A different perspective on PET/CT before treatment in patients with Hodgkin lymphoma: importance of volumetric and dissemination parameters.

The aim of this study is to investigate the role of the combination of volumetric and dissemination parameters obtained from pretreatment 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in predicting the interim response and progression status in patients with Hodgkin lymphoma (HL). Pretreatment PET/CT images of HL patients were analyzed with LIFEx software, and volumes of interest (VOIs) were drawn with a fixed SUV 4.0 threshold. MTV, SUVmax, and TLG values were obtained from each VOI. Total MTV (tMTV) was calculated by summing the MTV values in all VOIs, and similarly, total TLG (tTLG) was obtained by summing the TLG values. The distance between the centers of the lesions was noted as Dmax, and the distance between the outermost voxels of the lesions as DmaxVox. tMTV/DmaxVox was calculated by dividing the tMTV value by the DmaxVox value, and tTLG/DmaxVox was calculated by dividing the tTLG value by the DmaxVox value. The correlation of pretreatment PET parameters with response groups (complete/poor) and relapse/progression status (stable/progressive) was statistically evaluated. A total of 52 patients were included in the study. Bulky disease, tMTV, tTLG, and tMTV/DmaxVox values were found to be significantly higher in the poor response group. tMTV > 190.60 ml was found to be the only prognostic factor predicting interim PET response. The tMTV/DmaxVox and tTLG/DmaxVox showed statistically significant differences between the groups with and without progression. tMTV/DmaxVox > 7.70 was found to be the only prognostic factor in predicting relapse/progression. The evaluation of tumor burden and dissemination together in 18F-FDG PET/CT before treatment in patients with HL can help us to predict the results of the patients.

2-[18]F FDG PET/CT dissemination features in adult burkitt lymphoma Are predictive of outcome.

This retrospective study investigated the prognostic role of disease dissemination features (Dmax and Dmaxbsa) measured by 2-[18F]FDG PET/CT in newly diagnosed Burkitt Lymphoma (BL) patients, comparing their performance with other metabolic parameters. We included 78 patients diagnosed with BL between 2010 and 2022 with an available baseline PET, interim PET/CT (iPET) and end of treatment PET/CT (eotPET) and with a minimum of two 2-[18F]FDG avid lesions present at the baseline scan. Dmax was calculated from the three-dimensional coordinates of the baseline metabolic tumor volume (MTV) by using LIFEx software; Dmaxbsa was calculated as Dmax normalized for body surface area according to the Du Bois method. We evaluated their effect on metabolic treatment response evaluated by PET, on progression free survival (PFS) and on overall survival (OS). Dmaxbsa was significantly associated with tumor stage, bulky and extranodal disease, MTV and TLG. At a median follow-up of 49 months, the median PFS and OS were 45 and 48 months. Dmax and Dmaxbsa were significantly higher in not complete metabolic response than complete metabolic response group at iPET and eotPET.As far as PFS, parameters including iPET/CT, eotPET/CT outcomes, MTV and TLG showed to be independent prognostic factors while Dmax and Dmaxbsa were not significantly associated with the outcome. Dissemination features, together with eotPET/CT results, MTV and TLG, demonstrated to be significantly correlated with OS. In conclusion, in this study we demonstrated that dissemination features derived by 2[18F]-FDG PET/CT were significantly correlated with response to treatment and long-term outcome, independently from other PET features.

A Novel Method for Full-Section Assessment of High-Speed Railway Subgrade Compaction Quality Based on ML-Interval Prediction Theory.

The high-speed railway subgrade compaction quality is controlled by the compaction degree (K), with the maximum dry density (ρdmax) serving as a crucial indicator for its calculation. The current mechanisms and methods for determining the ρdmax still suffer from uncertainties, inefficiencies, and lack of intelligence. These deficiencies can lead to insufficient assessments for the high-speed railway subgrade compaction quality, further impacting the operational safety of high-speed railways. In this paper, a novel method for full-section assessment of high-speed railway subgrade compaction quality based on ML-interval prediction theory is proposed. Firstly, based on indoor vibration compaction tests, a method for determining the ρdmax based on the dynamic stiffness Krb turning point is proposed. Secondly, the Pso-OptimalML-Adaboost (POA) model for predicting ρdmax is determined based on three typical machine learning (ML) algorithms, which are back propagation neural network (BPNN), support vector regression (SVR), and random forest (RF). Thirdly, the interval prediction theory is introduced to quantify the uncertainty in ρdmax prediction. Finally, based on the Bootstrap-POA-ANN interval prediction model and spatial interpolation algorithms, the interval distribution of ρdmax across the full-section can be determined, and a model for full-section assessment of compaction quality is developed based on the compaction standard (95%). Moreover, the proposed method is applied to determine the optimal compaction thicknesses (H0), within the station subgrade test section in the southwest region. The results indicate that: (1) The PSO-BPNN-AdaBoost model performs better in the accuracy and error metrics, which is selected as the POA model for predicting ρdmax. (2) The Bootstrap-POA-ANN interval prediction model for ρdmax can construct clear and reliable prediction intervals. (3) The model for full-section assessment of compaction quality can provide the full-section distribution interval for K. Comparing the H0 of 50~60 cm and 60~70 cm, the compaction quality is better with the H0 of 40~50 cm. The research findings can provide effective techniques for assessing the compaction quality of high-speed railway subgrades.

Prognostic value of lesion dissemination in doxorubicin, bleomycin, vinblastine, and dacarbazine-treated, interimPET-negative classical Hodgkin Lymphoma patients: A radio-genomic study.

We evaluated the prognostic role of the largest distance between two lesions (Dmax), defined by positron emission tomography (PET) in a retrospective cohort of newly diagnosed classical Hodgkin Lymphoma (cHL) patients. We also explored the molecular bases underlying Dmax through a gene expression analysis of diagnostic biopsies. We included patients diagnosed with cHL from 2007 to 2020, initially treated with ABVD, with available baseline PET for review, and with at least two FDG avid lesions. Patients with available RNA from diagnostic biopsy were eligible for gene expression analysis. Dmax was deduced from the three-dimensional coordinates of the baseline metabolic tumor volume (MTV) and its effect on progression free survival (PFS) was evaluated. Gene expression profiles were correlated with Dmax and analyzed using CIBERSORTx algorithm to perform deconvolution. The study was conducted on 155 eligible cHL patients. Using its median value of 20 cm, Dmax was the only variable independently associated with PFS (HR = 2.70, 95% CI 1.1-6.63, pValue = 0.03) in multivariate analysis of PFS for all patients and for those with early complete metabolic response (iPET-). Among patients with iPET-low Dmax was associated with a 4-year PFS of 90% (95% CI 82.0-98.9) significantly better compared to high Dmax (4-year PFS 72.4%, 95% CI 61.9-84.6). From the analysis of gene expression profiles differences in Dmax were mostly associated with variations in the expression of microenvironmental components. In conclusion our results support tumor dissemination measured through Dmax as novel prognostic factor for cHL patients treated with ABVD.

Comparison of training responses and performance adaptations in endurance-trained men and women performing high-intensity interval training.

The efficacy of high-intensity interval training (HIIT) to elicit physiological and performance adaptations in endurance athletes has been established in men and to a lesser extent in women. This study compared lactate threshold (LT2) and performance adaptations to HIIT between men and women. Nine male and eight female cyclists and triathletes completed trials to determine their LT2 and 40 km cycling performance before, and after 10 HIIT sessions. Each HIIT session consisted of 10 × 90 s at peak power output, separated by 60 s active recovery. Main effects showed that HIIT improved peak power output (p = 0.05; ES: 0.2); relative peak power output (W.kg-1; p = 0.04; ES: 0.3 and W.kg-0.32; p = 0.04; ES: 0.3); incremental time to fatigue (p = 0.01; ES: 0.4), time trial time (p < 0.001; ES: 0.7) and time trial power output (p < 0.001; ES: 0.7) equally in both sexes. Although LT2 power output explained 77% of the performance improvement in women, no variable explained the performance improvement in men, suggesting another mechanism(s) was involved. Although HIIT improved cycling performance in men and women, it might not be appropriate to evaluate the effectiveness of HIIT using the same variables for both sexes.

Pelvic radiation therapy with volumetric modulated arc therapy and intensity-modulated radiotherapy after renal transplant: A report of 3 cases.

AIM: Describe characteristics and outcomes of three patients treated with pelvic radiation therapy after kidney transplant. BACKGROUND: The incidence of pelvic cancers in kidney transplant (KT) recipients is rising. Currently it is the leading cause of death. Moreover, treatment is challenging because anatomical variants, comorbidities, and associated treatments, which raises the concern of using radiotherapy (RT). RT has been discouraged due to the increased risk of urethral/ureteral stricture and KT dysfunction. MATERIALS AND METHODS: We reviewed the electronic health records and digital planning system of patients treated with pelvic RT between December 2013 and December 2018 to identify patients with previous KT. CASES DESCRIPTION: We describe three successful cases of KT patients in which modern techniques allowed full standard RT for pelvic malignances (2 prostate and 1 vaginal cancer) with or without elective pelvic nodal RT, without allograft toxicity at short and long follow-up (up to 60 months). CONCLUSION: When needed, RT modern techniques remain a valid option with excellent oncologic results and acceptable toxicity. Physicians should give special considerations to accomplish all OAR dose constraints in the patient's specific setting. Recent publications recommend KT mean dose <4 Gy, but graft proximity to CTV makes this unfeasible. We present 2 cases where dose constraint was not achieved, and to a short follow-up of 20 months renal toxicity has not been documented. We recommend the lowest possible mean dose to the KT, but never compromising the CTV coverage, since morbimortality from recurrent or progressive cancer disease outweighs the risk of graft injury.

Cardiotoxicity of mediastinal radiotherapy.

AIM: To explore available recent literature related to cardiotoxicity following mediastinal radiation. BACKGROUND: Radiotherapy-related heart injury is well documented, with no apparent safety threshold dose. The number of long-term cancer survivors exposed to mediastinal radiotherapy at some point of their treatment is increasing. Heart dosimetric parameters are of great importance in developing a treatment plan, but few data are available regarding radiosensitivity and dose-volume constraints for specific heart structures. MATERIALS AND METHODS: In October 2018, we identified articles published after 1990 through a PubMed/MEDLINE database search. The authors examined rough search results and manuscripts not relevant for the topic were excluded. We extracted clinical outcomes following mediastinal radiotherapy of childhood cancers, lymphoma, medulloblastoma, thymic cancers and hematopoietic cell transplantation survivors and evaluated treatment planning data, whenever available. RESULTS: A total of 1311 manuscripts were identified in our first-round search. Of these manuscripts, only 115 articles, matching our selection criteria, were included. CONCLUSIONS: Studies uniformly show a linear radiation dose-response relationship between mean absorbed dose to the heart (heart-Dmean) and the risk of dying as a result of cardiac disease, particularly when heart-Dmean exceeds 5 Gy. Limited data are available regarding dose-volume predictors for heart substructures and the risk of subsequent cardiac toxicity. An individual patient's cardiotoxicity risk can be modified with advanced treatment planning techniques, including deep inspiration breath hold. Proton therapy is currently showing advantages in improving treatment planning parameters when compared to advanced photon techniques in lymphoma, thymic malignancies, malignant mesothelioma and craniospinal irradiation.

Predictors of voiding dysfunction following extensive vaginal pelvic reconstructive surgery.

INTRODUCTION AND HYPOTHESIS: The objective of this study was to identify the predictors of postoperative voiding dysfunction in women following extensive vaginal pelvic reconstructive surgery. METHODS: We enrolled 1,425 women who had pelvic organ prolapse of POP-Q stage III or IV and had undergone vaginal pelvic reconstructive surgery with or without transvaginal mesh insertion from January 2006 to December 2014. All subjects were required to complete a 72-h voiding diary, and the IIQ-7, UDI-6, POPDI-6 and PISQ-12 questionnaires. Urodynamic study was performed preoperatively and postoperatively. RESULTS: Of the 1,425 women, 54 were excluded due to incomplete data, and 1,017 of the remaining 1,371 (74.2 %) had transvaginal mesh surgery and 247 (18 %) had concurrent midurethral sling insertion. Of 380 women (27.7 %) with preoperative voiding dysfunction, 37 (9.7 %) continued to have voiding dysfunction postoperatively. Of the remaining 991 women (72.3 %) with normal preoperative voiding function, 11 (1.1 %) developed de novo voiding dysfunction postoperatively. The overall incidence of postoperative voiding dysfunction was 3.5 % (48/1,371). Those with concurrent midurethral sling insertion were at higher risk of developing voiding dysfunction postoperatively (OR 3.12, 95 % CI 1.79 - 5.46, p < 0.001). Diabetes mellitus, preoperative detrusor pressure at maximal flow (Dmax) <10 cm H2O and postvoid residual volume ≥200 ml were significant risk factors for the development of postoperative voiding dysfunction (OR 3.07, 1.84 and 2.15, respectively; 95 % CI 1.69 - 5.60, 1.39 - 2.91 and 1.10 - 3.21, respectively). CONCLUSIONS: Diabetes mellitus, concurrent midurethral sling insertion, preoperative Dmax <10 cm H2O and postvoid residual volume ≥200 ml in patients with advanced pelvic organ prolapse were risk factors for the development of postoperative voiding dysfunction after vaginal pelvic reconstructive surgery. Therefore, counseling is worthwhile before considering vaginal pelvic reconstructive surgery.

Image-guided stereotactic radiosurgery for treatment of spinal hemangioblastoma.

OBJECTIVE Stereotactic radiosurgery (SRS) has been an attractive treatment option for hemangioblastomas, especially for lesions that are surgically inaccessible and in patients with von Hippel-Lindau (VHL) disease and multiple lesions. Although there has been a multitude of studies examining the utility of SRS in intracranial hemangioblastomas, SRS has only recently been used for spinal hemangioblastomas due to technical limitations. The purpose of this study is to provide a long-term evaluation of the effectiveness of image-guided radiosurgery in halting tumor progression and providing symptomatic relief for spinal hemangioblastomas. METHODS Between 2001 and 2011, 46 spinal hemangioblastomas in 28 patients were treated using the CyberKnife image-guided radiosurgery system at the authors' institution. Fourteen of these patients also had VHL disease. The median age at treatment was 43.5 years (range 19-85 years). The mean prescription radiation dose to the tumor periphery was 21.6 Gy (range 15-35 Gy). The median tumor volume was 0.264 cm3 (range 0.025-70.9 cm3). Tumor response was evaluated on serial, contrast-enhanced CT and MR images. Clinical response was evaluated by clinical and imaging evaluation. RESULTS The mean follow-up for the cohort was 54.3 months. Radiographic follow-up was available for 19 patients with 34 tumors; 32 (94.1%) tumors were radiographically stable or displayed signs of regression. Actuarial control rates at 1, 3, and 5 years were 96.1%, 92.3%, and 92.3%, respectively. Clinical evaluation on follow-up was available for 13 patients with 16 tumors; 13 (81.2%) tumors in 10 patients had symptomatic improvement. No patient developed any complications related to radiosurgery. CONCLUSIONS Image-guided SRS is safe and effective for the primary treatment of spinal hemangioblastomas and is an attractive alternative to resection, especially for those with VHL disease.

Spine radiosurgery: lessons learned from the first 100 treatment sessions.

OBJECTIVE Local therapy to spine tumors has been shown to be effective in selected cases. Spinal radiosurgery (SRS) is an evolving radiotherapy regimen allowing for noninvasive, highly efficacious local treatment. The learning curve can compromise the results of any newly employed technology and should be studied to minimize its effects. In this paper the first 100 SRSs performed at several medical centers are presented and analyzed for the effects of the learning curve on outcome. METHODS A retrospective analysis was undertaken to evaluate data from patients treated with SRS at Sheba Medical Center and Assuta Medical Centers in the period from September 2011 to February 2016. Medical history, clinical and neurological findings, pathological diagnoses, SRS variables, complications, and follow-up data were collected and analyzed. Local control rates were calculated, and local treatment failure cases were qualitatively studied. RESULTS One hundred treatment sessions were performed for 118 lesions at 179 spinal levels in 80 patients. The complication rate was low and did not correlate with a learning curve. Mean follow-up time was 302 days, and the overall local control rate was 95%. The local control rate was dose dependent and increased from 87% (among 35 patients receiving a dose of 16 Gy) to 97% (among 65 patients receiving a dose of 18 Gy). The 6 treatment failure cases are discussed in detail. CONCLUSIONS Spinal radiosurgery is a safe and effective treatment. Comprehensive education of the treating team and continuous communication are essential to limit the effects of the learning curve on outcome.

Solution conformation of adenovirus virus associated RNA-I and its interaction with PKR.

Adenovirus virus-associated RNA (VAI) provides protection against the host antiviral response in part by inhibiting the interferon-induced double stranded RNA-activated protein kinase (PKR). VAI consists of three base-paired regions; the apical stem responsible for the interaction with double-stranded RNA binding motifs (dsRBMs) of PKR, the central stem required for inhibition, and the terminal stem. The solution conformation of VAI and VAI lacking the terminal stem were determined using SAXS that suggested extended conformations that are in agreement with their secondary structures. Solution conformations of VAI lacking the terminal stem in complex with the dsRBMs of PKR indicated that the apical stem interacts with both dsRNA-binding motifs whereas the central stem does not. Hydrodynamic properties calculated from ab initio models were compared to experimentally determined parameters for model validation. Furthermore, SAXS envelopes were used as a constraint for the in silico modeling of tertiary structure for RNA and RNA-protein complex. Finally, full-length PKR was also studied, but concentration-dependent changes in hydrodynamic parameters prevented ab initio shape determination. Taken together, results provide an improved structural framework that further our understanding of the role VAI plays in evading host innate immune responses.

A structural model of PpoA derived from SAXS-analysis-implications for substrate conversion.

In plants and mammals, oxylipins may be synthesized via multi step processes that consist of dioxygenation and isomerization of the intermediately formed hydroperoxy fatty acid. These processes are typically catalyzed by two distinct enzyme classes: dioxygenases and cytochrome P450 enzymes. In ascomycetes biosynthesis of oxylipins may proceed by a similar two-step pathway. An important difference, however, is that both enzymatic activities may be combined in a single bifunctional enzyme. These types of enzymes are named Psi-factor producing oxygenases (Ppo). Here, the spatial organization of the two domains of PpoA from Aspergillus nidulans was analyzed by small-angle X-ray scattering and the obtained data show that the enzyme exhibits a relatively flat trimeric shape. Atomic structures of the single domains were obtained by template-based structure prediction and docked into the enzyme envelope of the low resolution structure obtained by SAXS. EPR-based distance measurements between the tyrosyl radicals formed in the activated dioxygenase domain of the enzyme supported the trimeric structure obtained from SAXS and the previous assignment of Tyr374 as radical-site in PpoA. Furthermore, two phenylalanine residues in the cytochrome P450 domain were shown to modulate the specificity of hydroperoxy fatty acid rearrangement.

Role of Novel Quantitative Imaging Techniques in Hematological Malignancies.

Hematological malignancies exhibit a widespread distribution, necessitating evaluation of disease activity over the entire body. In clinical practice, visual analysis and semiquantitative parameters are used to assess 18F-FDGPET/CT imaging, which solely represents measurements of disease activity from limited area and may not adequately reflect global disease assessment. An efficient method for assessing the global disease burden of hematological malignancies is to employ PET/computed tomography based novel quantitative parameters. In this article, we explored novel quantitative parameters on PET/CT imaging for assessing global disease burden and the potential role of artificial intelligence (AI) to determine these parameters in evaluation of hematological malignancies.

Modeling a space-variant cortical representation for apparent motion.

Receptive field sizes of neurons in early primate visual areas increase with eccentricity, as does temporal processing speed. The fovea is evidently specialized for slow, fine movements while the periphery is suited for fast, coarse movements. In either the fovea or periphery discrete flashes can produce motion percepts. Grossberg and Rudd (1989) used traveling Gaussian activity profiles to model long-range apparent motion percepts. We propose a neural model constrained by physiological data to explain how signals from retinal ganglion cells to V1 affect the perception of motion as a function of eccentricity. Our model incorporates cortical magnification, receptive field overlap and scatter, and spatial and temporal response characteristics of retinal ganglion cells for cortical processing of motion. Consistent with the finding of Baker and Braddick (1985), in our model the maximum flash distance that is perceived as an apparent motion (Dmax) increases linearly as a function of eccentricity. Baker and Braddick (1985) made qualitative predictions about the functional significance of both stimulus and visual system parameters that constrain motion perception, such as an increase in the range of detectable motions as a function of eccentricity and the likely role of higher visual processes in determining Dmax. We generate corresponding quantitative predictions for those functional dependencies for individual aspects of motion processing. Simulation results indicate that the early visual pathway can explain the qualitative linear increase of Dmax data without reliance on extrastriate areas, but that those higher visual areas may serve as a modulatory influence on the exact Dmax increase.

Prognostic value of 18F-FDG lesion dissemination features in patients with peripheral T-cell lymphoma (PTCL).

PURPOSE: To explore the prognostic value of the distance between the two lesions that were farthest apart (Dmax) on baseline 18F-FDG PET/CT in peripheral T lymphoma (PTCL) and establish a new prognostic model for predicting the survival outcomes of patients with PTCL. METHODS: In this study, a retrospective analysis of 95 patients with PTCL who underwent baseline 18F-FDG PET/CT was performed to assess the predictive value of Dmax. The total metabolic tumour volume (TMTV), total lesion glycolysis (TLG), standardized uptake value (SUV), and Dmax were calculated with LIFEx software. Progression-free survival (PFS) and overall survival (OS) were used as endpoints. The prognostic model was developed based on the results of the multivariate analysis. The time-dependent area under the ROC curve (tdAUC), calibration curves, Harrell C-index, and decision curve analysis (DCA) were used to assess the model. RESULTS: Patients were followed up for a median of 17.0 months. Multivariate analysis showed that bone marrow biopsy (BMB) and Dmax were independent predictors of PFS (HR: 1.889, P = 0.039; HR: 1.965, P = 0.047) and OS (HR: 1.923, P = 0.031; HR: 1.982, P = 0.034). The model consisting of Dmax, TMTV, and BMB had substantial prognostic value for survival outcomes of PTCL and could successfully identify four groups of patients with significantly different prognoses (χ2 = 13.731, P = 0.003 for PFS; χ2 = 11.841, P = 0.008 for OS). The tdAUC, C-index, calibration curves, and DCA supported that the model was superior to the prognostic index for T-cell lymphoma (PIT) and International Prognostic Index (IPI) scores. CONCLUSION: BMB and Dmax were independent predictors of PTCL in our study. Moreover, a prognostic model based on the Dmax, TMTV, and BMB could be useful for predicting the survival outcomes of patients with PTCL.

18F-FDG PET/CT Maximum Tumor Dissemination (Dmax) in Lymphoma: A New Prognostic Factor?

Recently, several studies introduced the potential prognostic usefulness of maximum tumor dissemination (Dmax) measured by 2-deoxy-2-fluorine-18-fluoro-D-glucose positron-emission tomography/computed tomography (18F-FDG PET/CT). Dmax is a simple three-dimensional feature that represents the maximal distance between the two farthest hypermetabolic PET lesions. A comprehensive computer literature search of PubMed/MEDLINE, Embase, and Cochrane libraries was conducted, including articles indexed up to 28 February 2023. Ultimately, 19 studies analyzing the value of 18F-FDG PET/CT Dmax in patients with lymphomas were included. Despite their heterogeneity, most studies showed a significant prognostic role of Dmax in predicting progression-free survival (PFS) and overall survival (OS). Some articles showed that the combination of Dmax with other metabolic features, such as MTV and interim PET response, proved to better stratify the risk of relapse or death. However, some methodological open questions need to be clarified before introducing Dmax into clinical practice.

Structure of Helicobacter pylori dihydroneopterin aldolase suggests a fragment-based strategy for isozyme-specific inhibitor design.

Dihydroneopterin aldolase (DHNA) is essential for folate biosynthesis in microorganisms. Without a counterpart in mammals, DHNA is an attractive target for antimicrobial agents. Helicobacter pylori infection occurs in human stomach of over 50% of the world population, but first-line therapies for the infection are facing rapidly increasing resistance. Novel antibiotics are urgently needed, toward which structural information on potential targets is critical. We have determined the crystal structure of H. pylori DHNA (HpDHNA) in complex with a pterin molecule (HpDHNA:Pterin) at 1.49-Å resolution. The HpDHNA:Pterin complex forms a tetramer in crystal. The tetramer is also observed in solution by dynamic light scattering and confirmed by small-angle X-ray scattering. To date, all but one reported DHNA structures are octameric complexes. As the only exception, ligand-free Mycobacterium tuberculosis DHNA (apo-MtDHNA) forms a tetramer in crystal, but its active sites are only partially formed. In contrast, the tetrameric HpDHNA:Pterin complex has well-formed active sites. Each active site accommodates one pterin molecule, but the exit of active site is blocked by two amino acid residues exhibiting a contact distance of 5.2 â€‹Å. In contrast, the corresponding contact distance in Staphylococcus aureus DHNA (SaDHNA) is twice the size, ranging from 9.8 to 10.5 â€‹Å, for ligand-free enzyme, the substrate complex, the product complex, and an inhibitor complex. This large contact distance indicates that the active site of SaDHNA is wide open. We propose that this isozyme-specific contact distance (ISCD) is a characteristic feature of DHNA active site. Comparative analysis of HpDHNA and SaDHNA structures suggests a fragment-based strategy for the development of isozyme-specific inhibitors.

Elective nodal radiotherapy with a gapless radiation field junction for oligorecurrent prostate cancer after previous radiotherapy.

Purpose: To evaluate the feasibility of subsequent elective nodal radiotherapy (ENRT) for nodal recurrences after previous radiotherapy with a defined planning approach for a gapless radiation field junction. Methods: Patients with 1) previous radiotherapy of prostate or prostatic fossa and subsequent pelvic ENRT or 2) previous pelvic radiotherapy and subsequent ENRT to paraaortic lymph nodes (LN) and gapless junction of both radiation fields were analyzed. The cumulative maximum dose (Dmax-cum) and the maximum cumulative dose in 1 cc (D1cc-cum) were estimated. Absolute toxicity and the toxicity exceeding baseline were evaluated. Results: Twenty-two patients with PSMA-PET/CT-staged nodal oligorecurrence after prior radiotherapy were treated with pelvic (14 patients) or paraaortic ENRT (9 patients). One patient was treated sequentially at both locations. Median time between first and second RT was 20.2 months. Median doses to the lymphatic pathways and to PET-positive LN were 47.5 Gy and 64.8 Gy, respectively. The planning constraint of an estimated Dmax-cum ≤ 95 Gy and of D1cc-cum < 90 Gy were achieved in 23/23 cases and 22/23 cases, respectively. Median follow-up was 33.5 months. There was no additional acute or late toxicity ≥ grade 3. Worst acute toxicity exceeding baseline was grade 1 in 68.2% and grade 2 in 22.7% of patients. Worst late toxicity exceeding baseline was grade 1 in 31.8% and grade 2 in 18.2% of patients. Conclusion: ENRT for nodal recurrences after a previous radiotherapy with gapless junction of radiation fields seems to be feasible, applying the dose constraints Dmax-cum ≤ 95 Gy and D1cc-cum < 90 Gy without grade 3 acute or late toxicities exceeding baseline.

Dual time point imaging of staging PSMA PET/CT quantification; spread and radiomic analyses.

OBJECTIVE: The aims were to evaluate the performance of models that predict Gleason Grade (GG) groups with radiomic data obtained from the prostate gland in dual time 68Ga-Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography/Computerized Tomography (PET/CT) images for prostate cancer (PCa) staging, and to analyze the contribution of late imaging to the radiomic model and to evaluate the relationship of the distance between tumor foci in the body (Dmax) obtained in early PET images with histopathology and prostate specific antigen (PSA) value. METHODS: Between October 2020 and August 2021, 41 patients who underwent 68Ga-PSMA PET/CT for staging of PCa were retrospectively analyzed. Volumetric and radiomics data were obtained from early and late PSMA PET images. The differences between age, metastasis status, PSA, standard uptake value (SUV), volumetric and radiomics parameters between GG groups were analyzed. Early and late PET radiomic models were created, area under curve (AUC), sensitivity, specificity and accuracy values of the models were obtained. In addition, the correlation of Dmax values with total PSMA-tumor volume (TV), Total lesion (TL)-PSMA and PSA values was evaluated. In metastatic patients, the difference in Dmax between GG groups was analyzed. RESULTS: There was a significant difference between patients with GG ≤ 3 and > 3 in 35 of the early PET radiomic features. In the early PET model, multivariate analyses showed that GLRLM_RLNU and PSA were the most meaningful parameters. The AUC, sensitivity, specificity and accuracy values of the early model in detecting patients with GG > 3 were calculated as 0.902, 76.2%, 84% and 78.1%, respectively. In 36 late PET radiomic features, there was a significant difference between patients with GG ≤ 3 and > 3. In multivariate analyses; SHAPE_compacity and PSA were obtained as the most meaningful parameters. The AUC, sensitivity, specificity and accuracy values of the late model in detecting patients with GG > 3 were calculated as 0.924, 85.7%, 85% and 85.4%. There was a strong correlation between Dmax and PSA values (p < 0.001, rho: 0.793). Dmax showed strong correlation with PSMA-TVtotal and TL-PSMAtotal (p < 0.001, rho: 0.797; p < 0.001, rho: 0.763, respectively). In patients with metastasis, median Dmax values of the GG > 3 group were higher than GG ≤ 3 group; A statistically significant difference was obtained between these two groups (p = 0.023). CONCLUSIONS: Model generated from the late PSMA PET radiomic data had better performance in the current study. Without the use of invasive methods, the heterogeneity and aggressiveness of the primary tumor and the prediction of GG groups may be possible with 68Ga-PSMA PET/CT images obtained for diagnostic purposes especially with late PSMA PET/CT imaging.

PP2A is activated by cytochrome c upon formation of a diffuse encounter complex with SET/TAF-Iß.

Intrinsic protein flexibility is of overwhelming relevance for intermolecular recognition and adaptability of highly dynamic ensemble of complexes, and the phenomenon is essential for the understanding of numerous biological processes. These conformational ensembles-encounter complexes-lack a unique organization, which prevents the determination of well-defined high resolution structures. This is the case for complexes involving the oncoprotein SET/template-activating factor-Iß (SET/TAF-Iß), a histone chaperone whose functions and interactions are significantly affected by its intrinsic structural plasticity. Besides its role in chromatin remodeling, SET/TAF-Iß is an inhibitor of protein phosphatase 2A (PP2A), which is a key phosphatase counteracting transcription and signaling events controlling the activity of DNA damage response (DDR) mediators. During DDR, SET/TAF-Iß is sequestered by cytochrome c (Cc) upon migration of the hemeprotein from mitochondria to the cell nucleus. Here, we report that the nuclear SET/TAF-Iß:Cc polyconformational ensemble is able to activate PP2A. In particular, the N-end folded, globular region of SET/TAF-Iß (a.k.a. SET/TAF-Iß ΔC)-which exhibits an unexpected, intrinsically highly dynamic behavior-is sufficient to be recognized by Cc in a diffuse encounter manner. Cc-mediated blocking of PP2A inhibition is deciphered using an integrated structural and computational approach, combining small-angle X-ray scattering, electron paramagnetic resonance, nuclear magnetic resonance, calorimetry and molecular dynamics simulations.