Drp1 splice variants regulate ovarian cancer mitochondrial dynamics and tumor progression.

Aberrant mitochondrial fission/fusion dynamics are frequently associated with pathologies, including cancer. We show that alternative splice variants of the fission protein Drp1 (DNM1L) contribute to the complexity of mitochondrial fission/fusion regulation in tumor cells. High tumor expression of the Drp1 alternative splice variant lacking exon 16 relative to other transcripts is associated with poor outcome in ovarian cancer patients. Lack of exon 16 results in Drp1 localization to microtubules and decreased association with mitochondrial fission sites, culminating in fused mitochondrial networks, enhanced respiration, changes in metabolism, and enhanced pro-tumorigenic phenotypes in vitro and in vivo. These effects are inhibited by siRNAs designed to specifically target the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the pathophysiological importance of Drp1 alternative splicing, highlight the divergent functions and consequences of changing the relative expression of Drp1 splice variants in tumor cells, and strongly warrant consideration of alternative splicing in future studies focused on Drp1.

A Model for the Coexistence of Competing Mechanisms for Ca 2 + Oscillations in T-lymphocytes.

Ca 2 + is a ubiquitous signaling mechanism across different cell types. In T-cells, it is associated with cytokine production and immune function. Benson et al. have shown the coexistence of competing Ca 2 + oscillations during antigen stimulation of T-cell receptors, depending on the presence of extracellular Ca 2 + influx through the Ca 2 + release-activated Ca 2 + channel (Benson in J Biol Chem 29:105310, 2023). In this paper, we construct a mathematical model consisting of five ordinary differential equations and analyze the relationship between the competing oscillatory mechanisms.. We perform bifurcation analysis on two versions of our model, corresponding to the two oscillatory types, to find the defining characteristics of these two families.

Adhesion-Lubrication Paradox of Articular Cartilage.

The friction of solids is primarily understood through the adhesive interactions between the surfaces. As a result, slick materials tend to be nonstick (e.g., Teflon), and sticky materials tend to produce high friction (e.g., tires and tape). Paradoxically, cartilage, the slippery bearing material of human joints, is also among the stickiest of known materials. This study aims to elucidate this apparent paradox. Cartilage is a biphasic material, and the most cited explanation is that both friction and adhesion increase as load transfers from the pressurized interstitial fluid to the solid matrix over time. In other words, cartilage is slippery and sticky under different times and conditions. This study challenges this explanation, demonstrating the strong adhesion of cartilage under high and low interstitial hydration conditions. Additionally, we find that cartilage clings to itself (a porous material) and Teflon (a nonstick material), as well as other surfaces. We conclude that the unusually strong interfacial tension produced by cartilage reflects suction (like a clingfish) rather than adhesion (like a gecko). This finding is surprising given its unusually large roughness, which typically allows for easy interfacial flow and defeats suction. The results provide compelling evidence that cartilage, like a clingfish, conforms to opposing surfaces and effectively seals submerged contacts. Further, we argue that interfacial sealing is itself a critical function, enabling cartilage to retain hydration, load support, and lubrication across long periods of inactivity.

Alternative splice variants of the mitochondrial fission protein DNM1L/Drp1 regulate mitochondrial dynamics and tumor progression in ovarian cancer.

Aberrant mitochondrial fission/fusion dynamics have been reported in cancer cells. While post translational modifications are known regulators of the mitochondrial fission/fusion machinery, we show that alternative splice variants of the fission protein Drp1 (DNM1L) have specific and unique roles in cancer, adding to the complexity of mitochondrial fission/fusion regulation in tumor cells. Ovarian cancer specimens express an alternative splice transcript variant of Drp1 lacking exon 16 of the variable domain, and high expression of this splice variant relative to other transcripts is associated with poor patient outcome. Unlike the full-length variant, expression of Drp1 lacking exon 16 leads to decreased association of Drp1 to mitochondrial fission sites, more fused mitochondrial networks, enhanced respiration, and TCA cycle metabolites, and is associated with a more metastatic phenotype in vitro and in vivo. These pro-tumorigenic effects can also be inhibited by specific siRNA-mediated inhibition of the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the significance of the pathophysiological consequences of Drp1 alternative splicing and divergent functions of Drp1 splice variants, and strongly warrant consideration of Drp1 splicing in future studies.

Apolipoprotein-E4: risk of severe malaria and mortality and cognitive impairment in pediatric cerebral malaria.

BACKGROUND: The relationship of apolipoprotein-E4 (APOE4) to mortality and cognition after severe malaria in children is unknown. METHODS: APOE genotyping was performed in children with cerebral malaria (CM, n = 261), severe malarial anemia (SMA, n = 224) and community children (CC, n = 213). Cognition was assessed over 2-year follow-up. RESULTS: A greater proportion of children with CM or SMA than CC had APOE4 (n = 162, 31.0%; n = 142, 31.7%; n = 103, 24.2%, respectively, p = 0.02), but no difference was seen in APOE3 (n = 310, 59.4%; n = 267, 59.6%; n = 282, 66.2%, respectively, p = 0.06), or APOE2 (n = 50, 9.6%; n = 39, 8.7%; and n = 41, 9.6%, respectively, p = 0.87). APOE4 was associated with increased mortality in CM (odds ratio, 2.28; 95% CI, 1.01, 5.11). However, APOE4 was associated with better long-term cognition (ß, 0.55; 95% CI, 0.04, 1.07, p = 0.04) and attention (ß 0.78; 95% CI, 0.26, 1.30, p = 0.004) in children with CM < 5 years old, but worse attention (ß, -0.90; 95% CI, -1.69, -0.10, p = 0.03) in children with CM ≥ 5 years old. Among children with CM, risk of post-discharge malaria was increased with APOE4 and decreased with APOE3. CONCLUSIONS: APOE4 is associated with higher risk of CM or SMA and mortality in children with CM, but better long-term cognition in CM survivors <5 years of age.

A multiple-oscillator mechanism underlies antigen-induced Ca2+ oscillations in Jurkat T-cells.

T-cell receptor stimulation triggers cytosolic Ca2+ signaling by inositol-1,4,5-trisphosphate (IP3)-mediated Ca2+ release from the endoplasmic reticulum (ER) and Ca2+ entry through Ca2+ release-activated Ca2+ (CRAC) channels gated by ER-located stromal-interacting molecules (STIM1/2). Physiologically, cytosolic Ca2+ signaling manifests as regenerative Ca2+ oscillations, which are critical for nuclear factor of activated T-cells-mediated transcription. In most cells, Ca2+ oscillations are thought to originate from IP3 receptor-mediated Ca2+ release, with CRAC channels indirectly sustaining them through ER refilling. Here, experimental and computational evidence support a multiple-oscillator mechanism in Jurkat T-cells whereby both IP3 receptor and CRAC channel activities oscillate and directly fuel antigen-evoked Ca2+ oscillations, with the CRAC channel being the major contributor. KO of either STIM1 or STIM2 significantly reduces CRAC channel activity. As such, STIM1 and STIM2 synergize for optimal Ca2+ oscillations and activation of nuclear factor of activated T-cells 1 and are essential for ER refilling. The loss of both STIM proteins abrogates CRAC channel activity, drastically reduces ER Ca2+ content, severely hampers cell proliferation and enhances cell death. These results clarify the mechanism and the contribution of STIM proteins to Ca2+ oscillations in T-cells.

Loss of STIM2 in colorectal cancer drives growth and metastasis through metabolic reprogramming and PERK-ATF4 endoplasmic reticulum stress pathway.

The endoplasmic reticulum (ER) stores large amounts of calcium (Ca2+), and the controlled release of ER Ca2+ regulates a myriad of cellular functions. Although altered ER Ca2+ homeostasis is known to induce ER stress, the mechanisms by which ER Ca2+ imbalance activate ER stress pathways are poorly understood. Stromal-interacting molecules STIM1 and STIM2 are two structurally homologous ER-resident Ca2+ sensors that synergistically regulate Ca2+ influx into the cytosol through Orai Ca2+ channels for subsequent signaling to transcription and ER Ca2+ refilling. Here, we demonstrate that reduced STIM2, but not STIM1, in colorectal cancer (CRC) is associated with poor patient prognosis. Loss of STIM2 causes SERCA2-dependent increase in ER Ca2+, increased protein translation and transcriptional and metabolic rewiring supporting increased tumor size, invasion, and metastasis. Mechanistically, STIM2 loss activates cMyc and the PERK/ATF4 branch of ER stress in an Orai-independent manner. Therefore, STIM2 and PERK/ATF4 could be exploited for prognosis or in targeted therapies to inhibit CRC tumor growth and metastasis.

Chronic Hepatitis B Infection: New Approaches towards Cure.

Chronic hepatitis B virus (HBV) infection leads to the development of cirrhosis and hepatocellular carcinoma. Lifelong treatment with nucleotides/nucleoside antiviral agents is effective at suppressing HBV replication, however, adherence to daily therapy can be challenging. This review discusses recent advances in the development of long-acting formulations for HBV treatment and prevention, which could potentially improve adherence. Promising new compounds that target distinct steps of the virus life cycle are summarized. In addition to treatments that suppress viral replication, curative strategies are focused on the elimination of covalently closed circular DNA and the inactivation of the integrated viral DNA from infected hepatocytes. We highlight promising long-acting antivirals and genome editing strategies for the elimination or deactivation of persistent viral DNA products in development.

Benign Enhancing Foramen Magnum Lesions.

Benign enhancing foramen magnum lesions have been previously described as T2-hyperintense small, enhancing lesions located posterior to the intradural vertebral artery. We present the first case with pathologic correlation. These lesions are fibrotic nodules adhering to the spinal accessory nerve. While they can enlarge with time on subsequent examinations, on the basis of the imaging characteristics and location, they do not necessitate surgical resection.

Psychometric Properties of the Brief Resilience Scale Among Alternative Sexuality Community Members.

Assessing resilience among alternative sexuality (alt-sex; e.g., kink, polyamory) community members is imperative as alt-sex individuals often face discrimination and possess intersecting marginalized identities. The Brief Resilience Scale (BRS) has extensive psychometric support; however, prior research indicates both a one- and two-factor (i.e., succumbing and resilience) structure. Further, the psychometric properties of the BRS have not been examined among alt-sex community members. As such, the current study examined the BRS factor structure among alt-sex individuals and measurement invariance across demographic groups (i.e., sexual orientation, gender identity, and sexual assault history). Confirmatory factor analyses and multi-groups invariance analyses were conducted. The two-factor BRS model demonstrated better fit to the data. Model fit did not differ by sexual orientation or gender identity. Measurement invariance was observed by lifetime sexual assault history, with higher factor loadings on succumbing items among alt-sex community members with a lifetime history of sexual assault. Our findings support use of the BRS to measure resilience among alt-sex individuals. Succumbing, or weakened resilience, is a salient factor for alt-sex community members who are sexual assault survivors, warranting further attention.

MR Imaging of Carotid Artery Atherosclerosis: Updated Evidence on High-Risk Plaque Features and Emerging Trends.

MR imaging is well-established as the criterion standard for carotid artery atherosclerosis imaging. The capability of MR imaging to differentiate numerous plaque components has been demonstrated, including those features that are associated with a high risk of sudden changes, thrombosis, or embolization. The field of carotid plaque MR imaging is constantly evolving, with continued insight into the imaging appearance and implications of various vulnerable plaque characteristics. This article will review the most up-to-date knowledge of these high-risk plaque features on MR imaging and will delve into 2 major emerging topics: the role of vulnerable plaques in cryptogenic strokes and the potential use of MR imaging to modify carotid endarterectomy treatment guidelines.

Utility of Photon-Counting Detector CT Myelography for the Detection of CSF-Venous Fistulas.

CSF-venous fistulas are an increasingly recognized type of CSF leak that can be particularly challenging to detect, even with recently improved imaging techniques. Currently, most institutions use decubitus digital subtraction myelography or dynamic CT myelography to localize CSF-venous fistulas. Photon-counting detector CT is a relatively recent advancement that has many theoretical benefits, including excellent spatial resolution, high temporal resolution, and spectral imaging capabilities. We describe 6 cases of CSF-venous fistulas detected on decubitus photon-counting detector CT myelography. In 5 of these cases, the CSF-venous fistula was previously occult on decubitus digital subtraction myelography or decubitus dynamic CT myelography using an energy-integrating detector system. All 6 cases exemplify the potential benefits of photon-counting detector CT myelography in identifying CSF-venous fistulas. We suggest that further implementation of this imaging technique will likely be valuable to improve the detection of fistulas that might otherwise be missed with currently used techniques.

Advances in Acute Ischemic Stroke Treatment: Current Status and Future Directions.

The management of acute ischemic stroke has undergone a paradigm shift in the past decade. This has been spearheaded by the emergence of endovascular thrombectomy, along with advances in medical therapy, imaging, and other facets of stroke care. Herein, we present an updated review of the various stroke trials that have impacted and continue to transform stroke management. It is critical for the radiologist to stay abreast of the ongoing developments to provide meaningful input and remain a useful part of the stroke team.

The clue is in the kidneys: greater renal contrast medium accumulation on ipsilateral side down CT myelogram after lateral decubitus digital subtraction myelogram as a predictor of laterality of cerebrospinal fluid leak.

AIM: To assess the potential correlation of the laterality of a cerebrospinal fluid (CSF)-venous fistula with the laterality of decubitus computed tomography (CT) myelogram (post decubitus digital subtraction myelogram) based on which side demonstrated more renal contrast medium excretion. MATERIALS AND METHODS: Patients with CSF-venous fistulas diagnosed at lateral decubitus digital subtraction myelograms were reviewed retrospectively. Patients who did not have CT myelogram following one or both left and right lateral decubitus digital subtraction myelograms were excluded. Two neuroradiologists independently interpreted the CT myelogram for the presence or absence of renal contrast, and whether subjectively more renal contrast medium was visualised on the left or right lateral decubitus CT myelogram. RESULTS: Renal contrast medium was seen in lateral decubitus CT myelograms in 28 of 30 (93.3%) patients with CSF-venous fistulas. Having more renal contrast medium in right lateral decubitus CT myelogram was 73.9% sensitive and 71.4% specific for the diagnosis of a right-sided CSF-venous fistula, whereas having more renal contrast medium in the left lateral decubitus CT myelogram was 71.4% sensitive and 82.6% specific for a left-sided CSF-venous fistula (p=0.02). CONCLUSION: When the CSF-venous fistula lies on the dependent side of a decubitus CT myelogram performed after decubitus digital subtraction myelogram, relatively more renal contrast medium is visualised compared to when the fistula lies on the non-dependent side.

Fluoroscopy- and CT-Guided Gold Fiducial Marker Placement for Intraoperative Localization during Spinal Surgery: Review of 179 Cases at a Single Institution-Technique and Safety Profile.

BACKGROUND AND PURPOSE: Wrong-level spinal surgery, especially in the thoracic spine, remains a challenge for a variety of reasons related to visualization, such as osteopenia, large body habitus, severe kyphosis, radiographic misinterpretation, or anatomic variation. Preoperative fiducial marker placement performed in a dedicated imaging suite has been proposed to facilitate identification of thoracic spine vertebral levels. In this current study, we report our experience using image-guided percutaneous gold fiducial marker placement to enhance the accuracy and safety of thoracic spinal surgical procedures. MATERIALS AND METHODS: A retrospective review was performed of all fluoroscopy- or CT-guided gold fiducial markers placed at our institution between January 3, 2019, and March 16, 2022. A chart review of 179 patients was performed detailing the procedural approach and clinical information. In addition, the method of gold fiducial marker placement (fluoroscopy/CT), procedure duration, spinal level of the gold fiducial marker, radiation dose, fluoroscopy time, surgery date, and complications (including whether wrong-level surgery occurred) were recorded. RESULTS: A total of 179 patients (104 female) underwent gold fiducial marker placement. The mean age was 57 years (range, 12-96 years). Fiducial marker placement was performed by 13 different neuroradiologists. All placements were technically successful without complications. All 179 (100%) operations were performed at the correct level. Most fiducial markers (143) were placed with fluoroscopy with the most common location at T6-T8. The most common location for placement in CT was at T3 and T4. CONCLUSIONS: All operations guided with gold fiducial markers were performed at the correct level. There were no complications of fiducial marker placement.

Erdheim-Chester Disease.

Erdheim-Chester disease is a rare non-Langerhans cell histiocytosis. The disease is widely variable in its severity, ranging from incidental findings in asymptomatic patients to a fatal multisystem illness. CNS involvement occurs in up to one-half of patients, most often leading to diabetes insipidus and cerebellar dysfunction. Imaging findings in neurologic Erdheim-Chester disease are often nonspecific, and the disease is commonly mistaken for close mimickers. Nevertheless, there are many imaging manifestations of Erdheim-Chester disease that are highly suggestive of the disease, which an astute radiologist could use to accurately indicate this diagnosis. This article discusses the imaging appearance, histologic features, clinical manifestations, and management of Erdheim-Chester disease.

Temporal Characteristics of CSF-Venous Fistulas on Digital Subtraction Myelography.

BACKGROUND AND PURPOSE: CSF-venous fistula can be diagnosed with multiple myelographic techniques; however, no prior work has characterized the time to contrast opacification and the duration of visualization. The purpose of our study was to evaluate the temporal characteristics of CSF-venous fistula on digital subtraction myelography. MATERIALS AND METHODS: We reviewed the digital subtraction myelography images of 26 patients with CSF-venous fistulas. We evaluated how long the CSF-venous fistula took to opacify after contrast reached the spinal level of interest and how long it remained opacified. Patient demographics, CSF-venous fistula treatment, brain MR imaging findings, CSF-venous fistula spinal level, and CSF-venous fistula laterality were recorded. RESULTS: Eight of the 26 CSF-venous fistulas were seen on both the upper- and lower-FOV digital subtraction myelography, for a total of 34 CSF-venous fistula views evaluated on digital subtraction myelography. The mean time to appearance was 9.1 seconds (range, 0-30 seconds). Twenty-two (84.6%) of the CSF-venous fistulas were on the right. The highest fistula level was C7, while the lowest was T13 (13 rib-bearing vertebral bodies). The most common CSF-venous fistula levels were T6 (4 patients) followed by T8, T10, and T11 (3 patients each). The mean age was 58.3 years (range, 31.7-87.6 years). Sixteen patients were women (61.5%). CONCLUSIONS: This is the first study to report the temporal characteristics of CSF-venous fistulas using digital subtraction myelography. We found that on average, the CSF-venous fistula appeared 9.1 seconds (range, 0-30 seconds) after intrathecal contrast reached the spinal level.

Too much of a good thing: The case of SOCE in cellular apoptosis.

Intracellular calcium (Ca2+) is an essential second messenger in eukaryotic cells regulating numerous cellular functions such as contraction, secretion, immunity, growth, and metabolism. Ca2+ signaling is also a key signal transducer in the intrinsic apoptosis pathway. The store-operated Ca2+ entry pathway (SOCE) is ubiquitously expressed in eukaryotic cells, and is the primary Ca2+ influx pathway in non-excitable cells. SOCE is mediated by the endoplasmic reticulum Ca2+ sensing STIM proteins, and the plasma membrane Ca2+-selective Orai channels. A growing number of studies have implicated SOCE in regulating cell death primarily via the intrinsic apoptotic pathway in a variety of tissues and in response to physiological stressors such as traumatic brain injury, ischemia reperfusion injury, sepsis, and alcohol toxicity. Notably, the literature points to excessive cytosolic Ca2+ influx through SOCE in vulnerable cells as a key factor tipping the balance towards cellular apoptosis. While the literature primarily addresses the functions of STIM1 and Orai1, STIM2, Orai2 and Orai3 are also emerging as potential regulators of cell death. Here, we review the functions of STIM and Orai proteins in regulating cell death and the implications of this regulation to human pathologies.

Conebeam CT as an Adjunct to Digital Subtraction Myelography for Detection of CSF-Venous Fistulas.

Lateral decubitus digital subtraction myelography is an effective technique for precisely localizing CSF-venous fistulas, a common cause of spontaneous intracranial hypotension. However, despite an optimal imaging technique, digital subtraction myelography fails to identify some CSF-venous fistulas for a variety of reasons. Here, we describe a technique involving conebeam CT performed during intrathecal contrast injection as an adjunct to digital subtraction myelography, allowing identification of some otherwise-missed CSF-venous fistulas.

Increased Labyrinthine T1 Postgadolinium Signal Intensity Is Associated with the Degree of Ipsilateral Sensorineural Hearing Loss in Patients with Sporadic Vestibular Schwannoma.

BACKGROUND AND PURPOSE: Vestibular schwannomas are benign, generally slow-growing tumors, commonly presenting with hearing loss. Alterations in the labyrinthine signal are seen in patients with vestibular schwannoma; however, the association between imaging abnormalities and hearing function remains poorly defined. The purpose of this study was to determine whether labyrinthine signal intensity is associated with hearing in patients with sporadic vestibular schwannoma. MATERIALS AND METHODS: This was an institutional review board-approved retrospective review of patients from a prospectively maintained vestibular schwannoma registry imaged in 2003-2017. Signal-intensity ratios of the ipsilateral labyrinth were obtained using T1, T2-FLAIR, and postgadolinium T1 sequences. Signal-intensity ratios were compared with tumor volume and audiometric hearing threshold data including pure tone average, word recognition score, and American Academy of Otolaryngology-Head and Neck Surgery hearing class. RESULTS: One hundred ninety-five patients were analyzed. Ipsilateral labyrinthine signal intensity including postgadolinium T1 images was positively correlated with tumor volume (correlation coefficient = 0.17, P = .02). Among signal-intensity ratios, postgadolinium T1 was significantly positively associated with pure tone average (correlation coefficient = 0.28, P < .001) and negatively associated with the word recognition score (correlation coefficient = -0.21, P = .003). Overall, this result correlated with impaired American Academy of Otolaryngology-Head and Neck Surgery hearing class (P = .04). Multivariable analysis suggested persistent associations independent of tumor volume with pure tone average (correlation coefficient = 0.25, P < .001) and the word recognition score (correlation coefficient = -0.17, P = .02) but not hearing class (P = .14). No consistent significant associations were noted between noncontrast T1 and T2-FLAIR signal intensities and audiometric testing. CONCLUSIONS: Increased ipsilateral labyrinthine postgadolinium signal intensity is associated with hearing loss in patients with vestibular schwannoma.