Improved Resolution and Image Quality of Musculoskeletal Magnetic Resonance Imaging using Deep Learning-based Denoising Reconstruction: A Prospective Clinical Study.

OBJECTIVE: To prospectively evaluate a deep learning-based denoising reconstruction (DLR) for improved resolution and image quality in musculoskeletal (MSK) magnetic resonance imaging (MRI). METHODS: Images from 137 contrast-weighted sequences in 40 MSK patients were evaluated. Each sequence was performed twice, first with the routine parameters and reconstructed with a routine reconstruction filter (REF), then with higher resolution and reconstructed with DLR, and with three conventional reconstruction filters (NL2, GA43, GA53). The five reconstructions (REF, DLR, NL2, GA43, and GA53) were de-identified, randomized, and blindly reviewed by three MSK radiologists using eight scoring criteria and a forced ranking. Quantitative SNR, CNR, and structure's full width at half maximum (FWHM) for resolution assessment were measured and compared. To account for repeated measures, Generalized Estimating Equations (GEE) with Bonferroni adjustment was used to compare the reader's scores, SNR, CNR, and FWHM between DLR vs. NL2, GA43, GA53, and REF. RESULTS: Compared to the routine REF images, the resolution was improved by 47.61% with DLR from 0.39 ± 0.15 mm2 to 0.20 ± 0.06 mm2 (p < 0.001). Per-sequence average scan time was shortened by 7.93% with DLR from 165.58 ± 21.86 s to 152.45 ± 25.65 s (p < 0.001). Based on the average scores, DLR images were rated significantly higher in all image quality criteria and the forced ranking (p < 0.001). CONCLUSION: This prospective clinical evaluation demonstrated that DLR allows approximately two times finer resolution and improved image quality compared to the standard-of-care images.

Natural small-molecules reverse Xeroderma Pigmentosum Complementation Group C (XPC) deficient-mediated drug-resistance in renal cell carcinoma.

BACKGROUND: Renal cancer is insensitive to radiotherapy or most chemotherapies. While the loss of the XPC gene was correlated with drug resistance in colon cancer, the expression of XPC and its role in the drug resistance of renal cancer have not yet been elucidated. With the fact that natural small-molecules have been adopted in combinational therapy with classical chemotherapeutic agents to increase the drug sensitivity and reduce adverse effects, the use of herbal compounds to tackle drug-resistance in renal cancer is advocated. PURPOSE: To correlate the role of XPC gene deficiency to drug-resistance in renal cancer, and to identify natural small-molecules that can reverse drug-resistance in renal cancer via up-regulation of XPC. METHODS: IHC was adopted to analyze the XPC expression in human tumor and adjacent tissues. Clinical data extracted from The Cancer Genome Atlas (TCGA) database were further analysed to determine the relationship between XPC gene expression and tumor staging of renal cancer. Two types of XPC-KD renal cancer cell models were established to investigate the drug-resistant phenotype and screen XPC gene enhancers from 134 natural small-molecules derived from herbal plants. Furthermore, the identified XPC enhancers were verified in single or in combination with FDA-approved chemotherapy drugs for reversing drug-resistance in renal cancer using MTT cytotoxicity assay. Drug resistance gene profiling, ROS detection assay, immunocytochemistry and cell live-dead imaging assay were adopted to characterize the XPC-related drug resistant mechanism. RESULTS: XPC gene expression was significantly reduced in renal cancer tissue compared with its adjacent tissue. Clinical analysis of TCGA database also identified the downregulated level of XPC gene in renal tumor tissue of stage IV patients with cancer metastasis, which was also correlated with their lower survival rate. 6 natural small-molecules derived from herbal plants including tectorigenin, pinostilbene, d-pinitol, polygalasaponin F, atractylenolide III and astragaloside II significantly enhanced XPC expression in two renal cancer cell types. Combinational treatment of the identified natural compound with the treatment of FDA-approved drug, further confirmed the up-regulation of XPC gene expression can sensitize the two types of XPC-KD drug-resistant renal cancer cells towards the FDA-approved drugs. Mechanistic study confirmed that GSTP1/ROS axis was activated in drug resistant XPC-KD renal cancer cells. CONCLUSION: XPC gene deficiency was identified in patient renal tumor samples, and knockdown of the XPC gene was correlated with a drug-resistant phenotype in renal cancer cells via activation of the GSTP1/ROS axis. The 6 identified natural small molecules were confirmed to have drug sensitizing effects via upregulation of the XPC gene. Therefore, the identified active natural small molecules may work as an adjuvant therapy for circumventing the drug-resistant phenotype in renal cancer via enhancement of XPC expression.

Liver X Receptor Inverse Agonist GAC0001E5 Impedes Glutaminolysis and Disrupts Redox Homeostasis in Breast Cancer Cells.

Liver X receptors (LXRs) are members of the nuclear receptor family of ligand-dependent transcription factors which regulate the expression of lipid and cholesterol metabolism genes. Moreover, LXRs and their ligands have been shown to inhibit tumor growth in a variety of cancers. We have previously identified the small molecule compound GAC0001E5 (1E5) as an LXR inverse agonist and a potent inhibitor of pancreatic cancer cells. Transcriptomic and metabolomic studies showed that 1E5 disrupts glutamine metabolism, an essential metabolic pathway commonly reprogrammed during malignant transformation, including in breast cancers. To determine the role of LXRs and potential application of 1E5 in breast cancer, we examined LXR expression in publicly available clinical samples, and found that LXR expression is elevated in breast tumors as compared to normal tissues. In luminal A, endocrine therapy-resistant, and triple-negative breast cancer cells, 1E5 exhibited LXR inverse agonist and "degrader" activity and strongly inhibited cell proliferation and colony formation. Treatments with 1E5 downregulated the transcription of key glutaminolysis genes, and, correspondingly, biochemical assays indicated that 1E5 lowered intracellular glutamate and glutathione levels and increased reactive oxygen species. These results indicate that novel LXR ligand 1E5 is an inhibitor of glutamine metabolism and redox homeostasis in breast cancers and suggest that modulating LXR activity and expression in tumor cells is a promising strategy for targeting metabolic reprogramming in breast cancer therapeutics.

Two-year outcomes with a bioinductive collagen implant used in augmentation of arthroscopic repair of full-thickness rotator cuff tears: final results of a prospective multicenter study.

BACKGROUND: Full-thickness rotator cuff tears (FTRCTs) represent a common shoulder injury that, if untreated, can progress in size, become increasingly painful, and inhibit function. These lesions are often surgically repaired, with double-row arthroscopic repair often preferred for larger tears. Biological augmentation technologies have been developed to improve rates of postoperative radiographic retear and enhance patient-reported outcomes after surgical FTRCT repair. This study sought to confirm that augmented repair with a bioinductive bovine collagen implant results in favorable retear rates and patient outcomes with follow-up to 2 years. METHODS: A prospective multicenter cohort study was undertaken to determine the efficacy and safety of augmenting single- or double-row arthroscopic repair of FTRCTs with a bioinductive bovine collagen implant. Of 115 adult patients participating, 66 (57.4%) had medium (1-3-cm) tears and 49 (42.6%) had large (3-5-cm) tears. Magnetic resonance imaging and patient-reported outcomes (American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form [ASES] and Constant-Murley Score [CMS]) were performed and recorded at baseline, 3 months, 1 year, and 2 years. RESULTS: Mean duration of follow-up was 2.1 years (range, 1.5-2.9 years). Between baseline and 2-year follow-up, mean total thickness of the supraspinatus tendon increased by 12.5% for medium tears and by 17.1% for large tears. Radiographic retear was noted in 7 of 61 available patients (11.5%) with medium tears, and in 14 of 40 patients (35.0%) with large tears. In both groups, these tears primarily occurred before the 3-month follow-up visit (13 of 21 [61.9%]). Radiographic retear with the supplemented double-row (DR) repair technique was 13.2% overall (12 of 91 DR patients; 11.3% for medium tears and 15.8% for large tears). The minimal clinically important difference was achieved by >90% of patients with both medium and large tears for both ASES and CMS. There were 2 serious adverse events classified by the treating surgeon as being possibly related to the device and/or procedure (1 case of swelling/drainage and 1 case of intermittent pain). Nine patients (7.8%; 4 medium tears and 5 large tears) required reoperation of the index rotator cuff surgery. CONCLUSION: Final 2-year data from this study confirm that using this implant in augmentation of arthroscopic double-row repair of FTRCTs provides favorable rates of radiographic retear and substantial functional recovery. The relative safety of the device is also further supported.

Association between headache and suicidality: An analysis of universal suicide screening data at a large urban county hospital.

BACKGROUND: Identifying individuals at increased risk of suicide is important, particularly those who present for treatment for nonpsychiatric chief complaints who may go undetected. It has been found that pain symptoms, such as headache, are associated with suicide, although this association requires further characterization. This study examined specific components of suicidality in relation to headache subtypes. METHODS: This study retrospectively reviewed 2,832,835 nonpsychiatric adult clinical encounters at a large county hospital, where a standardized suicide risk screening tool, the Columbia-Suicide Severity Rating Scale (C-SSRS), was universally implemented. The C-SSRS assesses specific components of suicidality: wish to be dead and suicidal ideation, method, intent, plan, and action. Multivariate logistic regressions were performed to assess the association between headache, as well as headache subtype (migraine, tension, or cluster), and each component of suicidality. RESULTS: There were significant positive associations between presenting with a headache and 2 specific components of suicidality: wish to be dead and suicidal action. Individuals with tension headache may have a lower risk of wishing to be dead compared to those with migraine and cluster headaches. CONCLUSIONS: The association of headaches with specific elements of sui-cidality demonstrates the potential yield of identification of suicide risk among individuals with nonpsychiatric presentations.

Shoulder Pathology on Magnetic Resonance Imaging in Asymptomatic Elite-Level Rock Climbers.

BACKGROUND: The prevalence of findings on shoulder magnetic resonance imaging (MRI) is high in asymptomatic athletes of overhead sports. PURPOSE/HYPOTHESIS: The purpose of this study was to determine the prevalence of atypical findings on MRI in shoulders of asymptomatic, elite-level climbers and to evaluate the association of these findings with clinical examination results. It was hypothesized that glenoid labrum, long head of the biceps tendon, and articular cartilage pathology would be present in >50% of asymptomatic athletes. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A total of 50 elite climbers (age range, 20-60 years) without any symptoms of shoulder pain underwent bilateral shoulder examinations in addition to dedicated bilateral shoulder 3-T† MRI. Physical examinations were performed by orthopaedic sports medicine surgeons, while MRI scans were interpreted by 2 blinded board-certified radiologists to determine the prevalence of abnormalities of the articular cartilage, glenoid labrum, biceps tendon, rotator cuff, and acromioclavicular joint. RESULTS: MRI evidence of tendinosis of the rotator cuff, subacromial bursitis, and long head of the biceps tendonitis was exceptionally common, at 80%, 79%, and 73%, respectively. Labral pathology was present in 69% of shoulders, with discrete labral tears identified in 56%. Articular cartilage changes were also common, with humeral pathology present in 57% of shoulders and glenoid pathology in 19% of shoulders. Climbers with labral tears identified in this study had significantly increased forward elevation compared with those without labral tears in both active (P = .026) and passive (P = .022) motion. CONCLUSION: The overall prevalence of intra-articular shoulder pathology detected by MRI in asymptomatic climbers was 80%, with 57% demonstrating varying degrees of glenohumeral articular cartilage damage. This high rate of arthritis differs significantly from prior published reports of other overhead sports athletes.

Cotyloid Fossa Coverage Percentages May Be Associated With Alpha Angle, Labral Tear, and Clinical Outcomes in Patients With Femoroacetabular Impingement.

BACKGROUND: Within the hip joint, the anatomy of the acetabulum and cotyloid fossa is well established. There is little literature describing the association between the size of the cotyloid fossa relative to the acetabulum and characteristics of patients with femoroacetabular impingement (FAI). PURPOSE/HYPOTHESIS: The purpose was to calculate the cotyloid fossa coverage percentage in the acetabulum and determine its association with patient characteristics, radiographic parameters, intra-articular findings, and preoperative patient-reported outcomes in patients with FAI. We hypothesized there is an association between the cotyloid fossa coverage percentage of the acetabulum and characteristics of patients with FAI. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Patients were included who underwent standard clinical 3-T magnetic resonance imaging of the hip and primary arthroscopic FAI correction surgery during 2015 and 2016. Exclusion criteria were age <18 or >40 years, osteoarthritis, labral reconstruction, previous ipsilateral hip surgery, and hip dysplasia. Measurements of the cotyloid fossa and surrounding lunate cartilage were performed to calculate cotyloid fossa width (CFW) and cotyloid fossa height (CFH) coverage percentages. The relationships between coverage percentages and patient characteristics and intraoperative findings were assessed using independent t tests or Pearson correlations. RESULTS: An overall 146 patients were included. Alpha angle negatively correlated with CFH coverage percentage (r = -0.19; P = .03) and positively correlated with labral tear size (r = 0.28; P < .01). CFH coverage percentage was negatively correlated with labral tear size (r = -0.24; P < .01). Among patients with degenerative tears, CFH was negatively correlated with labral tear size (r = -0.31; P < .01). However, this association was no longer significant after adjusting for sex (partial r = -0.10; P = .39). Cotyloid fossa coverage was not associated with the condition of the cotyloid fossa synovium (synovitis vs no synovitis). CFW coverage percentage was negatively correlated with the 12-Item Short Form Health Survey (SF-12) physical component summary score (r = -0.23; P < .01). CONCLUSION: The CFW and CFH coverage percentages may be associated with alpha angle, labral tear size, and SF-12 physical component summary score in patients with FAI. We may be able to predict the labral condition based on preoperative measurements of CFH and CFW coverage percentages.

How common are non-acute coronary syndrome (ACS) diagnoses in patients with suspected ACS investigated with coronary angiography in New Zealand? (ANZACS-QI 58).

BACKGROUND AND AIMS: The last two decades in New Zealand have seen increased availability of primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) and early invasive coronary angiography (ICA) for other high-risk acute coronary syndrome (ACS) patients. One metric to assess the clinical appropriateness of these invasive strategies is to examine the false-positive rate for the investigation (ie, the rate of non-ACS diagnoses). METHODS: All patients presenting to New Zealand public hospitals with suspected ACS who underwent ICA between 2015 and 2019 were recorded prospectively in the All New Zealand Acute Coronary Syndrome Quality Improvement registry. The cohort was divided according to clinical impression at presentation: (1) suspected STEMI <24h and (2) other suspected ACS. The final discharge diagnosis for each patient were obtained from the registry. RESULTS: There were 6,059 (20%) patients with suspected STEMI <24h and 24,258 (80%) with other suspected ACS. Of the suspected STEMIs <24h, 90.6% had a final diagnosis of STEMI, 3.5% non-ST segment elevation ACS (NSTEACS) and only 5.9% had a non-ACS diagnosis. Of those with other suspected ACS, 80.7% had a final ACS diagnosis. Across all New Zealand district health boards (DHBs), the proportion of non-ACS diagnoses was similar for suspected STEMI presentations. However, for other suspected ACS, the proportions were higher in DHBs with rapid access to coronary interventional facilities than in those without (17.6% vs 7.0%, p<0.001). CONCLUSIONS: False-positive catheter laboratory activations for suspected STEMI patients are low across New Zealand. The differences in the proportion of non-ACS diagnoses according to DHB interventional capability for other suspected ACS requires further investigation.

Automated analysis of immediate reliability of T2 and T2* relaxation times of hip joint cartilage from 3 T MR examinations.

BACKGROUND: Magnetic resonance (MR) T2 and T2* mapping sequences allow in vivo quantification of biochemical characteristics within joint cartilage of relevance to clinical assessment of conditions such as hip osteoarthritis (OA). PURPOSE: To evaluate an automated immediate reliability analysis of T2 and T2* mapping from MR examinations of hip joint cartilage using a bone and cartilage segmentation pipeline based around focused shape modelling. STUDY TYPE: Technical validation. SUBJECTS: 17 asymptomatic volunteers (M: F 7:10, aged 22-47 years, mass 50-90 kg, height 163-189 cm) underwent unilateral hip joint MR examinations. Automated analysis of cartilage T2 and T2* data immediate reliability was evaluated in 9 subjects (M: F 4: 5) for each sequence. FIELD STRENGTH/SEQUENCE: A 3 T MR system with a body matrix flex-coil was used to acquire images with the following sequences: T2 weighted 3D-trueFast Imaging with Steady-State Precession (water excitation; 10.18 ms repetition time (TR); 4.3 ms echo time (TE); Voxel Size (VS): 0.625 × 0.625 × 0.65 mm; 160 mm field of view (FOV); Flip Angle (FA): 30 degrees; Pixel Bandwidth (PB): 140 Hz/pixel); a multi-echo spin echo (MESE) T2 mapping sequence (TR/TE: 2080/18-90 ms (5 echoes); VS: 4 × 0.78 × 0.78 mm; FOV: 200 mm; FA: 180 degrees; PB: 230 Hz/pixel) and a MESE T2* mapping sequence (TR/TE: 873/3.82-19.1 ms (5 echoes); VS: 3 × 0.625 × 0.625 mm; FOV: 160 mm; FA: 25 degrees; PB: 250 Hz/pixel). ASSESSMENT: Automated cartilage segmentation and quantitative analysis provided T2 and T2* data from test-retest MR examinations to assess immediate reliability. STATISTICAL TESTS: Coefficient of variation (CV) and intraclass correlations (ICC2, 1) to analyse automated T2 and T2* mapping reliability focusing on the clinically important superior cartilage regions of the hip joint. RESULTS: Comparisons between test-retest T2 and (T2*) data revealed mean CV's of 3.385% (1.25%), mean ICC2, 1's of 0.871 (0.984) and median mean differences of -1.139ms (+0.195ms). CONCLUSION: The T2 and T2* times from automated analyses of hip cartilage from test-retest MR examinations had high (T2) and excellent (T2*) immediate reliability.

Non-Metabolic Functions of PKM2 Contribute to Cervical Cancer Cell Proliferation Induced by the HPV16 E7 Oncoprotein.

Pyruvate kinase M2 (PKM2) mainly catalyzes glycolysis, but it also exerts non-glycolytic functions in several cancers. While it has been shown to interact with the human papillomavirus 16 (HPV16) E7 oncoprotein, the functional significance of PKM2 in HPV-associated cervical cancer has been elusive. Here, we show that HPV16 E7 increased the expression of PKM2 in cervical cancer cells. TCGA data analyses revealed a higher level of PKM2 in HPV+ than HPV- cervical cancers and a worse prognosis for patients with high PKM2 expression. Functionally, we demonstrate that shRNA-mediated PKM2 knockdown decreased the proliferation of HPV+ SiHa cervical cancer cells. PKM2 knockdown also inhibited the E7-induced proliferation of cervical cancer cells. ML265 activating the pyruvate kinase function of PKM2 inhibited cell cycle progression and colony formation. ML265 treatments decreased phosphorylation of PKM2 at the Y105 position that has been associated with non-glycolytic functions. On the contrary, HPV16 E7 increased the PKM2 phosphorylation. Our results indicate that E7 increases PKM2 expression and activates a non-glycolytic function of PKM2 to promote cervical cancer cell proliferation.

Quantitative T2 mapping of the glenohumeral joint cartilage in asymptomatic shoulders and shoulders with increasing severity of rotator cuff pathology.

PURPOSE: To examine the relationship between glenohumeral cartilage T2 mapping values and rotator cuff pathology. METHOD: Fifty-nine subjects (age 48.2 ±â€¯13.5 years, 15 asymptomatic volunteers and 10 tendinosis, 13 partial-thickness tear, 8 full-thickness tear, and 13 massive tear patients) underwent glenohumeral cartilage T2 mapping. The humeral head cartilage was segmented in the sagittal and coronal planes. The glenoid cartilage was segmented in the coronal plane. Group means for each region were calculated and compared between the groups. RESULTS: Massive tear group T2 values were significantly higher than the asymptomatic group values for the humeral head cartilage included in the sagittal (45 ±â€¯7 versus 32 ±â€¯4 ms, p <  .001) and coronal (44 ± 6 versus 38 ± 1 ms, p =  0.01) plane images. Mean T2 was also significantly higher for massive than full-thickness tears (45 ± 7 versus 38 ± 5 ms, p =  0.02), massive than partial-thickness tears (45 ± 7 versus 34 ± 4 ms, p <  0.001), and massive tears than tendinosis (45 ± 7 versus 35 ± 4 ms, p =  0.001) in the sagittal-images humeral head region and significantly higher for massive tears than asymptomatic shoulders (44 ± 6 versus 38 ± 1 ms, p =  0.01) in the coronal-images humeral head region. CONCLUSION: Humeral head cartilage T2 values were significantly positively correlated with rotator cuff pathology severity. Massive rotator cuff tear patients demonstrated significantly higher superior humeral head cartilage T2 mapping values relative to subjects with no/lesser degrees of rotator cuff pathology.

Retear rates and clinical outcomes at 1 year after repair of full-thickness rotator cuff tears augmented with a bioinductive collagen implant: a prospective multicenter study.

BACKGROUND: Biologic technologies can potentially augment existing arthroscopic rotator cuff repair to improve retear rates and postoperative outcomes. The purpose of this study was to evaluate healing rates and clinical outcomes of full-thickness rotator cuff repairs augmented with a bioinductive bovine collagen implant. METHODS: In this prospective multicenter study, investigators enrolled 115 patients (mean age, 60.4 years) with full-thickness rotator cuff tears. There were 66 (57.4%) medium (1-3 cm) tears and 49 (42.6%) large (3-5 cm) tears. Eligible patients consisted of those ≥21 years of age with chronic shoulder pain lasting longer than 3 months and unresponsive to conservative therapy. Patients underwent single- or double-row repair augmented with a bioinductive bovine collagen implant. At the baseline, 3 months, and 1 year, magnetic resonance imaging was performed and patients were assessed for American Shoulder and Elbow Surgeons (ASES) Shoulder Score and Constant-Murley Score (CMS). The primary failure end point was retear, classified as any new full-thickness defect observed on magnetic resonance imaging. RESULTS: There were 13 retears (11.3%) at 3 months, with an additional 6 (19 total [16.5%]) found at 1 year. In large tears, double-row repair had a significantly lower rate of retear at 3 months (P = .0004) and 1 year (P = .0001) compared with single-row repair. ASES and CMS scores significantly improved between the baseline and 1 year for medium and large tears. At 1 year, the minimally clinically important difference for ASES and CMS was met by 91.7% (95% CI: 84.9-96.1) and 86.4% (95% CI: 78.2-92.4) of patients, respectively. Patients without retear and those <65 years of age had significantly better CMS scores at 1 year when compared with those with retear and those ≥65 years (P < .05). There was no statistically significant difference in outcomes based on treatment of the biceps tendon. Of 9 reported reoperations in the operative shoulder, only 2 were considered potentially related to the collagen implant. CONCLUSION: Interim results from this prospective study indicate a favorable rate of retear relative to the literature and improvement in clinical function at 1 year after adjunctive treatment with the study implant augmenting standard arthroscopic repair techniques.

Isolated bioinductive repair of partial-thickness rotator cuff tears using a resorbable bovine collagen implant: two-year radiologic and clinical outcomes from a prospective multicenter study.

BACKGROUND: Current surgical treatment options for partial-thickness tears (eg, takedown and repair, in situ repair) are limited by the degenerative nature of the underlying tendon and may require extensive intervention that can alter the anatomic footprint. The complexity of available techniques to address these issues led to the development of a resorbable collagen implant, which can be used to create a bioinductive repair of partial-thickness tears. METHODS: We prospectively enrolled 33 patients with chronic, degenerative, intermediate-grade (n = 12), or high-grade (n = 21) partial-thickness tears (11 articular, 10 bursal, 4 intrasubstance, and 8 hybrid) of the supraspinatus tendon in a multicenter study. After arthroscopic subacromial decompression without a traditional rotator cuff repair, a bioinductive implant was secured over the bursal surface of the tendon. Clinical outcomes were assessed using American Shoulder and Elbow Surgeons (ASES) and Constant-Murley scores (CMS) preoperatively and at 3 months, 1 year, and 2 years postoperatively. Magnetic resonance imaging was performed to assess postoperative tendon healing and thickness at the original tear site. RESULTS: At 2-year follow-up, mean ASES and CMS scores improved both clinically and statistically at 1 and 2 years, compared with baseline, for intermediate- and high-grade tears. There was magnetic resonance imaging evidence of new tissue fill-in within the original baseline tear in 100% of the intermediate-grade tears and 95% of the high-grade tears. In 90.9% of the intermediate-grade tears and 84.2% of the high-grade tears, this new tissue fill-in represented at least an additional 50% of the volume of the initial lesion. From baseline to 2-year follow-up, the mean tendon thickness increased by 1.2 mm (standard deviation, 1.3; P = .012) and 1.8 mm (standard deviation, 2.2; P = .003) in the intermediate- and high-grade tears, respectively. The analysis of tear grade and location revealed no statistically significant difference in the change in mean tendon thickness at any time point. One patient with a high-grade articular lesion demonstrated progression to a full-thickness tear; however, the patient was noncompliant and the injury occurred while shoveling snow 1 month after surgery. Neither tear location nor treatment of bicep pathology affected the ASES or CMS scores at any follow-up point. No serious adverse events related to the implant were reported. CONCLUSION: Final results from this 2-year prospective study indicate that the use of this resorbable bovine collagen implant for isolated bioinductive repair of intermediate- and high-grade partial-thickness rotator cuff tears of the supraspinatus is safe and effective, regardless of tear grade and location.

Progesterone Receptor Is a Haploinsufficient Tumor-Suppressor Gene in Cervical Cancer.

Tumor-suppressor genes (TSG) are often deleted or transcriptionally suppressed in cancer. PGR codes for progesterone receptor (PR), a transcription factor whose function depends on its ligand. Although PR expression is often undetectable in cervical cancer, its relevance to the endocrine-related etiology of this prevalent gynecological disease remains unclear. In this study, we show that the deletion of one Pgr allele in cervical epithelium promoted spontaneous cervical cancer in human papilloma viral oncogene-expressing transgenic mice as efficiently as the ablation of both Pgr alleles. We also show that tumors arising in the transgenic mice with one or both Pgr alleles did not express PR or expressed at the reduced levels compared with the normal epithelium. PR status correlated with estrogen receptor α (ERα) status in the mouse model and the Cancer Genome Atlas (TCGA) dataset. TCGA data analyses revealed that PGR expression significantly decreased in cervical cancer and that the biallelic deletion of PGR was rare. Furthermore, low PGR expression was associated with poor prognosis in young patients with cervical cancer. These discoveries point to PGR as a haploinsufficient TSG in the uterine cervix. They also raise the possibility that the restoration of PGR expression may improve the survival rate. IMPLICATIONS: The decreased expression of PR may increase the risk of cervical cancer in human papillomavirus-infected women. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/1/42/F1.large.jpg.

Accuracy of MRI-Based Talar Cartilage Thickness Measurement and Talus Bone and Cartilage Modeling: Comparison with Ground-Truth Laser Scan Measurements.

OBJECTIVE: The purpose of this work was to compare measurements of talar cartilage thickness and cartilage and bone surface geometry from clinically feasible magnetic resonance imaging (MRI) against high-accuracy laser scan models. Measurement of talar bone and cartilage geometry from MRI would provide useful information for evaluating cartilage changes, selecting osteochondral graft sources or creating patient-specific joint models. DESIGN: Three-dimensional (3D) bone and cartilage models of 7 cadaver tali were created using (1) manual segmentation of high-resolution volumetric sequence 3T MR images and (2) laser scans. Talar cartilage thickness was compared between the laser scan- and MRI-based models for the dorsal, medial, and lateral surfaces. The laser scan- and MRI-based cartilage and bone surface models were compared using model-to-model distance. RESULTS: Average cartilage thickness within the dorsal, medial, and lateral surfaces were 0.89 to 1.05 mm measured with laser scanning, and 1.10 to 1.22 mm measured with MRI. MRI-based thickness was 0.16 to 0.32 mm higher on average in each region. The average absolute surface-to-surface differences between laser scan- and MRI-based bone and cartilage models ranged from 0.16 to 0.22 mm for bone (MRI bone models smaller than laser scan models) and 0.35 to 0.38 mm for cartilage (MRI bone models larger than laser scan models). CONCLUSIONS: This study demonstrated that cartilage and bone 3D modeling and measurement of average cartilage thickness on the dorsal, medial, and lateral talar surfaces using MRI were feasible and provided similar model geometry and thickness values to ground-truth laser scan-based measurements.

Genes Associated with Calcium Signaling are Involved in Alcohol-Induced Breast Cancer Growth.

BACKGROUND: Alcohol consumption is a risk factor for breast cancer, contributing to up to nearly 23,000 new cases each year. Mechanistic studies show that alcohol increases tumor aggressiveness and metastatic potential, promotes angiogenesis, induces chronic inflammation, and dysregulates RNA polymerase III-related genes. Alcohol has also been shown to affect estrogen signaling in breast cancer, including in our study of the transcriptomic effects of alcohol in breast cancer cells. METHODS: To elucidate mechanisms of action of alcohol in breast cancer, we carried out secondary analyses of our alcohol-responsive transcriptome data using gene ontology and pathway databases and analysis tools and cistromic data analysis of candidate transcription factors which may mediate the transcriptomic alterations. Predicted alcohol-responsive pathways and mechanisms were perturbed and examined experimentally in breast cancer cells. The clinical relevance of identified genes was determined by expression profiles in patient samples and correlation with disease outcomes and alcohol consumption in previously published study cohorts. RESULTS: Gene ontology analysis showed that alcohol alters the expression of many metabolism-related genes, and cistromic data of differentially expressed genes revealed the potential involvement of nuclear factor of activated T cells 3 (NFATC3) in mediating the transcriptomic effects of alcohol. Pathway analysis also predicted regulation of calcium signaling by alcohol in breast cancer cells. Chemical perturbation of this pathway reversed the effect of alcohol on breast cancer cell growth and reduced the elevated cytosolic Ca2+ levels induced by alcohol. Expression levels of alcohol-responsive genes in tumor samples from breast cancer patients are associated with poor disease outcomes. Moreover, expression of some of these genes was altered in breast cancer patients who consumed alcohol previously as compared to those who did not drink. CONCLUSION: Alcohol alters expression of genes that regulate intracellular calcium levels and downstream signaling pathways which drive breast cancer cell proliferation and disease progression.

Novel Liver X Receptor Ligand GAC0001E5 Disrupts Glutamine Metabolism and Induces Oxidative Stress in Pancreatic Cancer Cells.

Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer with a high mortality rate due to the lack of early detection and effective treatment options for advanced diseases. Metabolic reprogramming, a common hallmark of malignant transformation in pancreatic cancer, is critical for the growth and survival of cancer cells and a potential target mechanism for the treatment of pancreatic cancer. PDAC cells have upregulated glutamine metabolism to meet their biosynthetic and oxidative demands. Liver X receptors (LXRs) are ligand-dependent transcription factors involved in maintaining metabolic homeostasis. LXRs regulate critical cancer-related processes and pathways, including cholesterol, glucose and lipid metabolism, and inflammatory and immune responses. Analysis of transcriptomic data from PDAC clinical samples reveals overexpression of LXRs and their target genes in tumors as compared to normal tissue controls. Targeting LXRs with the novel LXR inverse agonist and degrader GAC0001E5 inhibited PDAC cell proliferation. Using a metabolomics approach, we discovered that 1E5 inhibits glutamine anaplerosis and induces oxidative stress, which are detrimental to PDAC cells. These findings highlight a novel role for LXR in regulating cancer metabolism and the potential application of LXR modulators in targeting cancer metabolism in pancreatic cancer and other malignancies.

Atrial fibrillation in acute coronary syndrome: patient characteristics and appropriate utilisation of anti-thrombotic therapy in New Zealand (ANZACS-QI 39).

BACKGROUND: Concomitant atrial fibrillation (AF) and acute coronary syndrome (ACS) present the difficult therapeutic dilemma of balancing bleeding, cardio-embolic and coronary thrombotic risks with appropriate combinations of antithrombotic medications. We aim to evaluate current New Zealand practice by identifying the incidence of AF in ACS; describe the population characteristics; and assess our antithrombotic management. METHODS: Consecutive patients ≥18y presenting with ACS who had coronary angiography (2017-2018) were identified from the All New Zealand ACS Quality Improvement (ANZACS-QI) registry. The cohort was divided into three groups: 1) patients with pre-existing AF; 2) new-onset AF; and 3) no AF. Antithrombotic regimens included dual antiplatelet therapy (DAPT), dual antithrombotic therapy (DAT-single antiplatelet plus an oral anticoagulant (OAC)) and triple antithrombotic therapy (TAT). RESULTS: There were 9,489 patients, 9.6% with pre-existing AF, 4.4% new AF and 86% without AF. Both AF groups were older (median 74 vs 71 vs 65y, p=0.001), had poorer renal function, were more likely to present with heart failure (16% vs 19% vs 8%, p=0.001) and have left ventricular ejection fraction <40% (22% vs 28% vs 13%, p<0.001). They received less percutaneous coronary intervention (PCI) (53% vs 59% vs 70%, p=0.001). In the cohort, 25 different combinations of antithrombotic agents were utilised. Ninety-six percent of patients with any AF had a CHA2DS2VASC stroke risk score of ≥2, of whom 48% did not receive OAC. Twenty-four percent received TAT and 19% DAT. OAC use increased slightly with increasing stroke risk but were independent of CRUSADE bleeding risk. Of patients with AF treated with PCI, 53% received DAPT, 11% DAT and 35% TAT. 51% of those at high stroke risk were discharged on DAPT only. In contrast, 19% at low stroke risk received TAT. CONCLUSION: In New Zealand, one in seven patients presenting with ACS have AF, a third being new-onset AF. Antithrombotic management is inconsistent, with underutilisation of anticoagulants, particularly the DAT regimen, and is inadequately informed by stroke and bleeding risk scores.