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.

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.

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.

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.

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.

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.

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.

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.

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.

Yttrium-90 (Y-90) resin microsphere therapy for patients with unresectable hepatocellular carcinoma. Identification of successful treatment response predictors and patient selection.

AIM: Selective intraarterial radionuclide therapy (SIRT) with Yttrium-90 (Y-90) resin microspheres has been applied for hepatocellular carcinoma (HCC) lately. The aim of this study is to present our clinical experience of radiomicrosphere therapy in the treatment of unresectable HCC and determine the proper cases who could benefit from this therapy according to response results yielded by initial staging and control imaging modalities. METHODS: We administered 43 Y-90 microsphere therapy to 34 patients with unresectable HCC (twice in 9 patients). Patients with histopathologically confirmed HCC having a life expectancy of ≥3 months; Child A-B, Okuda stage 1-2 and BCLC stage A-B-C classifications were included in the study. The patients were divided into two groups: Group A consisted of 29 patients who responded to Y-90 therapy (complete response, partial response and stable disease), Group B 5 of non-responders (progressive disease). Predefined parameters were evaluated for response to SIRT and compared between two groups. RESULTS: We found a significant decrease in platelet and lymphocyte counts one month after therapy (p=0.02, p=0.01, respectively). On control imaging tests performed 3 months later, we observed complete response in 19% (n=6), partial response in 44% (n=15), stable disease in 25% (n=8) and progressive diease in 12% (n=5) of the patients. Mean overall survival (OS) was 19 (median value: 14) months. CONCLUSIONS: Y-90 microsphere therapy is a safe and effective treatment option for the patients with unresectable HCC without any serious side effect. Mean tumor dose delivery and lack of bilobar disease seem the best predictors for treatment success. KEY WORDS: Selective intraarterial Radionuclide therapy, Yttrium-90, hepatocellular carcinoma.

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.

Low bone density and osteoporosis among older adults with Alzheimer's disease, vascular dementia, and mixed dementia: A Cross-sectional Study With Prospective Enrollment.

OBJECTIVES: This study aims to examine bone mineral density (BMD) and osteoporosis in older adults with dementia compared to those with a normal cognitive status and to evaluate the type, severity, and duration of dementia. PATIENTS AND METHODS: Between May 2013 and May 2017, a total of 363 participants aged ≥65 years (136 males, 227 females; mean age 78.4±5.4 years; range 66 to 99 years) with and without Alzheimer's disease (AD), vascular dementia (VaD), or mixed dementia (AD-VaD) were included in this single-center, prospective, cross-sectional study. The dementia group included 93 patients with dementia and the control group included 270 age- and sex-matched healthy individuals. We used dual-energy X-ray absorptiometry (DXA) to measure BMD of the lumbar spine, total hip, and femoral neck. RESULTS: Controlled for age and sex, demented and non-demented participants had a similar BMD (g/cm2) at lumbar spine [F (1, 358):0.83, p=363], but lower BMD values of total hip [F (1, 359):10.26, p=0.001] and femoral neck [F (1, 359):15.21, p<0.001] in the patients with dementia. Adjusted percentage of osteoporosis and low bone mass based on total hip and femoral neck T-scores were also significantly higher in the patient group. The mean BMD values, frequency of osteoporosis, and low bone mass did not significantly differ according to the subtype of dementia, sex, and disease duration or severity. CONCLUSION: Our study results show that demented elders have a lower BMD and higher frequency of osteoporosis at the hip, but not at the lumbar spine, irrespective of sex and type of dementia. Based on these results, we can speculate that not only AD, but also VaD and AD-VaD may be associated with bone loss at the hip.

Farnesylation of human guanylate-binding protein 1 as safety mechanism preventing structural rearrangements and uninduced dimerization.

Human guanylate-binding protein 1 (hGBP1) belongs to the family of dynamin-like proteins and is activated by addition of nucleotides, leading to protein oligomerization and stimulated GTPase activity. In vivo, hGBP1 is post-translationally modified by attachment of a farnesyl group yielding farn-hGBP1. In this study, hydrodynamic differences in farn-hGBP1 and unmodified hGBP1 were investigated using dynamic light scattering (DLS), analytical ultracentrifugation (AUC) and analytical size-exclusion chromatography (SEC). In addition, we performed small-angle X-ray scattering (SAXS) experiments coupled with a SEC setup (SEC-SAXS) to investigate structural properties of nonmodified hGBP1 and farn-hGBP1 in solution. SEC-SAXS measurements revealed that farnesylation keeps hGBP1 in its inactive monomeric and crystal-like conformation in nucleotide-free solution, whereas unmodified hGBP1 forms a monomer-dimer equilibrium both in the inactive ground state in nucleotide-free solution as well as in the activated state that is trapped by addition of the nonhydrolysable GTP analogue GppNHp. Nonmodified hGBP1 is structurally perturbed as compared to farn-hGBP. In particular, GppNHp binding leads to large structural rearrangements and higher conformational flexibility of the monomer and the dimer. Structural changes observed in the nonmodified protein are prerequisites for further oligomer assemblies of farn-hGBP1 that occur in the presence of nucleotides. DATABASE: All SEC-SAXS data, corresponding fits to the data and structural models are deposited in the Small Angle Scattering Biological Data Bank [SASBDB (Nucleic Acids Res, 43, 2015, D357)] with project IDs: SASDEE8, SASDEF8, SASDEG8, SASDEH8, SASDEJ8, SASDEK8, SASDEL8 and SASDEM8.

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.

Gammagrafía paratiroidea con 99mTc-MIBI: valor complementario de la paratohormona en el aspirado y análisis histopatológico de los tipos de células en los adenomas paratiroideos / Complementary role of parathormone washout test to 99mTc-MIBI parathyroid scintigraphy and histopathologic analysis of cell types in parathyroid adenomas

Objetivo: La gammagrafía paratiroidea (GP) puede ser negativa o equívoca (N/E) en un número considerable de casos con alta sospecha clínica y bioquímica de adenoma de paratiroides (AP). Los objetivos de este estudio fueron investigar el papel complementario de la determinación de paratohormona en punción con aguja fina (PTH en PAAF) con la GP en pacientes con hiperparatiroidismo primario (HPTP) y evaluar los aspectos histopatológicos de los AP en comparación con los resultados de GP. Material y métodos: Fueron incluidos en el estudio 38 pacientes con HPTP remitidos para realizar GP. Diecisiete pacientes tuvieron resultados gammagráficos y ecográficos concordantes con AP (grupo A). Veintiún pacientes con GP N/E pero sospecha de AP en la ecografía formaron el grupo B. Se realizó PTH en PAAF en todos los pacientes y todos fueron operados. Se extirpó un adenoma en cada uno de ellos y en todos los casos se establecieron las características histopatológicas. Resultados: El tamaño del tumor en la ecografía fue mayor en aquellos pacientes cuyos adenomas se vieron en la GP (p<0,001). Los porcentajes de células principales, oxífilas y claras en AP no fueron estadísticamente diferentes entre los grupos. El nivel de paratohormona sérica y PTH en PAAF no fueron estadísticamente significativos entre los grupos A y B (p=0,095 y p=0,04, respectivamente). Conclusión: Aunque no existe un valor umbral definitivo, la sensibilidad de la GP aumenta con el tamaño de la lesión. Mientras que el contenido de células principales y oxífilas tiende a reducirse en los AP con GP N/E EP, la tasa de células claras aumenta sustancialmente. La combinación de GP con la ecografía y la PTH en PAAF aumenta la sensibilidad de detección y localización de los AP

Objective: Parathyroid scintigraphy (PS) can be negative or equivocal (N/E) in a considerable number of cases with highly suspicious clinical findings and biochemical results for parathyroid adenoma (PA). The aims of this study were to investigate the complementary role of parathormone washout test (PWT) to PS in patients with primary hyperparathyroidism (PHPT) and evaluate histopathologic aspects of PAs in comparison with PS results. Material and methods: Thirty-eight patients with PHPT referred for PS were included in the study. Seventeen patients had both scintigraphic and ultrasonographic findings concordant with PA (Group A). Twenty-one patients having N/E PS, but suspected lesions for PA on ultrasonography (US) formed Group B. PWT was performed for all patients and they underwent the surgical intervention. An adenoma was removed in all patients and the histopathologic cell characteristics were established. Results: The tumor size on US was larger in those patients whose adenomas were seen on the PS (P<.001). The percentages of chief (or principal), oxyphilic and clear cells in PAs were not statistically different between the groups. Serum parathormone level and PWT were not statistically significant between Group A and Group B (P=.095 and P=.04, respectively). Conclusion: Although there is not a definitive threshold value, the sensitivity of PS increases with lesion size. While chief cell and oxyphilic cell content of PAs tend to deplete in N/E PS, clear cell rate increases substantially. Combining PS with both US and PWT increases the sensitivity of detection and localization of PAs

Utility of FDG PET/CT in the Management of Primary Testicular Lymphoma.

OBJECTIVE: Primary testicular lymphoma (PTL) is a form of extra-nodal lymphoma originating from the testicles. Currently, positron emission tomography (PET) with glucose analogue 18F-fluorodeoxyglucose (18F-FDG) is the most popular and widely used modality for evaluating tumor metabolism, and PTL usually displays increased 18F-FDG uptake. Despite the rapid increase in clinical applications of FDG PET/ computed tomography (CT), its role in PTL has neither been clearly defined nor reviewed systematically. This study reviews the usefulness and limitation of FDG PET/CT in the diagnosis and treatment of PTL. METHODS: This study included 12 patients with PTL between 2004 and 2015. We retrospectively examined PET/CT results along with patient outcome. The maximum standardized uptake value (SUVmax) was calculated. RESULTS: The mean overall survival (OS) and disease-free survival (DFS) was 44.5 months and 35.5 months, respectively. The mean SUVmax was identified as 18.5 in recurrent/metastatic group. The 1-year and 3-year OS was 94% and 69%, while the 1-year and 2-year DFS was 93.5% and 56%, respectively. CONCLUSION: FDG PET/CT is very helpful in both staging and evaluating treatment response. Although it is not a perfect tool in the initial diagnosis, it might aid in the differential diagnosis of challenging testicular tumors. Pre-treatment and post-treatment FDG uptake values may also have a prognostic value in patients with PTL.

Complementary role of parathormone washout test to 99mTc-MIBI parathyroid scintigraphy and histopathologic analysis of cell types in parathyroid adenomas. / Gammagrafía paratiroidea con 99mTc-MIBI: valor complementario de la paratohormona en el aspirado y análisis histopatológico de los tipos de células en los adenomas paratiroideos.

OBJECTIVE: Parathyroid scintigraphy (PS) can be negative or equivocal (N/E) in a considerable number of cases with highly suspicious clinical findings and biochemical results for parathyroid adenoma (PA). The aims of this study were to investigate the complementary role of parathormone washout test (PWT) to PS in patients with primary hyperparathyroidism (PHPT) and evaluate histopathologic aspects of PAs in comparison with PS results. MATERIAL AND METHODS: Thirty-eight patients with PHPT referred for PS were included in the study. Seventeen patients had both scintigraphic and ultrasonographic findings concordant with PA (Group A). Twenty-one patients having N/E PS, but suspected lesions for PA on ultrasonography (US) formed Group B. PWT was performed for all patients and they underwent the surgical intervention. An adenoma was removed in all patients and the histopathologic cell characteristics were established. RESULTS: The tumor size on US was larger in those patients whose adenomas were seen on the PS (P<.001). The percentages of chief (or principal), oxyphilic and clear cells in PAs were not statistically different between the groups. Serum parathormone level and PWT were not statistically significant between Group A and Group B (P=.095 and P=.04, respectively). CONCLUSION: Although there is not a definitive threshold value, the sensitivity of PS increases with lesion size. While chief cell and oxyphilic cell content of PAs tend to deplete in N/E PS, clear cell rate increases substantially. Combining PS with both US and PWT increases the sensitivity of detection and localization of PAs.

Homo and hetero dimerisation of the human guanylate-binding proteins hGBP-1 and hGBP-5 characterised by affinities and kinetics.

The human guanylate-binding proteins (hGBPs) exhibit diverse antipathogenic and tumour-related functions which make them key players in the innate immune response. The isoforms hGBP-1 to hGBP-5 form homomeric complexes and localise to specific cellular compartments. Upon heteromeric interactions, hGBPs are able to guide each other to their specific compartments. Thus, homo- and heteromeric interactions allow the hGBPs to build a network within the cell which might be important for their diverse biological functions. We characterised homomeric complexes of hGBPs in vitro and presented most recently that nonprenylated hGBP-1 and hGBP-5 form dimers as highest oligomeric species while farnesylated hGBP-1 is able to form polymers. We continued to work on the biochemical characterisation of the heteromeric interactions between hGBPs and present here results for nonprenylated hGBP-1 and hGBP-5. Multiangle light scattering identified the GTP-dependent heteromeric complex as dimer. Also hGBP-5's tumour-associated splice variant (hGBP-5ta) was able to form a hetero dimer with hGBP-1. Intriguingly, both hGBP-5 splice variants were able to induce domain rearrangements within hGBP-1. We further characterised the homo and hetero dimers with Förster resonance energy transfer-based experiments. This allowed us to obtain affinities and kinetics of the homo and hetero dimer formation. Furthermore, we identified that the LG domains of hGBP-1 and hGBP-5 build an interaction site within the hetero dimer. Our in vitro study provides mechanistic insights into the homomeric and heteromeric interactions of hGBP-1 and hGBP-5 and present useful strategies to characterise the hGBP network further.

Interaction of isolated cross-linked short actin oligomers with the skeletal muscle myosin motor domain.

The cyclical interaction between F-actin and myosin in muscle cells generates contractile force. The myosin motor domain hydrolyses ATP, resulting in conformational changes that are amplified by the myosin lever arm that links the motor domain to the rod domain. Recent cryo-electron microscopic data have provided a clear picture of the myosin-ATP-F-actin complex, but structural insights into other stages of the myosin-actin interaction have been less forthcoming. To address this issue, we cross-linked F-actin subunits between Cys374 and Lys191, and separated them by gel filtration. Purified actin-dimers, -trimers and -tetramers retained the ability to polymerize and to stimulate myosin-subfragment 1 (myosin-S1) ATPase activity. To generate stable actin oligomer:myosin-S1 complexes, we blocked actin polymerization with gelsolin and Clostridium botulinum iota toxin-mediated ADP-ribosylation. After polymerization inhibition, actin-trimers and -tetramers retained the ability to stimulate the myosin-S1-ATPase, whereas the actin-dimer showed very little ATPase stimulation. We then analysed the stoichiometry and binding affinity of myosin-S1 to actin oligomers. Actin-trimers and -tetramers bound myosin-S1 in the absence of nucleotide; the trimer contains one myosin-S1 binding site. We calculated a dissociation constant (Kd ) of 1.1 × 10-10  m and 1.9 × 10-10  m for binding of native F-actin and the actin-trimer to myosin-S1, respectively. EM of the actin-trimer:myosin-S1 complex demonstrated the presence of single particles of uniform size. Image reconstruction allowed a reasonable fit of the actin-trimer and myosin-S1 into the obtained density clearly showing binding of one myosin-S1 molecule to the two long-pitch actins of the trimer, supporting the kinetic data.