Assembly of a GPCR-G Protein Complex.

The activation of G proteins by G protein-coupled receptors (GPCRs) underlies the majority of transmembrane signaling by hormones and neurotransmitters. Recent structures of GPCR-G protein complexes obtained by crystallography and cryoelectron microscopy (cryo-EM) reveal similar interactions between GPCRs and the alpha subunit of different G protein isoforms. While some G protein subtype-specific differences are observed, there is no clear structural explanation for G protein subtype-selectivity. All of these complexes are stabilized in the nucleotide-free state, a condition that does not exist in living cells. In an effort to better understand the structural basis of coupling specificity, we used time-resolved structural mass spectrometry techniques to investigate GPCR-G protein complex formation and G-protein activation. Our results suggest that coupling specificity is determined by one or more transient intermediate states that serve as selectivity filters and precede the formation of the stable nucleotide-free GPCR-G protein complexes observed in crystal and cryo-EM structures.

Structural and Functional Analysis of a ß2-Adrenergic Receptor Complex with GRK5.

The phosphorylation of agonist-occupied G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) functions to turn off G-protein signaling and turn on arrestin-mediated signaling. While a structural understanding of GPCR/G-protein and GPCR/arrestin complexes has emerged in recent years, the molecular architecture of a GPCR/GRK complex remains poorly defined. We used a comprehensive integrated approach of cross-linking, hydrogen-deuterium exchange mass spectrometry (MS), electron microscopy, mutagenesis, molecular dynamics simulations, and computational docking to analyze GRK5 interaction with the ß2-adrenergic receptor (ß2AR). These studies revealed a dynamic mechanism of complex formation that involves large conformational changes in the GRK5 RH/catalytic domain interface upon receptor binding. These changes facilitate contacts between intracellular loops 2 and 3 and the C terminus of the ß2AR with the GRK5 RH bundle subdomain, membrane-binding surface, and kinase catalytic cleft, respectively. These studies significantly contribute to our understanding of the mechanism by which GRKs regulate the function of activated GPCRs. PAPERCLIP.

Structure of a GRK5-Calmodulin Complex Reveals Molecular Mechanism of GRK Activation and Substrate Targeting.

The phosphorylation of G protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) facilitates arrestin binding and receptor desensitization. Although this process can be regulated by Ca2+-binding proteins such as calmodulin (CaM) and recoverin, the molecular mechanisms are poorly understood. Here, we report structural, computational, and biochemical analysis of a CaM complex with GRK5, revealing how CaM shapes GRK5 response to calcium. The CaM N and C domains bind independently to two helical regions at the GRK5 N and C termini to inhibit GPCR phosphorylation, though only the C domain interaction disrupts GRK5 membrane association, thereby facilitating cytoplasmic translocation. The CaM N domain strongly activates GRK5 via ordering of the amphipathic αN-helix of GRK5 and allosteric disruption of kinase-RH domain interaction for phosphorylation of cytoplasmic GRK5 substrates. These results provide a framework for understanding how two functional effects, GRK5 activation and localization, can cooperate under control of CaM for selective substrate targeting by GRK5.

Apparent diffusion coefficient histogram in the differentiation of benign and malignant testicular tumors.

Purpose: This retrospective study assessed the value of histogram parameters of the apparent diffusion coefficient (ADC) map (HA) in differentiating between benign and malignant testicular tumors. We compared the diagnostic performance of two different volume-of-interest (VOI) placement methods: VOI 1, the entire tumor; VOI 2, the tumor excluding its cystic, calcified, hemorrhagic, and necrotic portions. Materials and methods: We retrospectively evaluated 45 patients with testicular tumors examined with scrotal contrast-enhanced magnetic resonance imaging. These patients underwent surgery with the pathological result of seven benign and 39 malignant tumors. We calculated the HA parameters, including mean, median, maximum, minimum, kurtosis, skewness, entropy, standard deviation (SD), mean of positive pixels, and uniformity of positive pixels by the two different VOI segmentation methods. We compared these parameters using the chi-square test, Mann-Whitney U test, and area under the receiver operating characteristic curve (AUC) to determine their optimal cut-off, sensitivity (Se), and specificity (Sp). Result: This study included 45 patients with 46 testicular lesions (seven benign and 39 malignant tumors), one of which had bilateral testicular seminoma. With the VOI 1 method, benign lesions had significantly lower maximum ADC (p = 0.002), ADC skewness (p = 0.017), and ADC variance (p = 0.000) than malignant lesions. In contrast, their minimum ADC was significantly higher ADC (p = 0.000). With the VOI 2 method, the benign lesions had significantly higher ADC SD (p = 0.048) and maximum ADC (p = 0.015) than malignant lesions. In contrast, their minimum ADC was significantly lower (p = 0.000). With the VOI 1 method, maximum ADC, ADC variance, and ADC skewness performed well in differentiating benign and malignant testicular lesions with cut-offs (Se, Sp, AUC) of 1846.000 (74.4%, 100%, 0.883), 39198.387 (79.5%, 85.7%, 0.868), and 0.893 (48.7%, 100%, 0.758). Conclusion: The HA parameters showed value in differentiating benign and malignant testicular neoplasms. The entire tumor VOI placement method was preferable to the VOI placement method excluding cystic, calcified, hemorrhagic, and necrotic portions in measuring HA parameters. Using this VOI segmentation, maximum ADC performed best in discriminating benign and malignant testicular lesions, followed by ADC variance and skewness.

Dual-energy computed tomography in supporting prostatic artery embolization for benign prostatic hyperplasia.

Objective: Our study aims to evaluate the value of 256-slice dual-energy computed tomography (DECT) in supporting prostatic artery embolization (PAE) under digital subtraction angiography (DSA) for benign prostatic hyperplasia (BPH). Methods: The study was conducted on 88 patients who underwent PAE to treat BPH from January 2022 to November 2023. Of these, 38 patients who had PAE without DECT were placed in group 1, while the other 50 patients with pre-interventional DECT were assigned to group 2. The results of DECT imaging of the prostate artery (PA) were compared with the results of DSA imaging. Test for statistically significant differences between the variables of the two research groups using the T - student test and Mann-Whitney test algorithms with p < 0.05 corresponding to a 95% confidence interval. The data were analyzed according to medical statistical methods using SPSS 20.0 software. Results: DECT can detect the PA origin in 96.1% of cases, identify atherosclerosis at the root of the artery with a sensitivity of 66.7% and a specificity of 89.5%, and present anastomosis with a sensitivity of 72.7% and a specificity of 72.2%. There is no statistically significant difference in PA diameter on DECT compared to DSA with 95% confidence. Group 2 used DECT for 3D rendering of the PA before PAE had procedure time reduced by 25.8%, fluoroscopy time reduced by 23.2%, dose-area product (DAP) reduced by 25.6%, contrast medium volume reduced by 33.1% compared to group 1 not using DECT, statistically significant with 95% confidence. Conclusion: DECT is a valuable method for planning before PAE to treat BPH. 3D rendering DECT of PA provides anatomical information that minimizes procedure time, fluoroscopy time, dose-area product, and contrast medium volume.

Lingual bracket transfer accuracy of double vacuum-formed indirect bonding tray using 3D-printed model: an in vivo study.

INTRODUCTION: This study aimed to assess the transfer accuracy of a digital indirect bonding method for lingual brackets using double vacuum-formed trays in vivo. METHODS: Twenty-five patients in need of lingual orthodontic treatment were consecutively recruited. Bracket placement was performed on ideal setups, followed by fabricating indirect bonding trays through vacuum-forming on 3-dimensional printed models. Transfer accuracy was measured at each bracket after superimpositions of postbonding scans and reference data. One-tailed t tests were used to determine whether bracket deviations were within the limit of 0.5 mm and 2° for linear and angular dimensions, respectively. RESULTS: A total of 611 lingual brackets were evaluated. Mean linear transfer errors were 0.06 mm, 0.09 mm, and 0.12 mm, with frequencies of deviations within the 0.5 mm limit of 99.7%, 99.8%, and 98.0% for mesiodistal, buccolingual, and occlusogingival dimensions, respectively. Regarding angular measurements, mean transfer errors were 1.28°, 1.73°, and 2.96°, with frequencies of deviations within the 2° limit of 81.0%, 68.9%, and 51.1% for rotation, tip, and torque, respectively. Mean errors fell within the clinically accepted limits for all linear dimensions and rotation but exceeded the limit for tip and torque. CONCLUSIONS: Lingual bracket indirect bonding using double vacuum-formed trays fabricated on 3-dimensional printed models has high transfer accuracy in the mesiodistal, buccolingual, and occlusogingival dimensions and rotation. However, the transfer of tip and torque is less accurate.

Clinical characteristics and treatment outcomes of tuberculous tenosynovitis of the hand and wrist.

Objective: Vietnam is endemic with tuberculosis (TB), which is highly prevalent in the community. TB tenosynovitis of the wrist and hand is uncommon. Because of its insidious progression and atypical presentations, it is often difficult to diagnose, leading to treatment delays. This study investigates the characteristics of clinical and subclinical signs and treatment outcomes of patients with TB tenosynovitis in Vietnam. Patients and Methods: This prospective longitudinal cross-sectional study included 25 TB tenosynovitis patients in the Rheumatology Clinic at University Medical Center Ho Chi Minh City. The diagnosis was made based on a tuberculous cyst in histopathological specimens. The data were collected through medical history, physical examination, and medical records, including demographics, signs, symptoms, condition duration, and related laboratory tests and imaging. The outcomes of all participants were assessed after 12 months of treatment. Results: The most common symptom of TB tenosynovitis was swelling of the hand and wrist, which was present in all patients. Its other symptoms included mild pain and numbness of the hand in 72% and 24% of patients, respectively. It can affect any site on the hand. Hand ultrasound findings included thickening of the synovial membrane (80%), peritendinous effusion (64%), and soft tissue swelling (88%). Most patients (18/22) had a good outcome after the treatment with anti-tubercular drugs. Conclusions: TB tenosynovitis progression is often insidious. Its most common symptoms are swelling of the hand and mild pain. Ultrasound is a useful tool to support the diagnosis. A histological examination confirms the diagnosis. Most cases respond and have a good outcome after 9-12 months of anti-tuberculosis treatment.

Radiofrequency catheter ablation for paroxysmal supraventricular tachycardia in children: Insights on its safety and efficacy from a lower middle-income country.

OBJECTIVE: Radiofrequency catheter ablation (RFCA) is a safe and effective treatment for paroxysmal supraventricular tachycardia in adults. However, data on its use in children, particularly from low- and middle-income countries, are limited. This study aimed to evaluate the safety and efficacy of RFCA in children with paroxysmal supraventricular tachycardia from Vietnam. METHODS: A prospective study was conducted from January 2009 to July 2016 at the University Medical Center, Ho Chi Minh City, Vietnam. Ninety-five children diagnosed with paroxysmal supraventricular tachycardia were enrolled; 90 patients underwent cardiac electrophysiology and RFCA. The patients were followed up for 3-12 months, with a mean follow-up period of 7.5 ± 2.3 months. RESULTS: The average age of the patients was 10.5 ± 3 years, with the youngest patient being 4 years old; 46.3% of the patients were female and 53.7% were male. The patients' average weight was 35.2 ± 9.6 kg. Atrioventricular reentrant tachycardia accounted for 72.6% of the cases and atrioventricular nodal reentrant tachycardia for 27.4% of the cases; no patients had atrial tachycardia. The success rate of RFCA was 98.9% (89/90 patients). During the 12-month follow-up, 5.6% of the patients experienced recurrence but were successfully treated with a second ablation. No severe complications were reported during the procedure and follow-up. CONCLUSIONS: This study found RFCA to be a safe and effective treatment for paroxysmal supraventricular tachycardia in children. It demonstrated a high success rate and low recurrence and complication rates for RFCA in children, thereby highlighting the potential advantages of the procedure as a treatment option.

Treatment outcomes of EGFR-TKI with or without locoregional brain therapy in advanced EGFR-mutant non-small cell lung cancer patients with brain metastases.

Introduction: This study aimed to evaluate the treatment outcomes of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy alone or in combination with locoregional brain therapy for advanced EGFR-mutant non-small cell lung cancer (NSCLC) patients with brain metastases. Material and methods: A retrospective study involving 72 advanced EGFR-mutant NSCLC patients with brain metastases at the Vietnam National Cancer Hospital were conducted. Patients were divided into 2 groups: EGFR-TKI (erlotinib) monotherapy and EGFR-TKI combined with locoregional therapy (γ knife surgery - GKS or whole-brain radiation therapy). Evaluation criteria included clinical and laboratory characteristics, central nervous system (CNS) progression time, progression-free survival (PFS), overall survival (OS), T790M mutation rate, and adverse events. Results: Epidermal growth factor receptor tyrosine kinase inhibitor monotherapy patients had better performance status (PS), fewer CNS symptoms, and significantly fewer brain metastases (p < 0.05). Median PFS and OS were 11 and 25 months, respectively, in both groups. Patients with PS 0-1 had longer median PFS (15 months) than those with PS 2 (7 months) (p = 0.039). Exon 19 deletion patients in both groups had longer median OS (26 months) than those with L858R exon 21 (15 months) (p = 0.023). Patients with T790M mutation who received osimertinib after progression had longer median OS (41 months vs. 23 months, p = 0.0001). Median time to CNS progression was 13.9 months (48 patients). Longer time to CNS progression correlated with longer OS (R2 = 0.89). Conclusions: Epidermal growth factor receptor tyrosine kinase inhibitor therapy, with or without locoregional therapy, is effective for advanced EGFR-mutant NSCLC patients with brain metastases. Exon 19 deletion patients had better prognosis.

The value of diffusion-weighted and dynamic contrast-enhanced imaging in the diagnosis of thymic epithelial tumors.

Background: Thymic epithelial tumors (TETs) are clinically the most frequently encountered neoplasm of the prevascular mediastinum in adults. The role of chest magnetic resonance (MR) imaging has been increasingly stressed thanks to its excellent contrast resolution, freedom from ionizing radiation, and capability to provide additional information regarding tumors' cellular structure and vascularity. Methods: This study aimed to establish the relationship between the MR findings and pathological classification of TETs, focusing on diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) imaging. This retrospective cross-sectional study included 44 TET patients who underwent chest MR scanning. The tumors were classified into three groups according to the WHO classification: low-risk thymoma (LRT), high-risk thymoma (HRT), and non-thymoma (NT). Along with morphological characteristics, the apparent diffusion coefficient (ADC) value, time-intensity curve (TIC) pattern, and time to peak enhancement (TTP) of the tumors were recorded and compared between the three groups. Results: A smooth contour and complete or almost complete capsule were suggestive of LRTs. The median ADC value of the 44 tumors was 0.95 × 10-3 mm2/sec. Among the three groups, LRTs had the highest ADC values, while NTs had the lowest. The differences between the ADC values of the three groups were statistically significant (p = 0.006). Using an ADC cutoff of 0.82 × 10-3 mm2/sec to differentiate between LRTs and tumors of the two remaining groups, the area under the curve was 0.775, sensitivity was 100%, specificity was 50%, and accuracy was 65.91%. The washout (type 3) TIC pattern was the most prevalent, accounting for 45.45% of the population; this pattern was also predominantly observed in LRTs (71.43%). Although the median TTP of LRTs was lower than that of HRTs or NTs, no statistically significant differences were found between the TTPs of the three groups (p = 0.170). Conclusions: MR is a good imaging modality to preoperatively assess TETs. Morphological features, ADC value, TIC pattern, and TTP are helpful in preoperatively predicting TET pathology.

The value of quantitative magnetic resonance imaging signal intensity in distinguishing between spinal meningiomas and schwannomas.

Background: Prior studies have suggested a number of the subjective visual characteristics that help distinguish between spinal meningiomas and schwannomas on magnetic resonance imaging and computed tomography; however, objective quantification of the signal intensity can be useful information. This study assessed whether quantitative magnetic resonance imaging (MRI) signal intensity (SI) measurements could distinguish intradural-extramedullary schwannomas from meningiomas. Methods: From July 2019 to September 2021, 54 patients with intradural-extramedullary tumors (37 meningiomas and 17 schwannomas) underwent surgery, and tumors were verified pathologically. Defined regions of interest were used to quantify SI values on T1- (T1W) and T2-weighted images (T2W). Receiver operating characteristic curve analysis was used to obtain cutoff values and calculate the area under the curve (AUC), sensitivity (SE), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV). Results: Both Maximum (T2max) and mean (T2mean) T2W SI values demonstrated outstanding (AUC: 0.91) abilities to differentiate meningiomas from schwannomas with Se, Sp, PPV, and NPV values of 94.6%, 70.6%, 87.5%, and 85.7%, respectively, for T2max and 81.1%, 88.2%, 93.8%, and 68.2% for T2mean. The maximum SI value on contrast-enhanced T1W (T1CEmax) and the T2W tumor: fat SI ratio (rTF) demonstrated acceptable abilities (AUC: 0.73 and 0.79, respectively) to differentiate meningiomas from schwannomas with Se, Sp, PPV, and NPV values of 94.6%, 70.6%, 87.5%, and 85.7%, respectively, for T1CEmax and 81.1%, 88.2%, 93.8%, and 68.2% for rTF. Conclusions: Quantitative SI values (T2max, T2mean, T2min, T1CEmax, rTF) can be used to differentiate intradural-extramedullary schwannomas from meningiomas.

The impact of magnetic resonance imaging spectroscopy parameters on differentiating between paediatric medulloblastoma and ependymoma.

INTRODUCTION: The distinction of medulloblastomas and ependymomas plays an important role in the care plans and prognosis of children. We aimed to investigate the role of magnetic resonance spectroscopy (MRS) in the differentiation between medulloblastomas and ependymomas in children. MATERIALS AND METHODS: The institutional review board approved this prospective study. The brain magnetic resonance imaging protocol including axial multivoxel spectroscopy with a TE of 144 ms was assessed in 49 patients, who were divided into 2 groups: 40 patients with medulloblastomas and 9 patients with ependymomas. Receiver operating characteristic (ROC) curve analysis and the Youden index were utilized to determine the best cut-off, sensitivity, specificity, and area under the curve (AUC) values of the independent spectroscopy parameters. RESULTS: The choline level (Cho) and the choline/creatine (Cho/Cr) and choline/N-acetyl aspartate (Cho/NAA) ratios of medulloblastomas were significantly higher than those of ependymomas (p < 0.05). A Cho/NAA cut-off value of 1.24 to predict the diagnosis of medulloblastoma yielded the highest AUC and sensitivity of 80.3% and 97.5%, respectively, while a Cho cut-off value of 4.64 produced the highest specificity value of 88.9%. CONCLUSIONS: Our findings suggest that Cho and Cho/NAA derived from MRS could serve as differential factors between paediatric medulloblastomas and ependymomas. Among those, a Cho/NAA cut-off value of 1.24 to predict the diagnosis of medulloblastoma generated the highest accuracy.

The role of diffusion tensor imaging metrics in the discrimination between cerebellar medulloblastoma and brainstem glioma.

BACKGROUND: Differentiation between cerebellar medulloblastoma and brainstem glioma is necessary for certain clinical circumstances. We aimed to evaluate the function of diffusion tensor imaging (DTI) metrics in the differentiation between cerebellar medulloblastomas and brainstem gliomas in children. PROCEDURE: The institutional review board approved this prospective study. Brain magnetic resonance imaging (MRI), including DTI, was assessed in 40 patients, who were divided into two groups: a medulloblastoma group (group 1, n = 25) and a brainstem glioma group (group 2, n = 15). The Mann-Whitney U test was utilized to compare tumoral fractional anisotropy (FA) and diffusivity (MD) values and tumor-to-parenchyma ratios for these values (rFA and rMD, respectively) between the two groups. Receiver-operating characteristic (ROC) curve analysis and the Youden index were exploited to calculate the cutoff value, along with the area under the curve (AUC), sensitivity, and specificity. RESULTS: The FA value for medulloblastomas was significantly higher than that for brainstem gliomas (P < 0.05). In contrast, the MD and rMD values for medulloblastoma were significantly lower than those for brainstem gliomas (P < 0.05). A cutoff MD value of 0.97 was identified as the most effective factor for the differential diagnosis between medulloblastomas and brainstem gliomas, which reached a sensitivity of 96%, a specificity of 100%, and an AUC of 99.5%. CONCLUSION: DTI metrics play a significant role in the differentiation between medulloblastoma and brainstem glioma in pediatric patients.

Antimelanogenic Activity of Ocotillol-Type Saponins from Panax vietnamensis.

The ocotillol (OCT)-type saponins have been known as a tetracyclic triterpenoid, possessing five- or six-membered epoxy ring in the side chain. Interestingly, this type saponin was mostly found in Panax vietnamensis Ha et Grushv., Araliaceae (VG), hence making VG unique from the other Panax spp. Five OCT-type saponins, majonoside R2, vina-ginsenoside R2, majonoside R1, pseudoginsenoside RT4, vina-ginsenoside R11, together with three protopanaxadiol (PPD)-type saponins and four protopanaxatriol (PPT)-type saponins from VG were evaluated for their antimelanogenic activity. All of isolates were found to be active. More importantly, the five OCT-type saponins inhibited melanin production in B16-F10 mouse melanoma cells, without showing any cytotoxicity. Besides ginsenoside Rd and ginsenoside Rg3 in PPD and notoginsenoside R1 in PPT-type saponins, majonoside R2 was the most potent melanogenesis inhibitory activity in OCT-type saponins. In this article, we highlighted antimelanogenic activity of OCT-type saponins and potential structure-activity relationship (SAR) of ginsenosides. Our results suggested that OCT-type saponins could be used as a depigmentation agent.

Magnetic resonance imaging characteristics of thymoma in Vietnamese patients with myasthenia gravis in relation to histopathological type and disease staging.

INTRODUCTION: Myasthenia gravis (MG) is a relatively uncommon neuromuscular disease. The thymus plays an important role in the pathogenesis of MG, with 70% of patients presenting with thymic follicular hyperplasia and 20% presenting with thymoma. This study aimed to characterize magnetic resonance (MR) images of thymomas in patients with MG, associated with various stages and types. MATERIAL AND METHODS: A prospective study was performed in 46 MG patients with thymoma, who underwent surgery between August 2014 and September 2018, in Vietnam. Differences in MR imaging (MRI) images, according to type and stage, were assessed by the χ2 test or Fisher's exact test and Student's t-test. A p-value < 0.05 was considered significant. RESULTS: The proportions of each type of thymomas found to be invasive were 28.6%, 61.1%, 66.7%, 90.9%, and 100%, for type A, AB, B1, B2, and B3 thymomas, respectively. Heterogeneous signal intensities on T1- and T2-weighted images, necrosis, and cysts were more commonly observed in high-risk thymomas than in low-risk thymomas. Non-invasive thymomas were more likely to display smooth margins than invasive thymomas (p < 0.05). Only 16.7% of invasive thymomas were detected in MR findings. CONCLUSIONS: Only a few characteristic MRI features could be used to differentiate thymomas by stage or type.

The value of multidetector-row computed tomography in lymph node staging of gastric cancer: a preliminary Vietnamese study.

INTRODUCTION: Gastric cancer (GC) is the fourth most common malignant disease in the world, following breast cancer, colorectal cancer, and lung cancer. This study aimed to evaluate the usefulness of multidetector-row computed tomography (MDCT) in identifying the metastatic lymph node of GC. MATERIAL AND METHODS: A cross-sectional study was performed after receiving approval by the institutional review board. A total of 88 patients with GC, who underwent radical gastrectomy, were examined by MDCT. Categorical variables were compared using Fisher's exact test. The discriminating ability of lymph node size was determined according to an area under the receiver operating curve(AUROC) analysis, and the optimal cut-off point was determined. RESULTS: The proportion of metastatic lymph node patients in the proximal group (32.3%) was significantly higher than that in the distal group (18.4%). T categorisation and lymph node sizes were significantly different between the non-metastatic lymph node and metastatic lymph node groups. The AUROC for lymph node size was 0.738, with an optimal cut-off point of 7.5 mm,producing a sensitivity of 71.5% and a specificity of 70.5%. CONCLUSIONS: MDCT displayed medium accuracy for the determination of metastatic lymph nodes and N categorisation. Based on our findings, although MDCT is generally the first choice for preoperative assessments in GC patients, other diagnostic modalities should supplement MDCT in order to achieve more precise N staging.

Rufomycin Targets ClpC1 Proteolysis in Mycobacterium tuberculosis and M. abscessus.

ClpC1 is an emerging new target for the treatment of Mycobacterium tuberculosis infections, and several cyclic peptides (ecumicin, cyclomarin A, and lassomycin) are known to act on this target. This study identified another group of peptides, the rufomycins (RUFs), as bactericidal to M. tuberculosis through the inhibition of ClpC1 and subsequent modulation of protein degradation of intracellular proteins. Rufomycin I (RUFI) was found to be a potent and selective lead compound for both M. tuberculosis (MIC, 0.02 µM) and Mycobacterium abscessus (MIC, 0.4 µM). Spontaneously generated mutants resistant to RUFI involved seven unique single nucleotide polymorphism (SNP) mutations at three distinct codons within the N-terminal domain of clpC1 (V13, H77, and F80). RUFI also significantly decreased the proteolytic capabilities of the ClpC1/P1/P2 complex to degrade casein, while having no significant effect on the ATPase activity of ClpC1. This represents a marked difference from ecumicin, which inhibits ClpC1 proteolysis but stimulates the ATPase activity, thereby providing evidence that although these peptides share ClpC1 as a macromolecular target, their downstream effects are distinct, likely due to differences in binding.

Magnetic resonance imaging features influencing high-intensity focused ultrasound ablation of adenomyosis with a nonperfused volume ratio of ≥90% as a measure of clinical treatment success: retrospective multivariate analysis.

OBJECTIVE: This retrospective study aimed (1) to investigate the magnetic resonance imaging (MRI) features influencing a nonperfused volume ratio (NPVr) ≥ 90% after high-intensity focussed ultrasound (HIFU) ablation of adenomyosis, and (2) to assess the safety, which was defined in terms of adverse events (AEs) and changes in anti-Mullerian hormone (AMH) concentrations, and clinical efficacy, which was defined in terms of adenomyosis volume reduction and symptom improvement at 6 months' follow-up. METHODS: Sixty-six women who underwent HIFU treatment were divided into groups A (NPVr ≥90%; n = 26) and B (NPVr <90%, n = 40). Multivariate logistic regression analyses of MRI features were conducted to identify the potential predictors of an NPVr ≥90%. RESULTS: Generalized estimating equation (GEE) analysis was used to model the prediction of an NPVr ≥90% with four significant predictors from multivariate analyses: the thickness of the subcutaneous fat layer, adenomyosis volume, T2 signal intensity (SI) ratio of adenomyosis to myometrium, and the Ktrans ratio of adenomyosis to myometrium. Clinical efficacy was significantly greater in group A than in group B. The findings showed no serious AEs and no significant differences between AMH concentrations before and 6 months after treatment. CONCLUSIONS: The present retrospective study demonstrated that achievement of NPVr ≥90% as a measure of clinical treatment success in MRI-guided HIFU treatment of adenomyosis using multivariate analyses and a prediction model is clinically possible without compromising the safety of patients.

The role of T1 perfusion-based classification in predicting the outcome of magnetic resonance-guided high-intensity focused ultrasound treatment of adenomyosis.

OBJECTIVE: To assess the relationship between magnetic resonance (MR) T1 perfusion-based classification and the outcome of MR-guided high intensity focused ultrasound treatment of adenomyosis, defined as nonperfused volume (NPV) ratio. METHODS: The adenomyosis of 31 women was classified into group A (time-signal intensity [SI] curve of adenomyosis lower than that of the myometrium) and group B (time-SI curve of adenomyosis equal to or higher than that of the myometrium) on the basis of time-SI curves on dynamic contrast enhanced (DCE) MR images acquired at screening. NPV ratios immediately after treatment and adenomyosis volume reduction ratios and symptom severity scores (SSS) at the six-month follow-up were retrospectively assessed. Univariate and multivariate analysis of pretreatment parameters conducted to assess independent factors impacting on immediate NPV ratio. All adverse effects were recorded. RESULTS: The immediate NPV ratios in groups A and B were 89.2 ± 6.7% and 42.4 ± 19.0%, respectively. At the six-month follow-up, the adenomyosis volume reduction ratios in groups A and B were 0.27 ± 0.8 and 0.04 ± 0.1, respectively, with corresponding improvements of 0.7 ± 0.18 and 0.26 ± 0.25, respectively, in the mean transformed SSS. Univariate and multivariate analysis revealed that only T1 perfusion-based classification as an independent factor associated with the outcome of MR-guided high intensity focused ultrasound treatment. No serious adverse effects were reported. CONCLUSIONS: Our novel classification method introduced in this study might be clinically beneficial in classifying adenomyosis for predicting the immediate outcome of MR-guided high intensity focused ultrasound treatment.

The role of T1 perfusion-based classification in magnetic resonance-guided high-intensity focused ultrasound ablation of uterine fibroids.

OBJECTIVE: To comparatively evaluate the role of magnetic resonance (MR) T1 perfusion-based time-signal intensity (SI) curves of fibroid tissue and the myometrium in classification of fibroids for predicting treatment outcomes of high-intensity focused ultrasound (HIFU) treatment. METHODS: The fibroids of 74 women who underwent MR-HIFU treatment were classified into group A (time-SI curve of fibroid lower than that of the myometrium) and group B (time-SI curve of fibroid equal to or higher than that of the myometrium). Non-perfused volume (NPV) ratios immediately after treatment and fibroid volume reduction ratios and symptom severity scores (SSS) at the 6-month follow-up were retrospectively assessed. RESULTS: The immediate NPV ratios in groups A and B were 95.3 ± 6.3% (n = 62) and 63.8 ± 11% (n = 12), respectively. At the 6-month follow-up, the fibroid volume reduction ratios in groups A and B were 0.52 ± 0.14 (n = 50) and 0.07 ± 0.14 (n = 11), with the corresponding improvement in mean transformed SSS being 0.86 ± 0.14 and 0.19 ± 0.3, respectively. No serious adverse effects were reported. CONCLUSIONS: Our novel classification method could play an important role in classifying fibroids for predicting the immediate outcomes of HIFU treatment. KEY POINTS: • MRI is an important modality for outcome prediction in HIFU treatment • Patient selection is a significant factor for achieving high NPV ratio • NPV ratio is very strongly correlated with T1 perfusion-based classification • T1 perfusion-based classification is a strong predictor of treatment outcome.