Citations

» Benzoyl peroxide (BPO) 5% has been shown to reduce Cutibacterium acnes load on the skin. BPO 5% with miconazole nitrate (MN) 2% may be beneficial, whereas BPO 5% with clindamycin cream 1% to 1.2% does not seem to have additive effects when compared with BPO 5% alone. Chlorhexidine gluconate solutions reduce the total bacterial load on the skin, but do not seem to have a significant effect on C. acnes . » ChloraPrep seems to be the best surgical skin preparation to decrease overall positive skin cultures. Preincisional hydrogen peroxide 3% application has been shown to be a cost-effective practice to inhibit growth of C. acnes . Vancomycin powder before deltopectoral interval closure has antimicrobial effects against C. acnes and is a cost-effective practice. Finally, Bactisure surgical lavage is protective against the formation of biofilms. » IV cefazolin has been shown to be more effective for shoulder arthroplasty infection prophylaxis than antibiotic alternatives such as vancomycin. Thus, patients with a questionable history of penicillin allergy should undergo additional testing. » For shoulder surgery infection prophylaxis, we recommend the use of BPO 5% cream for 5 days preoperatively with chlorhexidine wipes the night before and the morning of surgery. IV cefazolin should be administered perioperatively, and patients with a questionable history of penicillin allergy should be tested. Surgeons should consider preincisional application of hydrogen peroxide 3% for 5 minutes, followed by standard ChloraPrep preparation. Normal saline should be used for preclosure lavage. Finally, application of vancomycin powder deep to the deltopectoral interval closure should be considered.

Background Optimal glenosphere positioning in reverse shoulder arthroplasty (RSA) remains highly debated. We aimed to characterize the association between the prosthesis scapular neck angle (PSNA) and postoperative range of motion (ROM) and clinical outcome scores. Methods A retrospective review of 284 RSAs using a single design with minimum 2-year follow-up was performed. Glenosphere tilt was measured postoperatively using PSNA. ROM and functional outcome scores were assessed preoperatively and at latest follow-up. The PSNA was dichotomized to inferior or superior groups (>90° vs ≤ 90°, respectively) and stratified into quartiles; ROM and outcome score measures were compared between groups controlling for inferior glenosphere overhang. Results No range of PSNA was consistently associated with superior ROM, clinical outcome scores, or rates of complications including scapular notching. However, greater preoperative to postoperative improvement in active FE was found for superiorly (PSNA ≤ 90°) versus inferiorly tilted glenospheres (37° ± 33° vs 53° ± 35°, P = 0.005) and the greater improvement in active FE (57° ± 35°, P = 0.004) was further isolated to the first quartile (mean 85.1° ± 3.5°). Discussion A lack of variation in clinical outcomes based on PSNA suggests negligible short-term (median follow-up 3.1 years) clinical significance when glenosphere tilt falls within the distribution of this cohort (mean 92.6° ± 6.2°).

Abstract Retinoblastoma (RB) protein can exert tumor suppressor functions even when it becomes phosphorylated. It is thus essential to understand how phosphorylated RB (p-RB) expression and function are regulated. Here, we demonstrated that RING finger domain protein TRIM28 bound and promoted ubiquitination and degradation of CDK4/6-phosphorylated RB protein. SETDB1, a known TRIM28 binding partner, protected p-RB from degradation through the binding of methylated RB by its Tudor domain independent of its methyltransferase activity. SETDB1 was found to be frequently overexpressed due to gene amplification and positively correlated with p-RB in prostate cancer patient specimens. Inhibition of SETDB1 expression using a gene-specific antisense oligonucleotide (ASO) reduced tumor growth but accelerated RB protein degradation, limiting the therapeutic efficacy. However, coadministration of the CDK4/6 inhibitor palbociclib blocked ASO-induced RB degradation and resulted in a much greater cancer-inhibitory effect than each inhibitor alone both in vitro and in vivo. This study identified CDK4/6-dependent, TRIM28-mediated proteasomal degradation as a mechanism of RB inactivation and reveals SETDB1 as a key inhibitor of this process. Our findings suggest that combined targeting of SETDB1 and CDK4/6 represents a viable approach for the treatment of cancers with SETDB1 gene amplification or overexpression. Significance: The identification of a role for TRIM28 and SETDB1 in regulating CDK4/6-phosphorylated RB stability uncovers a combination strategy using CDK4/6 and SETDB1 inhibition to decrease RB degradation and inhibit cancer growth.

Abstract IL-7 drives early B lymphopoiesis, but the underlying molecular circuits remain poorly understood, especially how Stat5-dependent and independent pathways contribute to this process. Combining transcriptome and proteome analyses and mouse genetic models, we show that IL-7 promotes anabolic metabolism and biosynthetic programs in pro-B cells. IL-7-mediated mTORC1 activation supported cell proliferation and metabolism in a Stat5-independent, Myc-dependent manner, but was largely dispensable for cell survival or Rag1 and Rag2 gene expression. mTORC1 was also required for Myc-driven lymphomagenesis. Importantly, PI3K and mTORC1 had discrete effects on Stat5 signaling and independently controlled B cell development. In fact, PI3K was actively suppressed by PTEN in pro-B cells to ensure proper IL-7R expression, Stat5 activation, heavy chain rearrangement and survival, suggesting the unexpected bifurcation of the classical PI3K-mTOR signaling. Altogether, our integrative analyses establish IL-7R-mTORC1-Myc and PTEN-mediated PI3K suppression as discrete signaling axes driving B cell development, with differential effects on IL-7R-Stat5 signaling.

Microglia play a critical role in the clearance of myelin debris, thereby ensuring functional recovery from neural injury. Here, using mouse model of demyelination following two-point LPC injection, we show that the microglial autophagic–lysosomal pathway becomes overactivated in response to severe demyelination, leading to lipid droplet accumulation and a dysfunctional and pro-inflammatory microglial state, and finally failed myelin debris clearance and spatial learning deficits. Data from genetic approaches and pharmacological modulations, via microglial Atg5 deficient mice and intraventricular BAF A1 administration, respectively, demonstrate that staged suppression of excessive autophagic–lysosomal activation in microglia, but not sustained inhibition, results in better myelin debris degradation and exerts protective effects against demyelination. Combined multi-omics results in vitro further showed that enhanced lipid metabolism, especially the activation of the linoleic acid pathway, underlies this protective effect. Supplementation with conjugated linoleic acid (CLA), both in vivo and in vitro, could mimic these effects, including attenuating inflammation and restoring microglial pro-regenerative properties, finally resulting in better recovery from demyelination injuries and improved spatial learning function, by activating the peroxisome proliferator-activated receptor (PPAR-γ) pathway. Therefore, we propose that pharmacological inhibition targeting microglial autophagic–lysosomal overactivation or supplementation with CLA could represent a potential therapeutic strategy in demyelinated disorders.

Abstract Bone marrow (BM) niche plays critical roles in promoting progression and chemoresistance of multiple myeloma (MM), but the iron metabolism bridging the malignant plasma cells and BM stromal cells (BMSCs) has not been well elucidated. Using in vitro and in vivo models of interaction of MM and BMSCs, we identified that iron level was augmented due to the elevated expression of transferrin in MM cells, and the accumulation of iron desensitized MM cells to proteasome inhibitors (PIs) treatment and promoted productions of cholesterol and lanosterol. Simultaneously, direct contact with BMSCs remarkably upregulated the protein level of GPX4, a ROS eraser, to obviate ferroptosis in MM cells. Mechanistic studies revealed that CD40/CD40 ligand (CD40L) signaling promoted the expressions of transferrin and SUMO-specific protease 3 (SENP3), and SENP3 stabilized GPX4 protein via deSUMOylation modification. GPX4 inhibitor induced ferroptosis was cell-cell contact dependent, since blocking CD40/CD40L interaction, or depletion of Cd40l in BMSCs from Cd40lfl/fl;Prx1Cre/+ mice, eliminated the anti-MM efficacy of RSL3 in the Vk*MYC mouse model of myeloma, but not in the patient-derived xenografts (PDX) model. Our study deciphers mechanism of iron metabolism in regulating MM chemoresistance, and clarifies the therapeutic potential of non-apoptosis strategies in managing refractory or relapsed MM patients.

AbstractObjectiveTo measure the accuracy of material decomposition using a dual‐source photon‐counting‐detector (DS‐PCD) CT operated in the high‐pitch helical scanning mode and compare the results against dual‐source energy‐integrating‐detector (DS‐EID) CT, which requires use of a low‐pitch value in dual‐energy mode.MethodsA DS‐PCD CT and a DS‐EID CT were used to scan a cardiac motion phantom consisting of a 3‐mm diameter iodine cylinder. Iodine maps were reconstructed using DS‐PCD in high‐pitch mode and DS‐EID in low‐pitch mode. Image‐based circularity, diameter, and iodine concentration of the iodine cylinder were calculated and compared between the two scanners. With institutional review board approval, in vivo exams were performed with the DS‐PCD CT in high‐pitch mode. Images were qualitatively compared against patients with similar heart rates that were scanned with DS‐EID CT in low‐pitch dual‐energy mode.ResultsOn iodine maps, the mean circularity was 0.97 ± 0.02 with DS‐PCD in high‐pitch mode and 0.95 ± 0.06 with DS‐EID in low‐pitch mode. The mean diameter was 2.9 ± 0.2 mm with DS‐PCD and 3.1 ± 0.2 mm with DS‐EID, both of which are close to the 3 mm ground truth. For DS‐PCD, the mean iodine concentration was 9.6 ± 0.8 mg/ml and this was consistent with the 9.4 ± 0.6 mg/ml value obtained with the cardiac motion disabled. For DS‐EID, the concentration was 12.7 ± 1.2 mg/ml with motion enabled and 11.7 ± 0.5 mg/ml disabled. The background noise in the iodine maps was 15.1 HU with DS‐PCD and 14.4 HU with DS‐EID, whereas the volume CT dose index (CTDIvol) was 3 mGy with DS‐PCD and 11 mGy with DS‐EID. On comparison of six patients (three on PCD, three on EID) with similar heart rates, DS‐PCD provided iodine maps with well‐defined coronaries even at a high heart rate of 86 beats per minute. Meanwhile, there were substantial motion artifacts in iodine maps obtained with DS‐EID for patients with similar heart rates.ConclusionIn a cardiac motion phantom, DS‐PCD CT can perform accurate material decomposition in high‐pitch mode, providing iodine maps with excellent geometric accuracy and robustness to motion at approximately 38% of the dose for similar noise as DS‐EID CT.

AbstractBackgroundDeep artificial neural networks such as convolutional neural networks (CNNs) have been shown to be effective models for reducing noise in CT images while preserving anatomic details. A practical bottleneck for developing CNN‐based denoising models is the procurement of training data consisting of paired examples of high‐noise and low‐noise CT images. Obtaining these paired data are not practical in a clinical setting where the raw projection data is not available. This work outlines a technique to optimize CNN denoising models using methods that are available in a routine clinical setting.PurposeTo demonstrate a phantom‐based training framework for CNN noise reduction that can be efficiently implemented on any CT scanner.MethodsThe phantom‐based training framework uses supervised learning in which training data are synthesized using an image‐based noise insertion technique. Ten patient image series were used for training and validation (9:1) and noise‐only images obtained from anthropomorphic phantom scans. Phantom noise‐only images were superimposed on patient images to imitate low‐dose CT images for use in training. A modified U‐Net architecture was used with mean‐squared‐error and feature reconstruction loss. The training framework was tested for clinically indicated whole‐body‐low‐dose CT images, as well as routine abdomen‐pelvis exams for which projection data was unavailable. Performance was assessed based on root‐mean‐square error, structural similarity, line profiles, and visual assessment.ResultsWhen the CNN was tested on five reserved quarter‐dose whole‐body‐low‐dose CT images, noise was reduced by 75%, root‐mean‐square‐error reduced by 34%, and structural similarity increased by 60%. Visual analysis and line profiles indicated that the method significantly reduced noise while maintaining spatial resolution of anatomic features.ConclusionThe proposed phantom‐based training framework demonstrated strong noise reduction while preserving spatial detail. Because this method is based within the image domain, it can be easily implemented without access to projection data.