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Original citation: J Clin Invest. 2017;127(7):2777-2788. https://doi.org/10.1172/JCI92958. Citation for this retraction: J Clin Invest. 2024;134(13):e183295. https://doi.org/10.1172/JCI183295. QIMR Berghofer Medical Research Institute recently notified the JCI of concerns regarding Figure 3C [...]

Abstract Penile traumatic injuries are rare with potentially severe consequences, with clinical assessment challenging due to pain and swelling. Ultrasound is the primary imaging modality for assessing the penis. It has a high spatial resolution and rapid availability and is portable. Contrast enhanced ultrasound is an advanced ultrasound technique that adds real-time dynamic vascular imaging safely, increasing diagnostic precision and confidence, allowing for better therapeutic management of traumatic penile injuries. Contrast enhanced ultrasound helps to delineate the extent of a haematoma, distinguishing this from the herniated corpus cavernosum, detecting the point of rupture of the tunica albuginea, showing vascular abnormalities, localising a dislocated penis and determining penile viability. The integrity of the urethra may be assessed with intracavitary contrast enhanced ultrasound. Additionally, contrast enhanced ultrasound allows monitoring of the response to endovascular and surgical treatment. This review aims to detail the anatomy and pathogenesis of penile trauma, to give guidance on optimising the contrast enhanced ultrasound technique and to obtain diagnostic examinations. Illustration of the spectrum of aspects of penile trauma will be complemented with a literature review. Critical relevance statement Contrast enhanced ultrasound is a safe and efficient imaging modality that allows for highly accurate diagnoses, helping achieve more successful and conservative treatments of penile trauma complications. Key points • Ultrasound is an accurate and safe imaging test for penile trauma. • CEUS adds dynamic vascular imaging in real-time increasing diagnostic confidence. • CEUS can delineate penile haematomas, locate fractures and demonstrate vessel integrity. • CEUS potentially allows for more conservative treatment of penile trauma complications. Graphical Abstract

Heart failure remains among the most common and morbid health conditions. The Heart Failure Strategically Focused Research Network (HF SFRN) was funded by the American Heart Association to facilitate collaborative, high‐impact research in the field of heart failure across the domains of basic, clinical, and population research. The Network was also charged with developing training opportunities for young investigators. Four centers were funded in 2016: Duke University, University of Colorado, University of Utah, and Massachusetts General Hospital‐University of Massachusetts. This report summarizes the aims of each center and major research accomplishments, as well as training outcomes from the HF SFRN.

The classification of breast lesions as indolent or aggressive to tailor treatment is crucial. Here, the authors use single-cell transcriptomics and multiparametric imaging of a breast cancer mouse model, report distinct tumor-immune features for the two types of lesions, and suggest the role of IL-17 signaling in disease progression.

Simple Summary: In our retrospective study at a tertiary centre, we reviewed the use of contrast-enhanced ultrasound (CEUS) and strain elastography (SE) as adjuncts to conventional greyscale and colour Doppler US (CDUS) for evaluating focal testicular abnormalities over a decade. This study highlights the potential of advanced ultrasound techniques to provide deeper insights into the characteristics of testicular abnormalities. In particular, we observed that contrast-enhanced ultrasound could detect vascular enhancement in all malignant cases, even those not identified by conventional CDUS, and more conclusively confirm benignity. While SE alone offered no distinctive advantage, incorporating a combination of CEUS and SE into the evaluation of focal testicular abnormalities improved diagnostic performance metrics over conventional CDUS. Our research underscores the enhanced performance achieved by utilising these advanced ultrasound techniques. The comprehensive diagnostic assessment provided by these techniques could facilitate a shift towards more conservative management of testicular lesions, supporting the preference for organ-preserving methods over more radical surgeries. Conventional ultrasonography (US), including greyscale imaging and colour Doppler US (CDUS), is pivotal for diagnosing scrotal pathologies, but it has limited specificity. Historically, solid focal testicular abnormalities often led to radical orchidectomy. This retrospective study evaluated the utilisation of contrast-enhanced ultrasound (CEUS) and strain elastography (SE) in investigating intratesticular focal abnormalities. A total of 124 cases were analysed. This study underscored the superior diagnostic capabilities of CEUS in detecting vascular enhancement in all malignant cases, even those with undetectable vascularity by CDUS. It also highlighted the potential of CEUS in identifying distinctive vascular patterns in benign vascular tumours. Definitive confirmation of benignity could be obtained when the absence of enhancement was demonstrated on CEUS. While SE alone offered no distinctive advantage in differentiating between benign and malignant pathologies, we demonstrated that incorporating a combination of CEUS and SE into the evaluation of focal testicular abnormalities could improve diagnostic performance metrics over conventional CDUS. Our findings underscore the role of advanced ultrasound techniques in enhancing the evaluation of focal testicular abnormalities in clinical practice and could aid a shift towards testis-sparing management strategies. [ABSTRACT FROM AUTHOR]

Abstract Lung cancer is one of the commonest malignancies worldwide and necessitates both early and personalised treatment. A key requirement is histological sampling with immunohistochemistry obtained usually from percutaneous biopsy. Conventionally thoracic biopsies are performed using CT guidance, but more recently, there has been development of physician led ultrasound biopsy for pleural lesions. Contrast-enhanced ultrasound (CEUS) has been increasingly used in interventional procedures and is able to offer benefits for thoracic biopsies including improving lesional visualisation and characterisation, targeting viable tissue and avoiding critical vascular structures as well as evaluating for the presence of post-procedural complications. This educational review aims to benefits of the role of CEUS in thoracic biopsies.

Blood vessel abnormalization alters cancer cell metabolism and promotes cancer dissemination and metastasis. However, the biological features of the abnormalized blood vessels that facilitate cancer progression and whether they can be targeted therapeutically have not been fully investigated. Here, we found that an axon guidance molecule, fibronectin leucine-rich transmembrane protein 2 (FLRT2), is expressed preferentially in abnormalized vessels of advanced colorectal cancers in humans and that its expression correlates negatively with long-term survival. Endothelial cell–specific deletion of Flrt2 in mice selectively pruned abnormalized vessels, resulting in a unique metabolic state termed “oxygen-glucose uncoupling,” which suppressed tumor metastasis. Moreover, Flrt2 deletion caused an increase in the number of mature vessels, resulting in a significant increase in the antitumor effects of immune checkpoint blockers. Mechanistically, we found that FLRT2 forms noncanonical interendothelial adhesions that safeguard against oxidative stress through homophilic binding. Together, our results demonstrated the existence of tumor-specific interendothelial adhesions that enable abnormalized vessels to facilitate cancer aggressiveness. Targeting this type of adhesion complex could be a safe and effective therapeutic option to suppress cancer progression.

Abstract Testicular trauma is common, usually trivial and rarely requires hospital attendance, but if it does, then imaging becomes essential as scrotal assessment may be difficult due to pain and/or scrotal disruption. Ultrasound (US) assumes a crucial role as other cross-sectional modalities have a limited use in the acute presentation. Despite the acceptable accuracy of conventional US techniques, there are limitations which hinder a thorough evaluation, critically the assessment of tissue viability, crucial for clinical management and prognosis. Contrast-enhanced ultrasound (CEUS) has been shown to offer improved flow visualisation and tissue perfusion compared with conventional Doppler techniques. CEUS can accurately and confidently demonstrate the viability of testicular parenchyma, delineate fracture lines and haematomas and guide treatment for testis-sparing surgery or orchidectomy. The purpose of this review is to present the literature, familiarise physicians with the principles of CEUS and findings of scrotal trauma and illustrate the main abnormalities through characteristic and educative cases.

Ultrasonography (US) is the first-line modality for the evaluation of vascular pathology. Although well-established for many diseases, US has inherent limitations that can occasionally hinder an accurate diagnosis. The value of US was improved by the introduction of microbubbles as ultrasonographic contrast agents (UCAs) and the emergence of contrast-enhanced ultrasonography (CEUS), following the introduction of second-generation UCAs and the emergence of modern contrast-specific techniques. CEUS offers valuable information about vascular disease, both on a macrovascular and a microvascular level, with well-established applications for carotid disease, post-interventional follow-up of abdominal aortic aneurysms, and the assessment of portal vein thrombosis. The purpose of this review is to discuss the principles of CEUS and to present an overview of its vascular applications.

As a relatively new sonographic technique, tissue elastography has emerged as a qualitative and potentially quantitative adjunctive tool to provide additional information on tissue stiffness, aiming to further improve diagnostic confidence in discriminating benign from malignant focal testicular lesions. The purpose of this review is to provide an overview of the elastography techniques used to assess focal testicular lesions and their typical appearance on tissue elastography.

Abstract. Promoting intestinal epithelial regeneration remains a major medical challenge. Female patients taking nonsteroidal anti-inflammatory drugs are less likely to have upper gastrointestinal bleeding and ulcers than males. Using a nonsteroidal anti-inflammatory drug-induced intestinal damage mouse model, we verified that female mice recover faster than males following acute intestinal insult. Using ex vivo intestinal organoid cultures, we showed that estrogen is necessary and sufficient in enhancing the female organoid formation from breached isolated crypts via the estrogen receptor β receptor. Thus, estrogen promotes female intestinal epithelial organoid regeneration to lower the incidence of intestinal bleeding and ulceration. Animal studies were approved by University of Utah IACUC under protocol number 16-05012 and 18-02010.

Blood vessel abnormalization alters cancer cell metabolism and promotes cancer dissemination and metastasis. However, the biological features of the abnormalized blood vessels that facilitate cancer progression and whether they can be targeted therapeutically have not been fully investigated. Here, we found that an axon guidance molecule, fibronectin leucine-rich transmembrane protein 2 (FLRT2), is expressed preferentially in abnormalized vessels of advanced colorectal cancers in humans and that its expression correlates negatively with long-term survival. Endothelial cell-specific deletion of Flrt2 in mice selectively pruned abnormalized vessels, resulting in a unique metabolic state termed 'oxygen-glucose uncoupling,' which suppressed tumor metastasis. Moreover, Flrt2 deletion caused an increase in the number of mature vessels, resulting in a significant increase in the antitumor effects of immune checkpoint blockers. Mechanistically, we found that FLRT2 forms noncanonical interendothelial adhesions that safeguard against oxidative stress through homophilic binding. Together, our results demonstrated the existence of tumor-specific interendothelial adhesions that enable abnormalized vessels to facilitate cancer aggressiveness. Targeting this type of adhesion complex could be a safe and effective therapeutic option to suppress cancer progression., Introduction Development and maintenance of the body's organs require an adequate blood supply to bring oxygen and nutrients to the tissues (1). Tumor growth also depends on formation of new [...]

Background Despite the success of immune checkpoint blockade therapy in the treatment of certain cancer types, only a small percentage of patients with solid malignancies achieve a durable response. Consequently, there is a need to develop novel approaches that could overcome mechanisms of tumor resistance to checkpoint inhibition. Emerging evidence has implicated the phenomenon of cancer plasticity or acquisition of mesenchymal features by epithelial tumor cells, as an immune resistance mechanism.Methods Two soluble factors that mediate tumor cell plasticity in the context of epithelial-mesenchymal transition are interleukin 8 (IL-8) and transforming growth factor beta (TGF-β). In an attempt to overcome escape mechanisms mediated by these cytokines, here we investigated the use of a small molecule inhibitor of the IL-8 receptors CXCR1/2, and a bifunctional agent that simultaneously blocks programmed death ligand 1 (PD-L1) and traps soluble TGF-β.Results We demonstrate that simultaneous inhibition of CXCR1/2, TGF-β, and PD-L1 signaling synergizes to reduce mesenchymal tumor features in murine models of breast and lung cancer, and to markedly increase expression of tumor epithelial E-cadherin while reducing infiltration with suppressive granulocytic myeloid-derived suppressor cells, significantly enhancing T-cell infiltration and activation in tumors, and leading to improved antitumor activity.Conclusions This study highlights the potential benefit of combined blockade of CXCR1/2 and TGF-β signaling for modulation of tumor plasticity and potential enhancement of tumor responses to PD-L1 blockade. The data provide rationale for the evaluation of this novel approach in the clinic.

Tramadol is widely used globally and is the second most prescribed opioid in the United States. It treats moderate to severe pain but lethal opioid-induced respiratory depression is uncommon even in large overdose. It is unknown why tramadol spares respiration. Here we show its active metabolite, desmetramadol, is as effective as morphine, oxycodone and fentanyl in eliciting G protein coupling at the human µ opioid receptor (MOR), but surprisingly, supratherapeutic concentrations spare human MOR-mediated βarrestin2 recruitment thought to mediate lethal opioid-induced respiratory depression.

The devastating sequelae of diabetes mellitus include microvascular permeability, which results in retinopathy. Despite clinical and scientific advances, there remains a need for new approaches to treat retinopathy. Here, we have presented a possible treatment strategy, whereby targeting the small GTPase ARF6 alters VEGFR2 trafficking and reverses signs of pathology in 4 animal models that represent features of diabetic retinopathy and in a fifth model of ocular pathological angiogenesis. Specifically, we determined that the same signaling pathway utilizes distinct GEFs to sequentially activate ARF6, and these GEFs exert distinct but complementary effects on VEGFR2 trafficking and signal transduction. ARF6 activation was independently regulated by 2 different ARF GEFs - ARNO and GEP100. Interaction between VEGFR2 and ARNO activated ARF6 and stimulated VEGFR2 internalization, whereas a VEGFR2 interaction with GEP100 activated ARF6 to promote VEGFR2 recycling via coreceptor binding. Intervening in either pathway inhibited VEGFR2 signal output. Finally, using a combination of in vitro, cellular, genetic, and pharmacologic techniques, we demonstrated that ARF6 is pivotal in VEGFR2 trafficking and that targeting ARF6-mediated VEGFR2 trafficking has potential as a therapeutic approach for retinal vascular diseases such as diabetic retinopathy., Introduction Over 25 million people in the United States have diabetes mellitus (1) and are prone to suffer from its devastating sequelae. The metabolic derangements seen in diabetes lead to [...]

In metastatic breast cancer, subclonal evolution can drive drug resistance. Here, the authors genetically and transcriptionally follow the evolution of four breast cancers over time and treatment, and suggest a phenotype-targeted treatment strategy to adapt to cancer as it evolves.

Simple Summary: Testicular lesions (TLs) are challenging clinical or ultrasound findings. When large, hard palpable lumps, TL management is mainly clinical, requiring conventional color-Doppler ultrasound (CDUS) to confirm that they are solid, vascularized lesions suggesting malignancy. However, when their CDUS characteristics are uncertain or when nonpalpable, multiparametric US (mp-US) (i.e., the combination of CDUS and more recent US techniques such as contrast-enhanced US and sonoelastography) plays a key role in their characterization, aimed at differentiating benign from malignant TL. This is relevant, since TLs are frequent, testicular tumors are the most common malignancies in young men, and the accurate assessment of a TL is critical to define its correct management including testicular salvage and US follow-up or orchiectomy. In this scenario, this narrative and pictorial review reports a practical mp-US "identity card" and iconographic characterization of several benign and malignant TLs, useful to the physician in daily clinical practice. Background: Ultrasonography (US) represents the gold standard imaging method for the assessment of testicular lesions (TL). The gray-scale (GSUS) and color-Doppler (CDUS) ultrasound examination allow sonographers to investigate the size, margins, echotexture, and vascular features of TLs with the aim to differentiate benign from malignant lesions. Recently, the use of contrast-enhanced US (CEUS) and sonoelastography (SE) has led to further improvements in the differential diagnosis of TL. Although GSUS and CDUS are often sufficient to suggest the benign or malignant nature of the TL, CEUS can be decisive in the differential diagnosis of unclear findings, while SE can help to strengthen the diagnosis. The contemporary combination of GSUS, CDUS, CEUS, and SE has led to a new diagnostic paradigm named multiparametric US (mp-US), which is able to provide a more detailed characterization of TLs than single techniques alone. This narrative and pictorial review aimed to describe the mp-US appearance of several TLs. Methods: An extensive Medline search was performed to identify studies in the English language focusing on the mp-US evaluation of TLs. Results: A practical mp-US "identity card" and iconographic characterization of several benign and malignant TLs is provided herein. Conclusions: The mp-US characterization of TL reported herein can be useful in daily clinical practice. [ABSTRACT FROM AUTHOR]

This study sought to investigate the effects of mechanical unloading on myocardial energetics and the metabolic perturbation of heart failure (HF) in an effort to identify potential new therapeutic targets that could enhance the unloading-induced cardiac recovery. The authors prospectively examined paired human myocardial tissue procured from 31 advanced HF patients at left ventricular assist device (LVAD) implant and at heart transplant plus tissue from 11 normal donors. They identified increased post-LVAD glycolytic metabolites without a coordinate increase in early, tricarboxylic acid (TCA) cycle intermediates. The increased pyruvate was not directed toward the mitochondria and the TCA cycle for complete oxidation, but instead, was mainly converted to cytosolic lactate. Increased nucleotide concentrations were present, potentially indicating increased flux through the pentose phosphate pathway. Evaluation of mitochondrial function and structure revealed a lack of post-LVAD improvement in mitochondrial oxidative functional capacity, mitochondrial volume density, and deoxyribonucleic acid content. Finally, post-LVAD unloading, amino acid levels were found to be increased and could represent a compensatory mechanism and an alternative energy source that could fuel the TCA cycle by anaplerosis. In summary, the authors report evidence that LVAD unloading induces glycolysis in concert with pyruvate mitochondrial oxidation mismatch, most likely as a result of persistent mitochondrial dysfunction. These findings suggest that interventions known to improve mitochondrial biogenesis, structure, and function, such as controlled cardiac reloading and conditioning, warrant further investigation to enhance unloading-induced reverse remodeling and cardiac recovery.

NK cells are highly efficient at preventing cancer metastasis but are infrequently found in the core of primary tumors. Here, have we demonstrated that freshly isolated mouse and human NK cells express low levels of the endo-[beta]-D-glucuronidase heparanase that increase upon NK cell activation. Heparanase deficiency did not affect development, differentiation, or tissue localization of NK cells under steady-state conditions. However, mice lacking heparanase specifically in NK cells ([Hpse.sup.fl/fl] NKp46-iCre mice) were highly tumor prone when challenged with the carcinogen methylcholanthrene (MCA). [Hpse.sup.fl/fl] NKp46-iCre mice were also more susceptible to tumor growth than were their littermate controls when challenged with the established mouse lymphoma cell line RMA-S-RAE-1[beta], which overexpresses the NK cell group 2D (NKG2D) ligand RAE-1[beta], or when inoculated with metastatic melanoma, prostate carcinoma, or mammary carcinoma cell lines. NK cell invasion of primary tumors and recruitment to the site of metastasis were strictly dependent on the presence of heparanase. Cytokine and immune checkpoint blockade immunotherapy for metastases was compromised when NK cells lacked heparanase. Our data suggest that heparanase plays a critical role in NK cell invasion into tumors and thereby tumor progression and metastases. This should be considered when systemically treating cancer patients with heparanase inhibitors, since the potential adverse effect on NK cell infiltration might limit the antitumor activity of the inhibitors., Introduction Extracellular matrix (ECM) comprises more than 50 different proteins, with the main components being large insoluble proteins such as type IV collagen, laminin, and heparan sulphate proteoglycans (HSPGs), creating [...]

Author(s): Xin Lu [1]; James W. Horner [2]; Erin Paul [2]; Xiaoying Shang [1]; Patricia Troncoso [3]; Pingna Deng [1]; Shan Jiang [2]; Qing Chang [2]; Denise J. Spring [1]; [...]