (p = 0.012). A correlation was found between increasing metabolic activity and decreasing attenuation (r = -0.65) (p = 0.032). An exception of this rule was seen in baseline blastic metastases which progressed with increasing in size, metabolic activity and attenuation. CONCLUSIONS: This study shows that the metabolic activity of lesions is a more reliable parameter than the radiographic patterns for the evaluation of therapy response.

Test-Retest Repeatability of Patlak Slopes versus Standardized Uptake Values for Hypermetabolic Lesions and Normal Organs in an Oncologic PET/CT Population.

PURPOSE: We aimed to determine the test-retest repeatability of quantitative metrics based on the Patlak slope (PS) versus the standardized uptake value (SUV) among lesions and normal organs on oncologic [18F]FDG-PET/CT. PROCEDURES: This prospective, single-center study enrolled adults undergoing standard-of-care oncologic [18F]FDG-PET/CTs. Early (35-50 min post-injection) and late (75-90 min post-injection) SUV and PS images were reconstructed from dynamic whole-body PET data. Repeat imaging occurred within 7 days. Relevant quantitative metrics were extracted from lesions and normal organs. Repeatability was assessed via mean test-retest percent changes [T-RT %Δ], within-subject coefficients of variation (wCVs), and intra-class correlation coefficients (ICCs). RESULTS: Nine subjects (mean age, 61.7 ± 6.2 years; 6 females) completed the test-retest protocol. Four subjects collectively had 17 [18F]FDG-avid lesions. Lesion wCVs were higher (i.e., worse repeatability) for PS-early-max (16.2%) and PS-early-peak (15.6%) than for SUV-early-max (8.9%) and SUV-early-peak (8.1%), with similar early metric ICCs (0.95-0.98). Lesion wCVs were similar for PS-late-max (8.5%) and PS-late-peak (6.4%) relative to SUV-late-max (9.7%) and SUV-late-peak (7.2%), with similar late metric ICCs (0.93-0.98). There was a significant bias toward higher retest SUV and PS values in the lesion analysis (T-RT %Δ [95% CI]: SUV-late-max, 10.0% [2.6%, 17.0%]; PS-late-max, 20.4% [14.3%, 26.4%]) but not in the normal organ analysis. CONCLUSIONS: Among [18F]FDG-avid lesions, the repeatability of PS-based metrics is similar to equivalent SUV-based metrics at late post-injection time points, indicating that PS-based metrics may be suitable for tracking response to oncologic therapies. However, further validation is required in light of our study's limitations, including small sample size and bias toward higher retest values for some metrics.

Patlak Slope versus Standardized Uptake Value Image Quality in an Oncologic PET/CT Population: A Prospective Cross-Sectional Study.

Patlak slope (PS) images have the potential to improve lesion conspicuity compared with standardized uptake value (SUV) images but may be more artifact-prone. This study compared PS versus SUV image quality and hepatic tumor-to-background ratios (TBRs) at matched time points. Early and late SUV and PS images were reconstructed from dynamic positron emission tomography (PET) data. Two independent, blinded readers scored image quality metrics (a four-point Likert scale) and counted tracer-avid lesions. Hepatic lesions and parenchyma were segmented and quantitatively analyzed. Differences were assessed via the Wilcoxon signed-rank test (alpha, 0.05). Forty-three subjects were included. For overall quality and lesion detection, early PS images were significantly inferior to other reconstructions. For overall quality, late PS images (reader 1 [R1]: 3.95, reader 2 [R2]: 3.95) were similar (p > 0.05) to early SUV images (R1: 3.88, R2: 3.84) but slightly superior (p ≤ 0.002) to late SUV images (R1: 2.97, R2: 3.44). For lesion detection, late PS images were slightly inferior to late SUV images (R1 only) but slightly superior to early SUV images (both readers). PS-based TBRs were significantly higher than SUV-based TBRs at the early time point, with opposite findings at the late time point. In conclusion, late PS images are similar to early/late SUV images in image quality and lesion detection; the superiority of SUV versus PS hepatic TBRs is time-dependent.

The large GTPase AtGBPL3 links nuclear envelope formation and morphogenesis to transcriptional repression.

Guanylate binding proteins (GBPs) are prominent regulators of immunity not known to be required for nuclear envelope formation and morphogenesis. Here we identify the Arabidopsis GBP orthologue AtGBPL3 as a lamina component with essential functions in mitotic nuclear envelope reformation, nuclear morphogenesis and transcriptional repression during interphase. AtGBPL3 is preferentially expressed in mitotically active root tips, accumulates at the nuclear envelope and interacts with centromeric chromatin as well as with lamina components transcriptionally repressing pericentromeric chromatin. Reduced expression of AtGBPL3 or associated lamina components similarly altered nuclear morphology and caused overlapping transcriptional deregulation. Investigating the dynamics of AtGBPL3-GFP and other nuclear markers during mitosis (1) revealed that AtGBPL3 accumulation on the surface of daughter nuclei precedes nuclear envelope reformation and (2) uncovered defects in this process in roots of AtGBPL3 mutants, which cause programmed cell death and impair growth. AtGBPL3 functions established by these observations are unique among dynamin-family large GTPases.

PET/MRI in colorectal and anal cancers: an update.

Positron emission tomography (PET) in the era of personalized medicine has a unique role in the management of oncological patients and offers several advantages over standard anatomical imaging. However, the role of molecular imaging in lower GI malignancies has historically been limited due to suboptimal anatomical evaluation on the accompanying CT, as well as significant physiological 18F-flurodeoxyglucose (FDG) uptake in the bowel. In the last decade, technological advancements have made whole-body FDG-PET/MRI a feasible alternative to PET/CT and MRI for lower GI malignancies. PET/MRI combines the advantages of molecular imaging with excellent soft tissue contrast resolution. Hence, it constitutes a unique opportunity to improve the imaging of these cancers. FDG-PET/MRI has a potential role in initial diagnosis, assessment of local treatment response, and evaluation for metastatic disease. In this article, we review the recent literature on FDG-PET/MRI for colorectal and anal cancers; provide an example whole-body FDG-PET/MRI protocol; highlight potential interpretive pitfalls; and provide recommendations on particular clinical scenarios in which FDG-PET/MRI is likely to be most beneficial for these cancer types.

Integrative dynamic structural biology unveils conformers essential for the oligomerization of a large GTPase.

Guanylate binding proteins (GBPs) are soluble dynamin-like proteins that undergo a conformational transition for GTP-controlled oligomerization and disrupt membranes of intracellular parasites to exert their function as part of the innate immune system of mammalian cells. We apply neutron spin echo, X-ray scattering, fluorescence, and EPR spectroscopy as techniques for integrative dynamic structural biology to study the structural basis and mechanism of conformational transitions in the human GBP1 (hGBP1). We mapped hGBP1's essential dynamics from nanoseconds to milliseconds by motional spectra of sub-domains. We find a GTP-independent flexibility of the C-terminal effector domain in the µs-regime and resolve structures of two distinct conformers essential for an opening of hGBP1 like a pocket knife and for oligomerization. Our results on hGBP1's conformational heterogeneity and dynamics (intrinsic flexibility) deepen our molecular understanding relevant for its reversible oligomerization, GTP-triggered association of the GTPase-domains and assembly-dependent GTP-hydrolysis.

Acquired epileptiform opercular syndrome: F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) findings and efficacy of levetiracetam therapy.

We report a five-year-old girl presenting with dysphagia, dysarthria, drooling, and generalized tonic convulsions in whom the final diagnosis was acquired epileptiform opercular syndrome. Levetiracetam monotherapy at a dosage of 40 mg/kg/day improved the clinical findings, and seizures were controlled at the end of the first month of treatment. Six months after the initial diagnosis, she presented with speech deterioration and dysarthria. At this time, although sleep and awake electroencephalography (EEG) were normal, FDG-PET showed hypometabolic and hypermetabolic regions in the anterior/inferior and anterior regions of the right frontal lobe, respectively. By increasing before levetiracetam dosage to 50 mg/kg/day, the clinical findings resolved and the patient is still seizure free. Acquired epileptiform opercular syndrome is a rare epileptic disorder in which the seizures are resistant to conventional antiepileptic drugs. Levetiracetam may be an effective antiepileptic drug in controlling seizures and other clinical findings in acquired opercular epileptiform syndrome. Hypometabolic and hypermetabolic regions in FDG-PET study may be due to ongoing seizure activity or impaired glucose metabolism in this disorder.

Correlation of Morphological and Functional Cardiac Images: Fusion of Myocardial Perfusion SPECT and CT Angiography.

Objectives: The current study evaluates the value of cardiac hybrid imaging (CHI), performed by the fusion of functional and anatomic cardiac images, in the detection of hemodynamically significant coronary stenosis in cases with multiple coronary stenosis. Methods: A total of 36 patients (10 female, 26 male) in whom ischemia or infarction was detected on gated myocardial perfusion single photon emission computed tomography (gMPS) and multiple coronary stenosis were concomitantly detected on coronary computed tomography angiography (CCTA) and undergone invasive coronary angiography (ICA) was included in this study. Statistical analyses were performed using SPSS 22 Windows software. McNemar test was applied to show concordance between coronary CT angiography, ICA and CHI in the detection of anatomically or hemodynamically significant stenosis in three major coronary arteries. Comparison results of coronary arteries responsible for perfusion defects on CHI and gMPS are presented as percentages (%). Results: There was total accordance between coronary arteries leading to perfusion defects detected by gMPS and CHI in 50% of patients. It was observed a partial accordance in 36.1% of the patients. Additionally, it was also detected perfusion defects originated from side branches in 25% of the patients. Between results of CCTA and ICA, no statistically significant difference was noted in the detection of anatomically significant stenoses in the left main coronary artery, left anterior descending artery (LAD), left circumflex artery (LCx) and right coronary artery (RCA) (p=1.000, 0.070, 0.549, and 1.000, respectively). In addition, no statistically significant difference was found in the detection of anatomically and hemodynamically significant stenoses in LAD, LCx and RCA by CCTA and CHI (p=0.344, 0.629, and 0.219, respectively). No statistically significant difference was observed in the detection of anatomically and hemodynamically significant stenoses in LAD, LCx and RCA by ICA and CHI (p=0.804, 1.000, and 0.344, respectively). Conclusion: It is possible to detect hemodynamically significant coronary stenosis directly by CHI modality in patients with multiple coronary stenosis, wide perfusion defects.

ATP-binding and hydrolysis of human NLRP3.

The innate immune system uses inflammasomal proteins to recognize danger signals and fight invading pathogens. NLRP3, a multidomain protein belonging to the family of STAND ATPases, is characterized by its central nucleotide-binding NACHT domain. The incorporation of ATP is thought to correlate with large conformational changes in NLRP3, leading to an active state of the sensory protein. Here we analyze the intrinsic ATP hydrolysis activity of recombinant NLRP3 by reverse phase HPLC. Wild-type NLRP3 appears in two different conformational states that exhibit an approximately fourteen-fold different hydrolysis activity in accordance with an inactive, autoinhibited state and an open, active state. The impact of canonical residues in the nucleotide binding site as the Walker A and B motifs and sensor 1 and 2 is analyzed by site directed mutagenesis. Cellular experiments show that reduced NLRP3 hydrolysis activity correlates with higher ASC specking after inflammation stimulation. Addition of the kinase NEK7 does not change the hydrolysis activity of NLRP3. Our data provide a comprehensive view on the function of conserved residues in the nucleotide-binding site of NLRP3 and the correlation of ATP hydrolysis with inflammasome activity.

FDG-PET/MRI for Nonoperative Management of Rectal Cancer: A Prospective Pilot Study.

Nonoperative management (NOM) is increasingly utilized for rectal cancer patients with a clinical complete response (cCR) following total neoadjuvant therapy (TNT). The objective of this pilot study was to determine whether FDG-PET/MRI alters clinical response assessments among stage I-III rectal cancer patients undergoing TNT followed by NOM, relative to MRI alone. This prospective study included 14 subjects with new rectal cancer diagnoses. Imaging consisted of FDG-PET/MRI for initial staging, post-TNT restaging, and surveillance during NOM. Two independent readers assessed treatment response on MRI followed by FDG-PET/MRI. Inter-reader differences were resolved by consensus review. The reference standard for post-TNT restaging consisted of surgical pathology or clinical follow-up. 7/14 subjects completed post-TNT restaging FDG-PET/MRIs. 5/7 subjects had evidence of residual disease and underwent total mesorectal excision; 2/7 subjects had initial cCR with no evidence of disease after 12 months of NOM. FDG-PET/MRI assessments of cCR status at post-TNT restaging had an accuracy of 100%, compared with 71% for MRI alone, as FDG-PET detected residual tumor in 2 more subjects. Inter-reader agreement for cCR status on FDG-PET/MRI was moderate (kappa, 0.56). FDG-PET provided added value in 82% (9/11) of restaging/surveillance scans. Our preliminary data indicate that FDG-PET/MRI can detect more residual disease after TNT than MRI alone, with the FDG-PET component providing added value in most restaging/surveillance scans.

Catalytic activity of human guanylate-binding protein 1 coupled to the release of structural restraints imposed by the C-terminal domain.

Human guanylate-binding protein 1 (hGBP-1) shows a dimer-induced acceleration of the GTPase activity yielding GDP as well as GMP. While the head-to-head dimerization of the large GTPase (LG) domain is well understood, the role of the rest of the protein, particularly of the GTPase effector domain (GED), in dimerization and GTP hydrolysis is still obscure. In this study, with truncations and point mutations on hGBP-1 and by means of biochemical and biophysical methods, we demonstrate that the intramolecular communication between the LG domain and the GED (LG:GED) is crucial for protein dimerization and dimer-stimulated GTP hydrolysis. In the course of GTP binding and γ-phosphate cleavage, conformational changes within hGBP-1 are controlled by a chain of amino acids ranging from the region near the nucleotide-binding pocket to the distant LG:GED interface and lead to the release of the GED from the LG domain. This opening of the structure allows the protein to form GED:GED contacts within the dimer, in addition to the established LG:LG interface. After releasing the cleaved γ-phosphate, the dimer either dissociates yielding GDP as the final product or it stays dimeric to further cleave the ß-phosphate yielding GMP. The second phosphate cleavage step, that is, the formation of GMP, is even more strongly coupled to structural changes and thus more sensitive to structural restraints imposed by the GED. Altogether, we depict a comprehensive mechanism of GTP hydrolysis catalyzed by hGBP-1, which provides a detailed molecular understanding of the enzymatic activity connected to large structural rearrangements of the protein. DATABASE: Structural data are available in RCSB Protein Data Bank under the accession numbers: 1F5N, 1DG3, 2B92.