Fate Mapping via Ms4a3-Expression History Traces Monocyte-Derived Cells.

Most tissue-resident macrophage (RTM) populations are seeded by waves of embryonic hematopoiesis and are self-maintained independently of a bone marrow contribution during adulthood. A proportion of RTMs, however, is constantly replaced by blood monocytes, and their functions compared to embryonic RTMs remain unclear. The kinetics and extent of the contribution of circulating monocytes to RTM replacement during homeostasis, inflammation, and disease are highly debated. Here, we identified Ms4a3 as a specific gene expressed by granulocyte-monocyte progenitors (GMPs) and subsequently generated Ms4a3TdT reporter, Ms4a3Cre, and Ms4a3CreERT2 fate-mapping models. These models traced efficiently monocytes and granulocytes, but no lymphocytes or tissue dendritic cells. Using these models, we precisely quantified the contribution of monocytes to the RTM pool during homeostasis and inflammation. The unambiguous identification of monocyte-derived cells will permit future studies of their function under any condition.

Classical monocyte ontogeny dictates their functions and fates as tissue macrophages.

Classical monocytes (CMs) are ephemeral myeloid immune cells that circulate in the blood. Emerging evidence suggests that CMs can have distinct ontogeny and originate from either granulocyte-monocyte- or monocyte-dendritic-cell progenitors (GMPs or MDPs). Here, we report surface markers that allowed segregation of murine GMP- and MDP-derived CMs, i.e., GMP-Mo and MDP-Mo, as well as their functional characterization, including fate definition following adoptive cell transfer. GMP-Mo and MDP-Mo yielded an equal increase in homeostatic CM progeny, such as blood-resident non-classical monocytes and gut macrophages; however, these cells differentially seeded various other selected tissues, including the dura mater and lung. Specifically, GMP-Mo and MDP-Mo differentiated into distinct interstitial lung macrophages, linking CM dichotomy to previously reported pulmonary macrophage heterogeneity. Collectively, we provide evidence for the existence of two functionally distinct CM subsets in the mouse that differentially contribute to peripheral tissue macrophage populations in homeostasis and following challenge.

Dendritic cell type 3 arises from Ly6C+ monocyte-dendritic cell progenitors.

Conventional dendritic cells (cDCs) are professional antigen-presenting cells that control the adaptive immune response. Their subsets and developmental origins have been intensively investigated but are still not fully understood as their phenotypes, especially in the DC2 lineage and the recently described human DC3s, overlap with monocytes. Here, using LEGENDScreen to profile DC vs. monocyte lineages, we found sustained expression of FLT3 and CD45RB through the whole DC lineage, allowing DCs and their precursors to be distinguished from monocytes. Using fate mapping models, single-cell RNA sequencing and adoptive transfer, we identified a lineage of murine CD16/32+CD172a+ DC3, distinct from DC2, arising from Ly6C+ monocyte-DC progenitors (MDPs) through Lyz2+Ly6C+CD11c- pro-DC3s, whereas DC2s develop from common DC progenitors (CDPs) through CD7+Ly6C+CD11c+ pre-DC2s. Corresponding DC subsets, developmental stages, and lineages exist in humans. These findings reveal DC3 as a DC lineage phenotypically related to but developmentally different from monocytes and DC2s.

Granulocyte-Monocyte Progenitors and Monocyte-Dendritic Cell Progenitors Independently Produce Functionally Distinct Monocytes.

Granulocyte-monocyte progenitors (GMPs) and monocyte-dendritic cell progenitors (MDPs) produce monocytes during homeostasis and in response to increased demand during infection. Both progenitor populations are thought to derive from common myeloid progenitors (CMPs), and a hierarchical relationship (CMP-GMP-MDP-monocyte) is presumed to underlie monocyte differentiation. Here, however, we demonstrate that mouse MDPs arose from CMPs independently of GMPs, and that GMPs and MDPs produced monocytes via similar but distinct monocyte-committed progenitors. GMPs and MDPs yielded classical (Ly6Chi) monocytes with gene expression signatures that were defined by their origins and impacted their function. GMPs produced a subset of "neutrophil-like" monocytes, whereas MDPs gave rise to a subset of monocytes that yielded monocyte-derived dendritic cells. GMPs and MDPs were also independently mobilized to produce specific combinations of myeloid cell types following the injection of microbial components. Thus, the balance of GMP and MDP differentiation shapes the myeloid cell repertoire during homeostasis and following infection.

Short-peptide-based enteral nutrition affects rats MDP translocation and protects against gut-lung injury via the PepT1-NOD2-beclin-1 pathway in vivo.

BACKGROUND: Peptide transporter 1 (PepT1) transports bacterial oligopeptide products and induces inflammation of the bowel. Nutritional peptides compete for the binding of intestinal bacterial products to PepT1. We investigated the mechanism of short-peptide-based enteral nutrition (SPEN) on the damage to the gut caused by the bacterial oligopeptide product muramyl dipeptide (MDP), which is transported by PepT1. The gut-lung axis is a shared mucosal immune system, and immune responses and disorders can affect the gut-respiratory relationship. METHODS AND RESULTS: Sprague-Dawley rats were gavaged with solutions containing MDP, MDP + SPEN, MDP + intact-protein-based enteral nutrition (IPEN), glucose as a control, or glucose with GSK669 (a NOD2 antagonist). Inflammation, mitochondrial damage, autophagy, and apoptosis were explored to determine the role of the PepT1-nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-beclin-1 signaling pathway in the small intestinal mucosa. MDP and proinflammatory factors of lung tissue were explored to determine that MDP can migrate to lung tissue and cause inflammation. Induction of proinflammatory cell accumulation and intestinal damage in MDP gavage rats was associated with increased NOD2 and Beclin-1 mRNA expression. IL-6 and TNF-α expression and apoptosis were increased, and mitochondrial damage was severe, as indicated by increased mtDNA in the MDP group compared with controls. MDP levels and expression of proinflammatory factors in lung tissue increased in the MDP group compared with the control group. SPEN, but not IPEN, eliminated these impacts. CONCLUSIONS: Gavage of MDP to rats resulted in damage to the gut-lung axis. SPEN reverses the adverse effects of MDP. The PepT1-NOD2-beclin-1 pathway plays a role in small intestinal inflammation, mitochondrial damage, autophagy, and apoptosis.

Allocation of Eavesdropping Attacks for Multi-System Remote State Estimation.

In recent years, the problem of cyber-physical systems' remote state estimations under eavesdropping attacks have been a source of concern. Aiming at the existence of eavesdroppers in multi-system CPSs, the optimal attack energy allocation problem based on a SINR (signal-to-noise ratio) remote state estimation is studied. Assume that there are N sensors, and these sensors use a shared wireless communication channel to send their state measurements to the remote estimator. Due to the limited power, eavesdroppers can only attack M channels out of N channels at most. Our goal is to use the Markov decision processes (MDP) method to maximize the eavesdropper's state estimation error, so as to determine the eavesdropper's optimal attack allocation. We propose a backward induction algorithm which uses MDP to obtain the optimal attack energy allocation strategy. Compared with the traditional induction algorithm, this algorithm has lower computational cost. Finally, the numerical simulation results verify the correctness of the theoretical analysis.

A Hybrid Handover Scheme for Vehicular VLC/RF Communication Networks.

Visible light communication (VLC) is a promising complementary technology to its radio frequency (RF) counterpart to satisfy the high quality-of-service (QoS) requirements of intelligent vehicular communications by reusing LED street lights. In this paper, a hybrid handover scheme for vehicular VLC/RF communication networks is proposed to balance QoS and handover costs by considering the vertical handover and horizontal handover together judging from the mobile state of the vehicle. A Markov decision process (MDP) is formulated to describe this hybrid handover problem, with a cost function balancing the handover consumption, delay, and reliability. A value iteration algorithm was applied to solve the optimal handover policy. The simulation results demonstrated the performance of the proposed hybrid handover scheme in comparison to other benchmark schemes.

Shear bond strength of universal adhesives to human enamel and dentin.

OBJECTIVE: The composition of universal adhesives is highly diverse. The purpose of this in vitro study was to compare the shear bond strength of a composite with five different universal adhesives to human enamel and dentin. MATERIALS AND METHODS: The shear bond strength of a composite (G-aenial Universal Injectable) to human enamel and dentin was tested in selective enamel etching mode before and after thermocyclic aging (10,000 cycles) using five different universal adhesive systems (Adhese Universal VivaPen, Clearfil Universal Bond Quick, G-Premio Bond, Prime&Bond active, and Scotchbond Universal Plus). Two-bottle systems (OptiBond FL and G2-Bond Universal) were used as control. Scanning electron microscopy was conducted of the bonding interface. RESULTS: Significant differences in shear bond strength values were found among the five evaluated universal adhesives. Lowest shear bond strength values were observed for 2-hydroxyethylmethacrylate (HEMA)-free systems. Thermocyclic aging did not significantly reduce shear bond strength values indicating that the initial bond remains stable. CONCLUSIONS: The clinical use of universal adhesives Adhese Universal VivaPen, Clearfil Universal Bond Quick, and Scotchbond Universal Plus can be encouraged as they provided comparable or even better shear bond strength values than the two-bottle controls. CLINICAL SIGNIFICANCE: Universal adhesives that were developed for the same indication and approved for clinical use demonstrated variety in shear bond strength values. When applied in the selective enamel etching mode, a stable bond can be expected from adhesives containing HEMA and monomers with phosphate groups.

The effect of restorative material selection and cementation procedures on the durability of endocrowns in the anterior teeth: an in-vitro study.

OBJECTIVE: To investigate the fracture resistance and failure modalities of anterior endocrown restorations fabricated employing diverse ceramic materials, and bonded using various cementation methodologies. MATERIALS AND METHODS: Forty maxillary central incisors were divided into two main groups based on the ceramic materials used; GroupI (Zir): zirconia endocrwons (Zolid HT+, Ceramill, Amanngirrbach) and GroupII (E-Max): e-max endocrowns (IPS e.max CAD, Ivoclar Vivadent). Both groups were further split into two subgroups depending on the cementation protocols; subgroup IA "ZirMDP": endocowns cemented with MDP primer + MDP resin cement, subgroup IB (ZirNon-MDP): cemented with MDP primer + non-MDP resin cement, subgroup IIA (E-maxMDP): cemented with MDP primer + MDP resin cement, subgroup IIB (E-maxNon-MDP): cemented with MDP primer + non-MDP resin cement. (n = 10/subgroup). Endocrowns were manufactured using CAD/ CAM. Teeth were subjected to 10,000 thermal cycles. The fracture test was performed at 45o with a palatal force direction until the fracture occurred. Test results were recorded in Newton. The failure mode was examined using a stereomicroscope. A One-way ANOVA test was utilized to compare different groups regarding fracture strength values. Tukey`s Post Hoc was utilized for multiple comparisons. RESULTS: The comparative analysis of fracture strength across the diverse groups yielded non-significant differences, as indicated by a p-value exceeding 0.05. Nonetheless, an observable trend emerged regarding the mode of failure. Specifically, a statistically significant prevalence was noted in fractures localized within the endocrown/tooth complex below the cementoenamel junction (CEJ) across all groups, except for Group IIB, "E-max Non-MDP," where fractures within the endocrown/tooth complex occurred above the CEJ. CONCLUSIONS: Combining an MDP-based primer with an MDP-based resin cement did not result in a significant effect on the anterior endocrown fracture strength. CLINICAL RELEVANCE: Regardless of the presence of the MDP monomer in its composition, adhesive resin cement achieved highly successful fracture strength when used with MDP-based ceramic primers. Additionally, ceramic materials exhibiting elastic moduli surpassing those of dentin are discouraged due to their propensity to induce catastrophic fractures within the tooth structure.

[Intraductal radiofrequency ablation under endosonography and cholangioscopy for residual adenoma of the major duodenal papilla with intraductal component]. / Vnutriprotokovaya radiochastotnaya ablyatsiya pod kontrolem endosonografii i kholangioskopii pri rezidual'noi adenome bol'shogo sosochka dvenadtsatiperstnoi kishki s vnutriprotokovym komponentom. Obzor literatury.

All adenomas of the major duodenal papilla (MDP) require resection regardless of morphological structure due to high risk of malignancy. Currently, intraluminal endoscopic interventions are preferable for these adenomas. MDP neoplasms with intraductal spread (type III and IV) are of particular difficulty for endoscopic techniques. Intraductal radiofrequency ablation provides new opportunities for minimally invasive treatment of patients with MDP adenomas and intraductal component. A 72-year-old patient after previous endoscopic papillectomy for MDP adenoma admitted to the Vishnevsky National Research Medical Center of Surgery due to residual adenomatous growths within the papillectomy zone extending to the common bile duct throughout 13 mm. The patient underwent intraductal RFA under endosonography and cholangioscopy. Despite difficult localization of residual growths extending to the common bile duct, endosonography-guided intraductal RFA provided total destruction of residual tumor that was confirmed by cholangioscopy. Length of treatment was 4 months, relapse-free period - 10 months. Minimally invasive endoscopic technology for residual MDP adenoma provided good clinical results.

[Impact of chemical surface treatment of samples made of domestic zirconium dioxide on adhesive strength]. / Vliyanie khimicheskikh metodov podgotovki poverkhnosti obraztsov iz otechestvennogo dioksida tsirkoniya na pokazateli adgezionnoi prochnosti.

Ceramic based on zirconium dioxide (ZD) is a modern, durable material for the manufacture of dentures. It is known that ZD is not etched as glass-ceramic, making it difficult to prepare this material before fixing. OBJECTIVE: To study the impact of various methods of surface treatment of ZD-based ceramic on adhesive strength. MATERIALS AND METHODS: Sandblasting with Al2O3 particles sized 50 µm and application of primers with 10-MDP phosphate monomer were used. Adhesive strength values for following 4 groups of samples were obtained: 1st group - RelyX U200 + sandblasting + Compofix new primer (n=9); 2nd group - Compofix + sandblasting + Compofix new primer (n=9); 3rd group - Panavia F 2.0 + sandblasting (n=9); 4th group (control) - Variolink Esthetic DC + sandblasting + Monobond Plus primer (n=9). RESULTS: The highest strength of adhesion was in the 4th group - 48.71±5.71MPa, the smallest in the 3rd group - 9.49±35.24 MPa. Fully domestic components used in the 2nd group allowed to obtain values of 42.50±9.79 MPa. Adhesive strength in the 1st group was 34.11±4.78 MPa. CONCLUSION: The absence of the 10-MDP-based primers application in the preparation of ZD ceramic reduces the adhesive strength between resin cement and its surface. The domestic set for fixation of dentures can be effectively used for ZD on the same basis as European analogue.

Design, synthesis and biological evaluation of novel lipophilic 2, 5-disubstituted tetrazole analogues of muramyl dipeptide as NOD2 agonists.

A focused library of six new 2, 5-disubstituted tetrazole (2, 5-DST) analogues of N-acetylmuramyl-l-alanyl-d-isoglutamine (MDP) as potential immunomodulators were synthesized by the bioisosteric replacement of α-amide of d-isoglutamine with 5-substituted tetrazole (5-ST). Another parameter 'lipophilicity' was also considered to improve the pharmacological properties of MDP through the alkylation of 5-substituted tetrazole during synthesis. In total, six 2, 5-DST analogues of MDP were synthesized and bio-evaluated for the study of human NOD2 stimulation activity in the innate immune response. Interestingly, among the varied lengths of the alkyl chain in 2, 5-disubstituted tetrazole derivatives, the tetrazole analogues 12b bearing the -Butyl (C4) and 12c having -Octyl (C8) chain showed the best NOD2 stimulation potency equivalent with reference compound MDP. These analogues were evaluated for their adjuvanticity against dengue antigen and analogues 12b and 12c have elicited a potent humoral and cell mediated response.

A "trained immunity" inducer-adjuvanted nanovaccine reverses the growth of established tumors in mice.

Innate immune cells are critical in antitumor immune surveillance and the development of antitumor adaptive cellular immunity. Trained innate immune cells demonstrate immune memory-like characteristics, producing more vigorous immune responses to secondary homologous or heterologous stimuli. This study aimed to investigate whether inducing trained immunity is beneficial when using a tumor vaccine to promote antitumor adaptive immune responses. A biphasic delivery system was developed with the trained immunity inducer Muramyl Dipeptide (MDP) and specific tumor antigen human papillomavirus (HPV) E7 peptide encapsulated by poly(lactide-co-glycolide)-acid(PLGA) nanoparticles (NPs), and the NPs along with another trained immunity agonist, ß-glucan, were further embedded in a sodium alginate hydrogel. The nanovaccine formulation demonstrated a depot effect for E7 at the injection site and targeted delivery to the lymph nodes and dendritic cells (DCs). The antigen uptake and maturation of DCs were significantly promoted. A trained immunity phenotype, characterized by increased production of IL-1ß, IL-6, and TNF-α, was induced in vitro and in vivo in response to secondary homologous or heterologous stimulation. Furthermore, prior innate immune training enhanced the antigen-specific INF-γ-expressing immune cell response elicited by subsequent stimulation with the nanovaccine. Immunization with the nanovaccine completely inhibited the growth of TC-1 tumors and even abolished established tumors in mice. Mechanistically, the inclusion of ß-glucan and MDP significantly enhanced the responses of tumor-specific effector adaptive immune cells. The results strongly suggest that the controlled release and targeted delivery of an antigen and trained immunity inducers with an NP/hydrogel biphasic system can elicit robust adaptive immunity, which provides a promising tumor vaccination strategy.

Small Sample Coherent DOA Estimation Method Based on S2S Neural Network Meta Reinforcement Learning.

Aiming at the existing Direction of Arrival (DOA) methods based on neural network, a large number of samples are required to achieve signal-scene adaptation and accurate angle estimation. In the coherent signal environment, the problems of a larger amount of training sample data are required. In this paper, the DOA of coherent signal is converted into the DOA parameter estimation of the angle interval of incident signal. The accurate estimation of coherent DOA under the condition of small samples based on meta-reinforcement learning (MRL) is realized. The meta-reinforcement learning method in this paper models the process of angle interval estimation of coherent signals as a Markov decision process. In the inner loop layer, the sequence to sequence (S2S) neural network is used to express the angular interval feature sequence of the incident signal DOA. The strategy learning of the existence of angle interval under small samples is realized through making full use of the context relevance of spatial spectral sequence through S2S neural network. Thus, according to the optimal strategy, the output sequence is sequentially determined to give the angle interval of the incident signal. Finally, DOA is obtained through one-dimensional spectral peak search according to the angle interval obtained. The experiment shows that the meta-reinforcement learning algorithm based on S2S neural network can quickly converge to the optimal state by only updating the gradient of S2S neural network parameters with a small sample set when a new signal environment appears.

Conservatively replacing missing anterior teeth with resin bonded ceramic restorations.

OBJECTIVE: This article describes improvements in materials and adhesion technologies that have facilitated new, minimally invasive treatment for the replacement of missing anterior teeth. CLINICAL CONSIDERATIONS: In the first of two case reports presented, the treatment of a 13-year-old female patient with a missing right lateral mandibular incisor is described. The patient was told she could not have an implant placed until she was 25 years of age and space post orthodontics was inadequate for implant placement. Treatment options included: a provisional removable appliance (flipper), an Essix appliance, or a resin-bonded one-wing lithium disilicate bridge with only slight modification to the right central incisor and a lingual wing on the canine. The second case report describes an adult female patient who had an impacted maxillary left canine that could not be pulled into position and wanted a replacement for the missing No. 11. This article demonstrates how the use a two-abutment bridge consisting of an inlay in the first premolar and a lingual wing with a proximal retention groove and a vertical path of insertion is a viable alternative to an implant or a conventional bridge to replace a maxillary canine with minimal removal of tooth structure. CONCLUSION: With the advent of new ceramic materials and improved adhesion minimally invasive prosthesis can be fabricated to replace missing teeth in the esthetic zone. Usually, one wing with a zirconia framework is recommended but Lithium disilicate can also be used depending on occlusal forces. CLINICAL SIGNIFICANCE: Resin-bonded fixed dental prostheses (RBFDPs) can be used on occasion as a viable alternative to implants but case selection and adherence to appropriate adhesive techniques are key to longevity.

Effect of adhesive strategy on resin cement bonding to dentin.

OBJECTIVE: The cement bonding strategy and the polymerization mode can influence the prognosis of indirect restorations. The microtensile bond strength (µTBS) and dentin endogenous enzymatic activity of a dual-cure resin cement (PV5) used in combination with two dentin surface conditioners (accelerator-enhancer primer, TP or universal adhesive, UA) were evaluated. MATERIALS AND METHODS: PV5 was used to lute composite overlays after dentin treatment with TP or UA. The resin cement was self-cured, SC (1 h at 37 °C) or dual-cured, DC (20 s light-cure followed by 15 min self-cure at 37°C). The µTBS test, fractographic analysis, and the in situ zymography evaluations were performed after 24 h (T0 ) or 1 yr (T12 ) of artificial storage. Data were statistically analyzed (α = 0.05). RESULTS: TP/DC obtained the highest adhesive strengths (45 ± 9 and 36.6 ± 8), while UA/SC (17 ± 8 and 11 ± 4) the lowest, both at T0 and T12 , respectively. DC resulted in superior bonding values than the SC, independent of the dentin surface treatment (p < 0.05). The type of adhesive, curing mode and aging influenced the gelatinolytic activity (p < 0.05). CONCLUSIONS: The dual-cure resin cement used in combination with its accelerator-enhancer primer showed superior bonding performances with respect to universal adhesive. Dual-curing the resin cement was determinant to enhance bonding capability over time, independent of the adhesive strategy. CLINICAL RELEVANCE: Clinicians must be aware to faithfully follow manufacturer's recommendation regarding the adhesive strategy suggested with the resin cement used.

Effect of ceramic primers with different chemical contents on the shear bond strength of CAD/CAM ceramics with resin cement after thermal ageing.

BACKGROUND: This study evaluated the effect of ceramic primers containing 10-methacryloyloxydecyl phosphate (10-MDP) and γ-methacryloxypropyl trimethoxysilane (γ-MPTS) agents on the shear bond strength (SBS) of CAD/CAM ceramics with different chemical structures and resin cement. METHODS: A total of 640 CAD/CAM ceramic specimens were obtained from Vita Mark II (VM), IPS E.max CAD (EM), Vita Suprinity (VS) and Vita Enamic (VE). The specimens were divided into two groups: etched with hydrofluoric acid (HF) and unetched. Each group was treated with a different ceramic primer (Clearfil Ceramic Primer Plus, G-Multi Primer and Monobond S), except for an untreated group (n = 10). After ceramic primers and resin cement were applied to each ceramic surface, half of the specimens were thermally aged at 10,000 cycles, 5-55 ± 1 °C, with a dwell time of 30 s. The SBS was tested with a universal testing machine at a 0.5 mm/min crosshead speed. Data were analysed by using statistical software (SPSS 20). Normal data distribution was checked with the Shapiro‒Wilk test. Three-way ANOVA was used to analyse the difference between the numeric data of the HF etched and thermally aged groups. A post hoc Tukey test was applied in the paired comparison of significant difference. The statistical significance level was accepted as p < 0.05. RESULTS: The highest SBS values were obtained in the HF etched G-Multi primer applied nonaged EM group (28.3 ± 2.62 MPa), while the lowest values were obtained in the nonetched and thermally aged EM group that received no treatment (2.86 ± 0.04 Mpa). The SBS significantly increased in all specimens on which the ceramic primer was applied (p < 0.001). Thermal ageing had a significant negative effect on the SBS values in all groups (p < 0.001). CONCLUSION: The positive combined effects of the 10-MDP and γ-MPTS agents resulted in a significant increase in the bonding strength of the resin cement to the CAD/CAM ceramics. In addition, the increase in the amount of inorganic filler provided a favourable effect on durable adhesion.

Head-To-Head Comparison of 68Ga-PSMA-11 PET/CT and 99mTc-MDP Bone Scintigraphy for the Detection of Bone Metastases in Patients With Prostate Cancer: A Meta-Analysis.

BACKGROUND. Bone scintigraphy (BS) using 99mTc-labeled methylene diphospho-nate (99mTc-MDP) remains the recommended imaging modality for the detection of bone metastases in patients with prostate cancer (PCa). However, PET/CT using prostate-specific membrane antigen (PSMA) ligands is increasingly recognized as a means of evaluating disease extent in patients with PCa, including use as a possible stand-alone test in high-risk patients. OBJECTIVE. The purpose of this study is to compare the diagnostic performance of 68Ga-PSMA-11 PET/CT with that of 99mTc-MDP BS for the detection of bone metastases in patients with PCa. EVIDENCE ACQUISITION. The PubMed, Embase, and Cochrane Library databases were searched through October 2021 to identify studies reporting a head-to-head comparison of 68Ga-PSMA-11 PET/CT and 99mTc-MDP BS for the detection of bone metastases in patients with PCa. Only studies with a well-defined reference standard (including various combinations of imaging and/or clinical follow-up) were included. Pooled diagnostic performance was calculated using a bivariate random-effects model, and an AUC was derived for each test from hierarchic summary ROC analysis. The complementary roles of the two tests in identifying bone metastases in patients in whom one of the tests was negative were summarized. EVIDENCE SYNTHESIS. Six studies with 546 patients were included. Pooled sensitivity and specificity, respectively, were 98% (95% CI, 94-99%) and 97% (95% CI, 91-99%) for 68Ga-PSMA-11 PET/CT versus 83% (95% CI, 69-91%) and 68% (95% CI, 41-87%) for 99mTc-MDP BS. The AUC was 0.99 (95% CI, 0.96-1.00) for 68Ga-PSMA-11 PET/CT and 0.85 (95% CI, 0.81-0.87) for 99mTc-MDP BS. Among 408 patients from five included studies, 68Ga-PSMA-11 PET/CT correctly identified bone metastases in 43 of 193 patients (22.3%) with negative 99mTc-MDP BS results, whereas 99mTc-MDP BS correctly identified bone metastases in four of 210 patients (1.9%) with negative 68Ga-PSMA-11 PET/CT results. CONCLUSION. On a per-patient basis, the diagnostic performance of 68Ga-PSMA-11 PET/CT is superior to that of 99mTc-MDP BS for the detection of PCa bone metastases. Furthermore, 99mTc-MDP BS offers limited additional information in patients with negative 68Ga-PSMA-11 PET/CT results. CLINICAL IMPACT. According to current evidence, 99mTc-MDP BS is highly unlikely to be additive to 68Ga-PSMA-11 PET/CT in identifying bone metastases in patients with PCa.

Prospective study of Na[18F]F PET/CT for cancer staging in morbidly obese patients compared with [99mTc]Tc-MDP whole-body planar, SPECT and SPECT/CT.

PURPOSE: This prospective study aims to assess the diagnostic test characteristics of Na[18F]F PET/CT for the skeletal staging of cancer in morbidly obese patients compared with 99mTc-methylene diphosphonate (MDP), whole-body planar (WBS), SPECT, and SPECT/CT acquisitions. MATERIAL AND METHODS: One hundred seventeen obese patients (BMI 46.5 ± 6.1 kg/m2 and mean age, 59.0 years; range 32-89 years) with BMI > 40 kg/m2 were prospectively enrolled and underwent [99mTc]Tc-MDP WBS, SPECT, SPECT/CT, and Na[18F]F PET/CT within two weeks for the osseous staging of a malignancy. Images were assessed qualitatively using a 3-point scale. Patient and lesion-based diagnostic test characteristics were estimated using an optimistic and pessimistic dichotomization method. RESULTS: Bone metastases were confirmed in 44 patients. Patient-based optimistic diagnostic test characteristics were (sensitivity, specificity, overall accuracy): Na[18F]F PET/CT (95.5%, 95.9%, 95.7%), [99mTc]Tc-MDP WBS (52.3%, 71.2%, 64.1%), SPECT (61.4%, 80.8%, 73.5%) and SPECT/CT (65.9%, 91.8%, 82.1%). Lesion-based optimistic diagnostic test characteristics were: Na[18F]F PET/CT (97.7%, 97.9%, 97.7%), [99mTc]Tc-MDP WBS (39%, 67%, 48.9%), SPECT (52.9%, 93.6%, 67.3%) and SPECT/CT (65.9%, 91.8%, 82.1%). There was no significant difference in the specificity of Na[18F]F and SPECT/CT. All other pairwise comparisons were significant (p<.001). ROC curve analysis showed a high overall accuracy of Na[18F]F with significantly higher AUCs for Na[18F]F PET/CT compared to [99mTc]Tc-MDP WBS, SPECT, and SPECT/CT on both patient and lesion-based analysis (p<.001). Moreover, Na[18F]F PET/CT changed patient management in 38% of patients. CONCLUSIONS: Na[18F]F PET/CT may be the preferred imaging modality for skeletal staging in morbidly obese patients. The technique provides excellent diagnostic test characteristics superior to [99mTc]Tc-MDP bone scan (including SPECT/CT), impacts patient management, has an acceptable radiation exposure profile, and is well-tolerated. Further cost-effectiveness evaluations are warranted.

Synthesis and biological evaluation of novel 2-azido muramyl dipeptide as NOD2 agonistic adjuvants.

Novel 2-Azido muramyl dipeptide was synthesized by the bio-isosteric replacement of the N-acetyl group of the muramic acid fragment with the azide functionality at the C2 position. In order to examine the effect of hydrophilic-lipophilic balance on the adjuvant activity, derivatives were synthesized by removing protecting groups sequentially to tune the polarity. Amongst five novel azido derivatives of MDP studied here, di- and mono-benzylated azido derivatives 10 and 11 exhibited good DENV specific antibody(IgG) response with Th1 polarization compared to parent compound Muramyl dipeptide (MDP) whereas all five new derivatives responded positively to NOD2 agonistic assays with compound 10 showing highest stimulation.