Abstract Prostate-specific membrane antigen (PSMA) is highly expressed in tumor-associated neovasculature in hepatocellular carcinoma (HCC), highlighting its promise as a theranostic target. This prospective study aimed to evaluate the utility of novel biomarkers derived from PSMA positron emission tomography computed tomography (PET/CT) to assess treatment response in advanced HCC patients (pts) receiving first line immune checkpoint inhibitors (ICI). Methods: This study (NCT05176223) enrolled unresectable, advanced HCC pts eligible for first-line ICI (atezolizumab/bevacizumab [A/B] or durvalumab/tremelimumab [D/T]) with measurable disease according to RECIST criteria. Primary endpoints: progression-free survival (PFS) per RECIST 1.1 and mRECIST; overall survival (OS); and best overall response. The survival distribution was estimated using the Kaplan-Meier method. Observed agreement is defined as the proportion of pts whose responses, as classified by PET/CT or CT, were concordant. Weighted kappa and Cohen’s kappa were used to quantify the strength of agreement between PET/CT and CT. Pts completed up to five 68Ga-PSMA PET/CT scans and blood collections. Results: Twenty-six pts were enrolled (25 evaluable) between Oct 2022 and Nov 2024. Median follow up was 22.1 months (m) (Q1, Q3: 14.5-23.7). Median age 68 yrs, 72% male, 88% White, 68% Child-Pugh [CP] A, 32% CP B, 32% Barcelona Clinic Liver Cancer [BCLC] stage B, 68% BCLC stage C, 36% with microvascular invasion; 56% received A/B and 40% received D/T treatment. PSMA was positive in 96% of pts at baseline with median SUVmax 14.3 (range 5.1-40.5) and median background liver SUVmax 3.9 (range 2.1-6.8). Median (95%CI) PFS was 5.6 m (4.6-12.5) by both RECIST and mRECIST. Median (95%CI) OS was 18.6 m (7.2-not estimable), with 56% deceased. The observed agreement between PET/CT adapted PERCIST criteria compared to RECIST and mRECIST in determining the best response was 46% and 50% and weighted kappa of 0.63 (95% CI: 0.37-0.90) and 0.66 (0.41-0.92), respectively. Observed agreement between PERCIST compared to RECIST and mRECIST for responders’ assessment was 67% and 71% with Cohen’s kappa of 0.36 (0.03-0.68) and 0.43 (0.11-0.76), respectively. Conclusion: In this cohort, PSMA PET/CT avidity was observed in all but one pt with advanced HCC, each demonstrating moderate to high SUVmax values. Median OS and PFS were consistent with outcomes reported in clinical trials. Response assessment using 68Ga-PSMA PET/CT according to PERCIST criteria showed good concordance with both RECIST and mRECIST standards. Analysis of immune biomarkers is ongoing. Citation Format: Nguyen H. Tran, Jacob Hirdler, Ajith Antony, Jacob Teske, Sudhakar K. Venkatesh, Amit Mahipal, Michael S. Torbenson, Scott M. Thompson, Thor R. Halfdanarson, Zhaohui Jin, Lionel Aurelien Kankeu Fonkoua, Leslie A. Washburn, Alexander Revzin, Haidong Dong, Robert R. Mcwilliams, Aminah Jatoi, Hani M. Babiker, Mitesh J. Borad, Tanios Bekaii-Saab, Gregory J. Gores, Lewis R. Roberts, Geoffrey B. Johnson, Ajit H. Goenka. Prospective evaluation of 68Ga-PSMA PET imaging in advanced hepatocellular carcinoma patients undergoing first line immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2611.

Long-established prostate cancer cell lines provide limited insight into how contemporary early prostate cancer evolves into drug-resistant and neuroendocrine-like refractory disease. Patient-derived three-dimensional (3D) ex vivo models may better preserve this transition. Here, we found that 8 of 10 magnetic resonance imaging-guided biopsy specimens from patients with early-stage prostate cancer generated sustained 3D tumor spheroid cultures. After 12 weeks of enzalutamide selection, only one patient-derived culture acquired a resistant phenotype with treatment-emergent neuroendocrine prostate cancer (t-NEPC)-like features, including increased chromogranin A (CgA) and synaptophysin (SYP); reduced androgen receptor (AR), prostate-specific antigen (PSA), and prostate-specific membrane antigen (PSMA); and conversion from compact spheroids into irregular resistant aggregates. During this transition, WD repeat and SOCS box-containing protein 1 (WSB1) increased, whereas PSMA progressively decreased. WSB1 silencing restored PSMA, AR, and PSA expression and reduced neuroendocrine-associated features. A similar WSB1 dependency was observed in enzalutamide-resistant LNCaP cells, the castration-resistant prostate cancer model 22Rv1, and the neuroendocrine/small-cell prostate cancer model NCI-H660. Mechanistically, WSB1 functioned as a SOCS box-dependent E3 ubiquitin ligase adaptor that promoted PSMA ubiquitination and degradation. SOCS box deletion or T380A mutation impaired this process, while Aurora kinase A (AURKA) inhibition reduced WSB1-dependent PSMA ubiquitination. WSB1 depletion, AURKA inhibition with alisertib, and combined AURKA inhibition with EZH2 suppression reduced resistant aggregate growth and increased apoptosis-associated markers in patient-derived enzalutamide-resistant neuroendocrine-like spheroids and related models. These findings nominate the AURKA-WSB1-PSMA axis as a therapeutic vulnerability in refractory prostate cancer.

BACKGROUNDAmino acid (AA) concentrations are increased in prediabetes and diabetes. Since AAs stimulate glucagon secretion, which should then increase hepatic AA catabolism, it has been hypothesized that hepatic resistance (associated with hepatic fat content) to glucagon's actions on AA metabolism leads to hyperglucagonemia and hyperglycemia.METHODSTo test this hypothesis, we therefore studied lean and obese individuals, the latter group with and without hepatic steatosis as defined by proton density fat fraction (PDFF) > 5%. After an overnight fast, femoral vein, femoral artery, and hepatic vein catheters were placed. [3-3H] glucose and l-[1-13C,15N]-leucine were used to measure glucose turnover and leucine oxidation, respectively. During a hyperglycemic clamp, an AA mixture was infused together with insulin and glucagon (1.5 ng/kg/min 0-120 minutes; 3.0 ng/kg/min 120-240 minutes). Tracer-based measurement of hepatic leucine oxidation in response to rising glucagon concentrations and splanchnic balance (measured using arteriovenous differences across the liver) of the other AAs were the main outcomes measured.RESULTSThe presence of hepatic steatosis did not alter hepatic glucose metabolism and leucine oxidation in response to insulin and rising concentrations of glucagon. Splanchnic balance of a few AAs and related metabolites differed among the groups. However, across-group differences of AA splanchnic balance in response to glucagon were unaffected by the presence of hepatic steatosis.CONCLUSIONThe action of glucagon on hepatic AA metabolism is unaffected by hepatic steatosis in humans.TRIAL REGISTRATIONClinical Trials.gov: NCT05500586.FUNDINGNIH National Institute of Diabetes and Digestive and Kidney Diseases DK116231, DK78646, DK116231, DK126206, and DK116231.

An acute increase in excitatory synaptic transmission contributes to the rapid antidepressant actions of neuroplastogens, including ketamine and its bioactive metabolite, (2R,6R)-hydroxynorketamine (HNK). It is hypothesized that drug-induced metaplastic changes in synaptic strength account for therapeutically relevant behavioral adaptations in vivo. Using the plasticity-deficient Wistar Kyoto model of treatment-resistant depression, we demonstrate that (2R,6R)-HNK potentiates glutamatergic transmission, promotes synaptic strength, restores long-term potentiation (LTP), and reverses deficits in hippocampal-dependent synaptic activity and behavior. (2R,6R)-HNK selectively potentiated CA1 pyramidal neuron activity during novelty exploration and restored Schaffer collateral-dependent spatial recognition memory. Prior experience with spatial learning partially occluded LTP in control rats, an effect mimicked in LTP-impaired rats in which spatial learning deficits were reversed by (2R,6R)-HNK. These findings demonstrate that (2R,6R)-HNK exerts rapid neuroplastogenic effects in vivo, which improve cognitive function and promote adaptive changes in synaptic strength at functionally impaired synapses.

Accurate treatment response assessment in HCC is crucial but challenged by interpretive variability on CT/MRI. PSMA has emerged as a theranostic biomarker in HCC; however, interpretive reliability is a prerequisite for its validation against oncologic outcomes. Therefore, we evaluated interpretive consistency of a qualitative 68Ga-PSMA PET framework for treatment response assessment in HCC, benchmarking it against CT/MRI criteria. Patients with treatment-naïve HCC were prospectively enrolled for 68Ga-PSMA PET under an FDA IND application. Eligibility for analyses necessitated a baseline 68Ga-PSMA-avid target lesion with post-treatment 68Ga-PSMA PET and CT/MRI for response assessment following either locoregional therapy (LRT) or immune checkpoint inhibitor therapy (ICI). Three radiologists independently assessed response on 68Ga-PSMA PET using a 4-point scale, subsequently dichotomized to viable (uptake > liver) versus non-viable status (uptake ≤ liver). Reliability was benchmarked against binary mRECIST, defined by arterial phase hyperenhancement (APHE), ordinal and binary RECIST 1.1, and binary LR-TR criteria. Inter- and intra-reader agreement were quantified using Gwet’s agreement coefficients (AC1/AC2), with differences between dichotomized methods compared using non-parametric bootstrapping. From 88 patients with baseline 68Ga-PSMA PET, 13 were eligible: 7 with 10 lesions received LRT, and 6 with 19 lesions received ICI. Overall inter-reader agreement on 68Ga-PSMA PET was almost perfect for both the 4-point qualitative scale (Gwet’s AC2: 0.86, 95

Major depressive disorder (MDD) is a common psychiatric disease that significantly impairs quality of life and productivity. Standard monoamine-based therapies are marred by poor efficacy. Disruptions in the balance of glutamate- and GABA (gamma-aminobutyric acid)-mediated neurotransmission in regions associated with reward, emotion, and cognitive processing likely underpin the neurobiology of depression. Subunit-preferring compounds may positively (GABA-positive allosteric modulators [PAMs]) or negatively (GABA-negative allosteric modulators [NAMs]) modulate the ability of GABA to activate inhibitory GABAA receptors containing α5 subunits, predominantly expressed in these corticolimbic structures. Despite opposing mechanistic actions, both classes of compounds have recently demonstrated promise in preclinical models of depression-like symptoms. This review therefore aims to bridge the gap by summarizing the current preclinical literature of α5-preferring GABA-PAMs and GABA-NAMs in models of affective disease. As MDD is a uniquely human disorder with diverse symptoms, effects in individual rodent behavioral models are further classified into discrete categories of reward behavior, despair-like behavior, anxiety-like behavior, and cognitive behavior. From the literature, we identified a clear trend: α5-preferring GABA-PAMs have greatest preclinical efficacy in anxiolytic behavioral paradigms and generally reduce despair-like behavior. In contrast, α5-preferring GABA-NAMs dramatically reverse reward-seeking behavioral deficits following chronic stress, thus effectively relieving anhedonia-a primary symptom of MDD. However, while α5-preferring GABA-NAMs demonstrate anti-despair-like actions, they are largely not anxiolytic. Both classes demonstrate nootropic effects; however, α5-preferring GABA-PAMs have shown additional efficacy in preclinical models characterized by GABAergic hypofunction. Modulating α5-mediated GABAergic transmission has broad potential to treat psychiatric illness, and compounds that demonstrate efficacy across diverse preclinical behavioral domains represent promising translational candidates.

PURPOSE:To investigate thermal injury risks from either radiofrequency (RF)-heating or excessive cooling by high-pressure gas supply lines (HPGSL) during MRI-guided cryoablations, and to identify clinically viable safety precautions. MATERIALS AND METHODS:Ex vivo experiments were performed on a 1.5 Tesla MRI scanner utilizing an MRI conditional cryoablation system. A cryoneedle was inserted into a porcine tissue specimen with an HPGSL routed out of the scanner along the tissue surface and either connected to or disconnected from the ablation system. Experiments were performed with varied layers of operating room (OR) towels or a 2.5 cm thick foam pad between the HPGSL and tissue. Fiber-optic sensors were used to measure temperatures on the HPGSL surface, cryoneedle, and tissue surface during MRI at different specific absorption rates (SAR) or during active freezing. RESULTS:During MRI, tissue surface temperatures nearest the HPGSL increased by up to 40.7 ± 6.9 °C. Tissue temperature increases were reduced to less than 0.1°C as thicker insulation with OR towels or the foam pad were added between the HPGSL and tissue. Disconnecting the HPGSL reduced tissue heating near the HPGSL by 47 %. Tissue heating decreased linearly with decreased SAR. During freezing, the HPGSL cooled to 53.3 ± 1.2 °C below room temperature of 20.9°C. With the foam pad added, the tissue surface cooled to 1.2 ± 0.2 °C below room temperature. CONCLUSION:During MRI-guided cryoablations the HPGSL poses significant patient risks of RF-burns or frostbite, which can be mitigated by ensuring adequate distance between the HPGSL and tissue using insulating materials.

Microdosing, the prolonged ingestion of psychedelics at subhallucinogenic doses, has gained popularity for its perceived cognitive and emotional benefits. Psychedelics have high affinity for 5-HT2B receptors, a receptor known to cause human heart disease with strong chronic activation. We investigated the effects of microdosed psychedelics on cardiovascular health in mice using echocardiography after chronically administering either serotonin or d-fenfluramine as positive controls or lysergic acid diethylamide (LSD) at two subhallucinogenic doses. Serotonin produced significant ventricular thickening at 4- and 8-weeks, and d-fenfluramine caused aortic valve regurgitation at 4-weeks. No significant changes were observed in any vehicle or LSD group. We determined the affinity and potency of LSD, psilocybin, and norfenfluramine at mouse and human 5-HT2BRs and observed no significant differences. We calculated that levels of 5-HT2B activation by low-dose LSD were substantial, but short-lived, compared to the cardiotoxin d-fenfluramine. Together, these data provide no evidence of ventricular or valvular remodeling associated with prolonged administration of low-dose LSD in mice.

( 2R,6R)-Hydroxynorketamine (HNK) is a ketamine metabolite that shows rapid antidepressant-like effects in preclinical studies and lacks the adverse NMDA receptor (NMDAR)-inhibition-related properties of ketamine. Investigating how ( 2R,6R)-HNK exerts its antidepressant actions may be informative in the design of novel pharmacotherapies with improved safety and efficacy. We sought to identify the molecular substrates through which ( 2R,6R)-HNK induces functional changes at excitatory synapses - a prevailing hypothesis for how rapid antidepressant effects are initiated. We recorded excitatory postsynaptic potentials in hippocampal slices from male Wistar Kyoto rats, which have impaired hippocampal plasticity and are resistant to traditional antidepressants. ( 2R,6R)-HNK (10 µM) led to a rapid potentiation of electrically-evoked excitatory postsynaptic potentials at Schaffer collateral CA1 stratum radiatum synapses. This potentiation was associated with a decrease in paired pulse facilitation, suggesting an increase in the probability of glutamate release. The ( 2R,6R)-HNK-induced potentiation was blocked by inhibiting either cyclic adenosine monophosphate (cAMP) or its downstream target, cAMP-dependent protein kinase (PKA). Since cAMP is a potent regulator of brain-derived neurotrophic factor (BDNF) release, we assessed whether ( 2R,6R)-HNK exerts this acute potentiation through a rapid increase in cAMP-dependent BDNF-TrkB signaling. We found that the cAMP-PKA-dependent potentiation was not dependent on TrkB activation by BDNF, which functionally delimits the acute synaptic effects of ( 2R,6R)-HNK from its sustained BDNF-dependent actions in vivo. These results suggest that, by potentiating glutamate release via cAMP-PKA signaling, ( 2R,6R)-HNK initiates acute adaptations in fast excitatory synaptic transmission that promote structural plasticity leading to maintained antidepressant action.

Abstract Background Internal hemorrhoids (IH) is a common medical condition that can result in morbidity secondary to bleeding and discomfort. Treatment for IH has traditionally consisted of dietary and conservative medical management, focal treatments including banding and sclerotherapy or hemorrhoidectomy. Recently, rectal artery embolization (RAE) has been studied as a potential treatment for bleeding predominant IH. We performed a common design and data element analysis of studies that report on RAE. Materials and methods We conducted a qualitative systematic literature review for rectal artery embolization (RAE) for symptomatic hemorrhoidal disease. The screening process involved five online databases (PubMed, Embase, Google Scholar, DOAJ, and Scopus). Additionally, ClinicalTrials.gov was examined for active, unpublished completed studies. The initial search yielded 2000 studies, with 15 studies meeting the inclusion criteria after screening and assessment. The included studies comprised one RCT, one case series, one pilot study and 12 cohort studies. Results The population analysis revealed a male predominance across all studies, with varying cohort sizes. The baseline Goligher hemorrhoid grade was utilized in 80% of studies. The majority (73.3%) employed a transfemoral approach, and coils were the primary embolic material in 60% of studies, 26.6% were combination of coils and particles, and 6.6% were particles only. Patient selection criteria highlighted RAE's applicability for high surgical risk patients and those with anemia, chronic hematochezia, or treatment-refractory cases. Exclusion criteria emphasized factors such as previous surgeries, colorectal cancer, rectal prolapse, acute hemorrhoidal complications, and contrast allergy. Study designs varied, with cohort studies being the most common (12/15; 80%). Procedural details included the use of metallic coils and detachable micro-coils, with a high technical success rate reported in most studies ranging from 72 to 100%. The follow-up ranged from 1 to 18 months. The majority of studies reported no major immediate or post-procedural complications. Conclusion While all studies focused on RAE as a treatment for IH, there was a great degree of heterogeneity among included studies, particularly regarding inclusion criteria, exclusion criteria, outcomes measures and timeframe. Future literature should attempt to standardize these design elements to help facilitate secondary analyses and increase understanding of RAE as a treatment option.

The predominant inhibitory neurotransmitter in the brain, γ-aminobutyric acid (GABA), acts at ionotropic GABA A receptors to counterbalance excitation and regulate neuronal firing. GABA A receptors are heteropentameric channels comprised from subunits derived from 19 different genes. GABA A receptors have one of the richest and well-developed pharmacologies of any therapeutic drug target, including agonists, antagonists, and positive and negative allosteric modulators (PAMs, NAMs). Currently used PAMs include benzodiazepine sedatives and anxiolytics, barbiturates, endogenous and synthetic neurosteroids, and general anesthetics. In this article, I will review evidence that these drugs act at several distinct binding sites and how they can be used to alter the balance between excitation and inhibition. I will also summarize existing literature regarding (1) evidence that changes in GABAergic inhibition play a causative role in major depression, anxiety, postpartum depression, premenstrual dysphoric disorder, and schizophrenia and (2) whether and how GABAergic drugs exert beneficial effects in these conditions, focusing on human studies where possible. Where these classical therapeutics have failed to exert benefits, I will describe recent advances in clinical and preclinical drug development. I will also highlight opportunities to advance a generation of GABAergic therapeutics, such as development of subunit-selective PAMs and NAMs, that are engendering hope for novel tools to treat these devastating conditions.

The serotonin deficit hypothesis explanation for major depressive disorder (MDD) has persisted among clinicians and the general public alike despite insufficient supporting evidence. To combat rising mental health crises and eroding public trust in science and medicine, researchers and clinicians must be able to communicate to patients and the public an updated framework of MDD: one that is (1) accessible to a general audience, (2) accurately integrates current evidence about the efficacy of conventional serotonergic antidepressants with broader and deeper understandings of pathophysiology and treatment, and (3) capable of accommodating new evidence. In this article, we summarize a framework for the pathophysiology and treatment of MDD that is informed by clinical and preclinical research in psychiatry and neuroscience. First, we discuss how MDD can be understood as inflexibility in cognitive and emotional brain circuits that involves a persistent negativity bias. Second, we discuss how effective treatments for MDD enhance mechanisms of neuroplasticity-including via serotonergic interventions-to restore synaptic, network, and behavioral function in ways that facilitate adaptive cognitive and emotional processing. These treatments include typical monoaminergic antidepressants, novel antidepressants like ketamine and psychedelics, and psychotherapy and neuromodulation techniques. At the end of the article, we discuss this framework from the perspective of effective science communication and provide useful language and metaphors for researchers, clinicians, and other professionals discussing MDD with a general or patient audience.

RATIONALE AND OBJECTIVES:Genicular artery embolization (GAE) is an emerging, potentially effective treatment option in patients with knee osteoarthritis (OA). This study aimed to describe the current state of common design data elements (CDDEs) and core outcome measures (COMs) in recent trials of GAE for knee OA. MATERIALS AND METHODS:A comprehensive search of seven online databases were searched within the Nested Knowledge AutoLit living review platform, followed by categorization of primary and secondary outcomes. Studies were tagged with the relevant outcomes of interest in each article. Results were synthesized and examined for the CDDEs. RESULTS:Pain is the most frequent reported outcome, present in 23 of the 24 studies (95.8%). However, there is considerable variability in the description of in the study designs, procedural techniques, embolic materials, time points, and MRI parameters. Greater consistency is observed in eligibility criteria, and adverse events reporting. Although findings thus far have been favorable, current data is still constrained by the heterogeneity of the study design, embolization area nomenclature, limited follow-up, and in many cases, the absence of control group. CONCLUSION:To enhance the potential for future meta-analyses and robust, evidence-based evaluations of GAE as a treatment for knee OA, further research is required to address the identified shortcomings. By establishing more standardized protocols, the efficacy and safety of GAE can be more accurately assessed and understood.

Motor-evoked potential (MEP) monitoring is an electrophysiologic technique useful for testing peripheral motor nerve integrity during cryoablation cases with risk of nerve injury. Previously, neuromonitoring within the magnetic resonance imaging (MRI) suite for cryoablation has not been performed as magnetic needles are used which could cause magnetic field interactions with neuromonitoring leads. We present the first report of a patient who underwent MEP monitoring during MRI-guided cryoablation of a vascular malformation adjacent to the brachial plexus. We demonstrate that MEPs may be safely and accurately performed by interleaving MRI and MEPs during treatment, reducing the risk of postprocedural complications.

Hepatic sinusoids are highly specialized microcirculatory conduits within the hepatic lobules that facilitate liver functions. The sinusoids can be affected by various disorders, including sinusoidal dilatation, sinusoidal obstruction syndrome (SOS), sinusoidal cellular infiltration, perisinusoidal infiltration, and endothelial neoplasms, such as hemangioendothelioma and angiosarcoma. While these disorders, particularly SOS and neoplasms, can be life threatening, their clinical manifestation is often nonspecific. Patients may present with right upper quadrant pain, jaundice, hepatomegaly, ascites, splenomegaly, and unexplained weight gain, although the exact manifestation depends on the cause, severity, and duration of the disease. Ultimately, invasive tests may be necessary to establish the diagnosis. A comprehensive understanding of imaging manifestations of various sinusoidal disorders contributes to early diagnosis and can help radiologists detect subclinical disease. Additionally, specific imaging features may assist in identifying the cause of the disorder, leading to a more focused and quicker workup. For example, a mosaic pattern of enhancement of the liver parenchyma is suggestive of sinusoidal dilatation; peripheral and patchy reticular hypointensity of the liver parenchyma on hepatobiliary MR images is characteristic of SOS; and associated diffuse multiple hyperintensities on diffusion-weighted images may be specific for malignant sinusoidal cellular infiltration. The authors provide an overview of the pathogenesis, clinical features, and imaging appearances of various hepatic sinusoidal disorders, with a special emphasis on SOS. (c) RSNA, 2024 center dot radiographics.rsna.org

To provide an update on the current state of percutaneous thermal ablation in the treatment of sarcoma. Data continue to accrue in support of ablation for local control and palliation of specific sarcoma subtypes such as extra-abdominal desmoid fibromatosis and for broader indications such as the treatment of oligometastatic disease. The synergistic possibilities of various combination therapies such as cryoablation and immunotherapy represent intriguing areas of active investigation. Histotripsy is an emerging non-invasive, non-thermal ablative modality that may further expand the therapeutic arsenal for sarcoma treatment. Percutaneous thermal ablation is a valuable tool in the multidisciplinary management of sarcoma, offering a minimally invasive adjunct to surgery and radiation therapy. Although there remains a paucity of high-level evidence specific to sarcomas, ablation techniques are demonstrably safe and effective for achieving local tumor control and providing pain relief in select patients and are of particular benefit in those with metastatic disease or requiring palliative care.