Unconventional mechanism of action and resistance to rapalogs in renal cancer.

mTORC1 is aberrantly activated in renal cell carcinoma (RCC) and is targeted by rapalogs. As for other targeted therapies, rapalogs clinical utility is limited by the development of resistance. Resistance often results from target mutation, but mTOR mutations are rarely found in RCC. As in humans, prolonged rapalog treatment of RCC tumorgrafts (TGs) led to resistance. Unexpectedly, explants from resistant tumors became sensitive both in culture and in subsequent transplants in mice. Notably, resistance developed despite persistent mTORC1 inhibition in tumor cells. In contrast, mTORC1 became reactivated in the tumor microenvironment (TME). To test the role of the TME, we engineered immunocompromised recipient mice with a resistance mTOR mutation (S2035T). Interestingly, TGs became resistant to rapalogs in mTORS2035T mice. Resistance occurred despite mTORC1 inhibition in tumor cells and could be induced by coculturing tumor cells with mutant fibroblasts. Thus, enforced mTORC1 activation in the TME is sufficient to confer resistance to rapalogs. These studies highlight the importance of mTORC1 inhibition in nontumor cells for rapalog antitumor activity and provide an explanation for the lack of mTOR resistance mutations in RCC patients.

Disruption of the ZFP574-THAP12 complex suppresses B cell malignancies in mice.

Despite the availability of life-extending treatments for B cell leukemias and lymphomas, many of these cancers remain incurable. Thus, the development of new molecular targets and therapeutics is needed to expand treatment options. To identify new molecular targets, we used a forward genetic screen in mice to identify genes required for development or survival of lymphocytes. Here, we describe Zfp574, an essential gene encoding a zinc finger protein necessary for normal and malignant lymphocyte survival. We show that ZFP574 interacts with zinc finger protein THAP12 and promotes the G1-to-S-phase transition during cell cycle progression. Mutation of ZFP574 impairs nuclear localization of the ZFP574-THAP12 complex. ZFP574 or THAP12 deficiency results in cell cycle arrest and impaired lymphoproliferation. Germline mutation, acute gene deletion, or targeted degradation of ZFP574 suppressed Myc-driven B cell leukemia in mice, but normal B cells were largely spared, permitting long-term survival, whereas complete lethality was observed in control animals. Our findings support the identification of drugs targeting ZFP574-THAP12 as a unique strategy to treat B cell malignancies.

Creation and Validation of a Novel 3-Dimensional Pediatric Hip Ultrasound Model.

OBJECTIVES: The aim of this study was to create and validate a 3-dimensional (3D) ultrasound model with normal and abnormal pediatric hip joint anatomy that is comparable to a pediatric hip joint in appearance and anatomy and replicates sonographic characteristics of a pediatric hip joint. METHODS: A 3D rendering of the bone and soft tissue was created from a computed tomography pelvic scan of a pediatric patient. This rendering was modified to include a unilateral joint effusion. The bone was 3D printed with a photopolymer plastic, whereas the soft tissue was cast with a silicone mixture in a 3D-printed mold. The effusion was simulated by injecting saline into the soft tissue cavity surrounding the bone. The ultrasound model was validated by pediatric point-of-care ultrasonographers at an international pediatric ultrasound conference. RESULTS: A pediatric hip ultrasound model was developed that simulates both normal and abnormal pediatric hip joint anatomy, each with an appropriately sized, measurable joint effusion. Validation by pediatric point-of-care ultrasonographers showed that the key aspects of a normal pediatric hip joint (femoral physis, sloped femoral neck, and adequate soft tissue) with an identifiable and measurable effusion were included in the ultrasound model. CONCLUSIONS: In this study, we successfully created a cost-effective, reusable, and reproducible 3D pediatric hip ultrasound model. The majority of pediatric point-of-care ultrasonographers who evaluated the model agreed that this model is comparable to a pediatric patient for the purpose of teaching ultrasound skills and joint space measurement.

Point-of-Care Ultrasound, an Unexpected Cardiac Mass in a Neonate.

ABSTRACT: Neonatal cardiac masses are uncommon and often not obvious based on physical examination or plain radiography. The objective of this clinical case report is to demonstrate how cardiac point-of-care ultrasound was pivotal in the clinical course of a seemingly well neonate with vague symptoms. A 6-week-old male infant presented to the emergency department with fatigue and pallor that was reported to have resolved before arrival. In the emergency department, he had a normal physical examination and stable vital signs. Cardiac point-of-care ultrasound was performed and demonstrated a mass near the mitral valve. These ultrasound findings prompted additional evaluation, cardiology consultation, admission, and subsequent diagnosis of a rhabdomyoma due to tuberous sclerosis.

Point-of-Care Ultrasound Assessment of Orbital Rhabdomyosarcoma in a Pediatric Patient.

ABSTRACT: Rhabdomyosarcoma is the most common soft tissue tumor in children and orbital lesions account for 10% of these diagnoses. This case describes a young boy who presented with eyelid swelling that was initially concerning for an expanding hematoma given a history of recent trauma to the eye. Point-of-care ultrasound identified 2 distinct lesions surrounding the globe, which prompted further investigation, including ophthalmology consult and computed tomography. The case presented highlights the initial misdiagnosis on both point-of-care ultrasound and computed tomography and the importance of using color Doppler on ultrasound to distinguish an orbital rhabdomyosarcoma from a posttraumatic hematoma.

Clinicoradiographic predictors of percutaneous bone biopsy results among patients with suspected thoracolumbar spine infection.

BACKGROUND: Image-guided percutaneous thoracolumbar spine biopsy is frequently performed in the setting of suspected septic facet arthritis or discitis osteomyelitis (DOM). There are limited data regarding factors associated with a positive biopsy result among these patients. MATERIALS AND METHODS: Patients with suspected DOM who underwent spine biopsy were identified. Samples yielding a positive culture and/or histopathology suggestive of acute osteomyelitis were considered positive. The associations between selected medical comorbidities, laboratory values, pre-biopsy antibiotic administration, imaging findings and biopsy results were investigated. RESULTS: 121 patients underwent percutaneous biopsy with 35.5% yielding positive results. Biopsy results showed no correlation with comorbidities. The only laboratory value that correlated with a positive biopsy yield was blood culture positivity (p = 0.03). The imaging findings that correlated with a positive biopsy yield were the presence of a paraspinal fluid collection or epidural abscess (p = 0.003 and 0.018, respectively). Sampling paraspinal fluid collections, when present, resulted in a higher rate of a positive biopsy yield compared to sampling of bone or disc (p = 0.006). Patients who received antibiotics had a higher rate of a positive biopsy yield (p = 0.014). In those with positive blood cultures, biopsy yielded the same antimicrobial susceptibility profile in 13/14 cases. CONCLUSION: The presence of a paraspinal fluid collection or epidural abscess is correlated with positive biopsy yield, and paraspinal fluid collections should be targeted for biopsy. Other imaging findings did not correlate with biopsy yield. Biopsy may not offer additional information for patients with positive blood cultures.

A comprehensive review of the normal, abnormal, and post-operative MRI appearance of the distal biceps brachii.

The biceps brachii myotendinous unit is a common source of shoulder, arm, and elbow pain. Its complex anatomy can present a challenge when interpreting MR images. We discuss the clinical and imaging presentations of injury related to the proximal biceps brachii separately in another manuscript. The purpose of this manuscript is to review the distal biceps anatomy along with pathology and post-operative appearance as seen on MRI.

MRN findings of lateral antebrachial cutaneous nerve impingement in a collegiate athlete.

Dynamic compression of the lateral antebrachial cutaneous nerve (LABCN) occurs with forearm pronation when the LABCN becomes compressed by the lateral margin of the biceps tendon. LABCN compression is a rare occurrence and is often overlooked as an etiology for forearm pain. While this entity has been described in several case reports in the orthopedic literature, it has not yet been described in radiology literature. We present a case of LABCN compression by the biceps tendon which was suggested by high-resolution magnetic resonance neurography in combination with the clinical findings and was subsequently confirmed and corrected surgically.

A comprehensive review of the normal, abnormal, and post-operative MRI appearance of the proximal biceps brachii.

The biceps brachii myotendinous unit, particularly the long head of the biceps tendon and its labral attachment, is a common cause of shoulder and arm pain. Its complex anatomy and normal variations can present a challenge when interpreting MR images. The purpose of this manuscript is to review the proximal biceps anatomy, variants, pathology, and post-operative appearance as seen on MRI. Recent data regarding the accuracy of clinical examination and MRI will be summarized.

The Human Leukocyte Antigen (HLA)-B27 Peptidome in Vivo, in Spondyloarthritis-susceptible HLA-B27 Transgenic Rats and the Effect of Erap1 Deletion.

HLA-B27 is a class I major histocompatibility (MHC-I) allele that confers susceptibility to the rheumatic disease ankylosing spondylitis (AS) by an unknown mechanism. ERAP1 is an aminopeptidase that trims peptides in the endoplasmic reticulum for binding to MHC-I molecules. ERAP1 shows genetic epistasis with HLA-B27 in conferring susceptibility to AS. Male HLA-B27 transgenic rats develop arthritis and serve as an animal model of AS, whereas female B27 transgenic rats remain healthy. We used large scale quantitative mass spectrometry to identify over 15,000 unique HLA-B27 peptide ligands, isolated after immunoaffinity purification of the B27 molecules from the spleens of HLA-B27 transgenic rats. Heterozygous deletion of Erap1, which reduced the Erap1 level to less than half, had no qualitative or quantitative effects on the B27 peptidome. Homozygous deletion of Erap1 affected approximately one-third of the B27 peptidome but left most of the B27 peptidome unchanged, suggesting the possibility that some of the HLA-B27 immunopeptidome is not processed in the presence of Erap1. Deletion of Erap1 was permissive for the AS-like phenotype, increased mean peptide length and increased the frequency of C-terminal hydrophobic residues and of N-terminal Ala, Ser, or Lys. The presence of Erap1 increased the frequency of C-terminal Lys and Arg, of Glu and Asp at intermediate residues, and of N-terminal Gly. Several peptides of potential interest in AS pathogenesis, previously identified in human cell lines, were isolated. However, rats susceptible to arthritis had B27 peptidomes similar to those of non-susceptible rats, and no peptides were found to be uniquely associated with arthritis. Whether specific B27-bound peptides are required for AS pathogenesis remains to be determined. Data are available via ProteomeXchange with identifier PXD005502.

Use of Dynamic MRI of the Pelvic Floor in the Assessment of Anterior Compartment Disorders.

PURPOSE OF REVIEW: Approximately 25% of women in the USA suffer from pelvic floor disorders. Disorders of the anterior compartment of the pelvic floor, in particular, can cause symptoms such as incomplete urinary voiding, urinary incontinence, pelvic organ prolapse, dyspareunia, and pelvic pain, potentially negatively impacting a woman's quality of life. In some clinical situations, clinical exam alone may be insufficient, especially when patient's symptoms are in excess of their pelvic exam findings. In many of these patients, dynamic magnetic resonance imaging (dMRI) of the pelvic floor can be a valuable imaging tool allowing for comprehensive assessment of the entire pelvic anatomy and its function. RECENT FINDINGS: Traditionally, evaluation of the anterior compartment has been primarily through clinical examination with occasional use of urodynamic testing and ultrasound. In recent years, dMRI has continued to gain popularity due to its improved imaging quality, reproducibility, and ability to display the entire pelvic floor. Emerging evidence has also shown utility of dMRI in the postoperative setting. In spite of advances, there remains an ongoing discussion in contemporary literature regarding the accuracy of dMRI and its correlation with clinical examination and with patient symptoms. Dynamic pelvic MRI is a helpful adjunct to physical examination and urodynamic testing, particularly when a patient's symptoms are in excess of the physical examination findings. Evaluation with dMRI can guide preoperative and postoperative surgical management in many patients, especially in the setting of multicompartmental disorders. This review will summarize relevant pelvic floor anatomy and discuss the clinical application, imaging technique, imaging interpretation, and limitations of dMRI.

Comparison of Times to Ureteral Efflux after Administration of Sodium Fluorescein and Phenazopyridine.

PURPOSE: There is currently a national shortage of indigo carmine. In efforts to identify the most efficient aid for visualizing ureteral efflux intraoperatively we investigated the time to excretion of phenazopyridine vs a newly identified alternative, sodium fluorescein. MATERIALS AND METHODS: We analyzed prospectively collected data on a cohort of women who underwent pelvic reconstructive surgery in 2015. Per provider preference patterns a number of patients were administered 200 mg phenazopyridine orally with a sip of water 1 hour prior to the start of operative time. Other patients were given 0.5 ml 10% sodium fluorescein intravenously in the operating room. In all cases time was measured between the administration of the agent and the visualization of color changes consistent with agent efflux in an indwelling catheter, which was placed at the start of the operation. Differences in excretion times between the groups were compared with the Wilcoxon rank sum test. RESULTS: Seven women received phenazopyridine and 5 received sodium fluorescein. Mean excretion time was significantly longer in the phenazopyridine group compared to the sodium fluorescein group (81.9 vs 5.1 minutes, p = 0.0057). Median excretion time for phenazopyridine was 70 minutes (range 59 to 127) and for sodium fluorescein it was 5 minutes (range 3 to 9). CONCLUSIONS: Sodium fluorescein is excreted significantly faster in the operating room compared to phenazopyridine. Depending on the cost of these agents at an institution, in addition to the desire to decrease operative time, this may impact practice patterns and agent selection.

Evaluation of Sodium Polystyrene Sulfonate Dosing Strategies in the Inpatient Management of Hyperkalemia.

BACKGROUND: Hyperkalemia occurs frequently in an inpatient setting, for which sodium polystyrene sulfonate (SPS) is a common treatment modality. Few studies have investigated the dose-response of SPS. OBJECTIVE: To quantify the change in serum potassium after 15-, 30-, and 60-g oral and 30-g rectal doses of SPS. Secondary objectives were to compare the proportion of patients attaining post-SPS dose normokalemia between dosing groups and to investigate the effect of certain characteristics on SPS dose-response. METHODS: The reduction in serum potassium after 15-, 30-, and 60-g oral and 30-g rectal doses of SPS administered to adult inpatients was evaluated through a retrospective chart review. Ottawa Hospital Research Ethics Board approval was obtained prior to data collection. RESULTS: A total of 118 patients were included in the analysis. Serum potassium levels were reduced by 0.39, 0.69, 0.91, and 0.22 mEq/L following 15-, 30-, and 60-g oral doses and a 30-g rectal dose of SPS, respectively. A greater proportion of patients (50% vs 23%) remained hyperkalemic in the 15-g versus the 60-g group (P = 0.018), and all patients in the rectal group remained hyperkalemic. No patient in any group experienced postdose hypokalemia. The influence of all studied interindividual characteristics on SPS dose-response was clinically nonsignificant. CONCLUSION: Mild hyperkalemia can be effectively treated with a single 60-g oral dose of SPS as monotherapy, with minimal risk of hypokalemia. Moderate to severe hyperkalemic episodes warrant alternative therapy. The potassium-lowering effect is correlated to SPS dose and is independent of interindividual characteristics.

Imaging-guided biopsy of (18)F-FDG-avid extrapulmonary lesions: do lesion location and morphologic features on CT affect the positive predictive value for malignancy?

OBJECTIVE: The purpose of our study was to analyze the effect of lesion location and morphologic appearance on CT on the positive predictive value (PPV) for malignancy of all extrapulmonary lesions that were (18)F-FDG avid on PET/CT and that were biopsied under imaging guidance. MATERIALS AND METHODS: Between January 2004 and December 2010, 227 patients underwent imaging-guided biopsy of 231 PET-positive extrapulmonary lesions with diagnostic pathologic results. The PET PPV for malignancy was retrospectively calculated and stratified according to lesion location and morphologic appearance. RESULTS: The overall PET PPV for malignancy was 72%. Inflammatory processes accounted for the majority of benign biopsy results. Lesion location significantly affected the PPV (p < 0.001). Bone (96%) and liver (90%) lesions had significantly higher PPVs for malignancy compared with other locations, whereas lymph nodes (60%) had a significantly lower PPV for malignancy. Lesions that were morphologically suspicious and morphologically benign according to CT findings alone were associated with PPVs of 74% and 57%, respectively (p = 0.05). FDG-avid subcentimeter lymph nodes (n = 8) had a PPV for malignancy of 38%. CONCLUSION: Over half of PET-avid morphologically benign-appearing lesions and one third of PET-avid subcentimeter lymph nodes were found to be malignant at biopsy, suggesting that benign morphologic appearance alone should not preclude further workup of a PET-positive lesion. Biopsies of FDG-avid lesions in liver and bone yielded high rates of true malignancy, whereas biopsies of lymph nodes yielded a lower rate of malignancy compared with other lesion locations.

Head-to-pelvis CT imaging after sudden cardiac arrest: Current status and future directions.

Causes for sudden circulatory arrest (SCA) can vary widely making early treatment and triage decisions challenging. Additionally, cardiopulmonary resuscitation (CPR), while a life-saving link in the chain of survival, can be associated with traumatic injuries. Computed tomography (CT) can identify many causes of SCA as well as its sequelae. However, the diagnostic and therapeutic impact of CT in survivors of SCA has not been reviewed to date. This general review outlines the rationale and potential applications of focused head, chest, and abdomen/pelvis CT as well as comprehensive head-to-pelvis CT imaging after SCA. CT has a diagnostic yield approaching 30% to identify causes of SCA while the addition of ECG-gated chest CT provides further information about coronary anatomy and cardiac function. Risks of CT include radiation exposure, contrast-induced kidney injury, and incidental findings. This review's findings suggest that routine head-to-pelvis CT can yield clinically actional findings with the potential to improve clinical outcome after SCA that merits further investigation.

Government expenditure and economic growth: does the role of corruption control matter?

This study focuses on analyzing the role of corruption control in the impact of government expenditure on economic growth. The data were collected from 16 Emerging Markets and Developing Economies (EMDEs) in Asia over the period 2002-2019. Generalized method of moments (GMM) and threshold model were used to estimate research models. The estimation results show that government expenditure and corruption control have a negative impact on economic growth. Specifically, the interaction between government expenditure and corruption control can reduce the level of the negative impact of these two factors on economic growth, which is an interesting finding of this study. Moreover, unlike previous studies, the threshold model estimation results reveal that corruption control has two threshold values of -0.61 and 0.01, respectively. Accordingly, EMDEs in Asia can make the positive impact of government expenditure on economic growth if corruption control is above the threshold value of 0.01.