A phase 1b open-label study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of py314 in combination with pembrolizumab in patients with advanced renal cell carcinoma.

Checkpoint inhibition (CPI) is a standard therapeutic approach in metastatic renal cell carcinoma (RCC). However, not all patients respond to CPI, and the immune suppressive characteristics of the RCC tumor microenvironment may contribute to treatment failure. Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) is a transmembrane protein expressed on a subset of myeloid cells with M2-like anti-inflammatory properties that has previously been associated with disease recurrence after nephrectomy and poor outcomes when expressed at high levels. PY314 is a humanized monoclonal antibody targeting TREM2 that depletes tumor-associated macrophages. In this study, the combination of PY314 and pembrolizumab was investigated in patients with CPI-refractory RCC. Eligible patients had clear cell RCC with disease progression on prior CPI either in combination or sequentially with VEGF-TKI. Patients were treated with PY314 10 mg/kg in combination with pembrolizumab 200 mg IV every 21 days. The primary objective was to assess safety and tolerability and secondary objectives included pharmacokinetics and anti-tumor activity by RECIST v1.1. Seventeen patients were enrolled with a median age of 67 years, 82% male, 100% had prior CPI, and 76% had received three or more prior lines of therapy. The combination of PY314 and pembrolizumab demonstrated an acceptable safety profile with 47.1% any grade treatment-related adverse events (AE) (including only 5.9% grade ≥ 3), the most common being fatigue, pyrexia, nausea, and infusion-related reactions. One patient achieved a partial response (6%), and four patients had stable disease (24%) as their best response. The median PFS was 1.4 months (95% CI 1.2- 3.8). The combination of PY314 and pembrolizumab was safe, but the limited anti-tumor effect observed suggests that TREM2 targeting in conjunction with PD-1 blockade may not overcome resistance to prior CPI. Further investigation is warranted to determine if improved efficacy can be achieved in IO-naïve settings. Trial Registration: NCT04691375.

Dynamic assessment of serum chromogranin A and treatment response with abiraterone acetate in metastatic castration-resistant prostate cancer.

OBJECTIVE: Elevated serum chromogranin A (CGA) is associated with intrinsic or treatment-related neuroendocrine differentiation (NED) in men with metastatic castration-resistant prostate cancer (mCRPC). Fluctuations in serum CGA during treatment of mCRPC have had conflicting results. We analyzed the impact of (i) rising serum CGA and (ii) baseline CGA/PSA ratio during treatment to identify associations with abiraterone acetate (AA) therapy. METHODS: Between June 2013 and August 2015, 92 men with mCRPC were enrolled in a prospective trial with uniform serum CGA processing performed before initiating abiraterone acetate/prednisone (AA/P) and serially after 12 weeks of AA/P treatments. Serum CGA was measured using a homogenous automated immunofluorescent assay. Patients receiving proton pump inhibitors or with abnormal renal function were excluded due to possible false elevations of serum CGA (n = 21 excluded), therefore 71 patients were analyzed. All patients underwent a composite response assessment at 12-weeks. Kaplan-Meier estimates and Cox Regression models were used to calculate the association with time-to-treatment failure analyses and overall survival. RESULTS: An increase in chromogranin was associated with a lower risk of treatment failure (hazard ratio [HR]: 0.52, p = 0.0181). The median CGA/PSA ratio was 7.8 (2.6-16.0) and an elevated pretreatment CGA/PSA ratio above the median was associated with a lower risk of treatment failure (HR: 0.54 p value = 0.0185). An increase in CGA was not found to be associated with OS (HR: 0.71, 95% CI: 0.42-1.21, p = 0.207). An elevated baseline CGA/PSA ratio was not associated with OS (HR: 0.62, 95% CI: 0.37-1.03, p = 0.062). An increase in PSA after 12 weeks of treatment was associated with an increased risk of treatment failure (HR: 4.14, CI: 2.21-7.73, p = < 0.0001) and worse OS (HR: 2.93, CI: 1.57-4.45, p = < 0.0001). CONCLUSIONS: We show that an increasing chromogranin on AA/P and an elevated baseline CGA/PSA in patients with mCRPC were associated with a favorable response to AA/P with no changes in survival. There may be limited clinical utility in serum CGA testing to evaluate for lethal NED as AA/P did not induce lethal NED in this cohort. This highlights that not all patients with an increasing CGA have a worse OS.

Peer-to-peer: The Social Transmission of Symptoms Online.

BACKGROUND: Social learning can be highly adaptive-for example, avoiding a hotplate your friend just burnt themselves on-but it has also been implicated in symptom transmission. Social learning is particularly pertinent given the rapid increase in the use of online mediums for social interaction. Yet, little is known about the social transmission of symptoms online or social chains extending further than a single model-observer interaction. PURPOSE: To explore whether socially induced symptoms could be propagated through a three-generation social transmission chain in an online setting. METHODS: We explored the social transmission of cybersickness following a virtual reality (VR) experience through online webcam interactions. One hundred and seventy-seven adults viewed a VR video in one of four links along a social transmission chain, after: viewing an actor model cybersickness to the VR video (First-Generation); viewing the First-Generation participant undergo VR (Second-Generation); viewing the Second-Generation participant undergo VR (Third-Generation); or naïve (Control). RESULTS: Cybersickness was strongest in First-Generation participants, indicating social transmission from the model. This was mediated by expectancy and anxiety. Whether or not subsequent generations experienced cybersickness depended on what the observed participant verbally reported, which is consistent with social transmission. CONCLUSIONS: Results demonstrate that symptoms can be readily transmitted online, and that expectancy and anxiety are involved. Although it is inconclusive as to whether symptoms can propagate along a social transmission chain, there is some evidence of protection from symptoms when a model who does not report any symptoms is observed. As such, this research highlights the role of social transmission in the modulation of symptoms through virtual mediums.

Social learning is a ubiquitous cognitive process whereby our own behaviors and experiences are influenced by observing others. Occasionally, this can involve the observation of an individual experiencing negative outcomes (e.g., pain or symptoms) following exposure to a treatment or intervention (e.g., consumption of medicine). Previous research has found that individuals may experience an increase in symptoms due to this social learning, even when their treatment has no active components. While research has primarily explored situations in which there is one model and one observer, it was of interest as to whether these socially induced symptoms can be transmitted beyond the first observer. Moreover, with social interaction through online mediums such as social media and video conferencing becoming more common, it was also of interest as to whether these symptoms can be transmitted online. The present findings highlight the significant role of social learning in symptom transmission, even when interactions occur online. With expectancy and anxiety being key features of this social transmission, this study highlights important implications for understanding how individuals can learn about their own future experiences through the observation of others.

Molecular Characteristics of Cisplatin-Induced Ototoxicity and Therapeutic Interventions.

Cisplatin is a commonly used chemotherapeutic agent with proven efficacy in treating various malignancies, including testicular, ovarian, cervical, breast, bladder, head and neck, and lung cancer. Cisplatin is also used to treat tumors in children, such as neuroblastoma, osteosarcoma, and hepatoblastoma. However, its clinical use is limited by severe side effects, including ototoxicity, nephrotoxicity, neurotoxicity, hepatotoxicity, gastrointestinal toxicity, and retinal toxicity. Cisplatin-induced ototoxicity manifests as irreversible, bilateral, high-frequency sensorineural hearing loss in 40-60% of adults and in up to 60% of children. Hearing loss can lead to social isolation, depression, and cognitive decline in adults, and speech and language developmental delays in children. Cisplatin causes hair cell death by forming DNA adducts, mitochondrial dysfunction, oxidative stress, and inflammation, culminating in programmed cell death by apoptosis, necroptosis, pyroptosis, or ferroptosis. Contemporary medical interventions for cisplatin ototoxicity are limited to prosthetic devices, such as hearing aids, but these have significant limitations because the cochlea remains damaged. Recently, the U.S. Food and Drug Administration (FDA) approved the first therapy, sodium thiosulfate, to prevent cisplatin-induced hearing loss in pediatric patients with localized, non-metastatic solid tumors. Other pharmacological treatments for cisplatin ototoxicity are in various stages of preclinical and clinical development. This narrative review aims to highlight the molecular mechanisms involved in cisplatin-induced ototoxicity, focusing on cochlear inflammation, and shed light on potential antioxidant and anti-inflammatory therapeutic interventions to prevent or mitigate the ototoxic effects of cisplatin. We conducted a comprehensive literature search (Google Scholar, PubMed) focusing on publications in the last five years.

On the frequency response of prestin charge movement in membrane patches.

Outer hair cell (OHC) nonlinear membrane capacitance derives from voltage-dependent sensor charge movements within the membrane protein prestin (SLC26a5) that drive OHC electromotility. The ability of the protein to influence hearing depends on its reaction to membrane receptor potentials across auditory frequency. Estimates of prestin's frequency response have been evaluated by several groups out to tens of kHz in voltage-clamped macro-patches of OHC membrane. The response is a power function of frequency that is down 40 dB at 77 kHz. Despite these observations, concerns remain that the macro-patch approach is flawed due to mechanical constraints of pipette solution column load or patch size itself. In the absence of these influences, prestin's frequency response is posited by some to be ultrasonic in nature. Here we evaluate the influence of these putative confounding factors on prestin's frequency response. We show that neither pipette column height nor negative or positive pipette pressure substantially influence total sensor charge frequency response. Additionally, patch surface area has negligible influence. We conclude that the speed of voltage-driven conformational changes in prestin within the plasma membrane is accurately assessed with the macro-patch technique, permitting investigations of membrane characteristics that can substantially alter prestin's performance bandwidth. We illustrate significant alterations in bandwidth by perturbation of membrane fluidity and chloride anion concentration. Finally, we speculate that OHC membrane characteristics may differ along the tonotopic axis of the cochlea to tune nonlinear membrane capacitance frequency cutoffs.

Randomized Phase II Study of Two Doses of Pixantrone in Patients with Metastatic Breast Cancer (NCCTG N1031, Alliance).

BACKGROUND: Anthracycline use in metastatic breast cancer (MBC) is hindered by cumulative exposure limits and risk of cardiotoxicity. Pixantrone, a novel aza-anthracenedione with structural similarities to mitoxantrone and anthracyclines, is theorized to exhibit less cardiotoxicity, mainly due to lack of iron binding. We conducted a randomized phase II study to evaluate the efficacy and safety of 2 dosing schedules of pixantrone in patients with refractory HER2-negative MBC. METHODS: Intravenous pixantrone was administered at 180 mg/m2 every 3 weeks (group A) versus 85 mg/m2 on days 1, 8, and 15 of a 28-day cycle (group B). Primary endpoint was objective response rate (ORR) and secondary endpoints included progression-free survival (PFS), median 6-month PFS, overall survival (OS), safety, quality of life, and serial assessment of circulating tumor cells. A 20% ORR was targeted as sufficient for further testing of pixantrone in this patient population. RESULTS: Forty-five patients were evaluable, with 2 confirmed partial responses in group A and 1 in group B. The trial was terminated due to insufficient activity. Overall median PFS and OS were 2.8 (95% confidence interval [CI]: 2.0-4.1) and 16.8 (95% CI: 8.9-21.6) months, respectively. Notable overall grade 3-4 adverse events were the following: neutrophil count decrease (62%), fatigue (16%), and decrease in ejection fraction (EF) (4%). CONCLUSION: Pixantrone has insufficient activity in the second- and third-line MBC setting. It appears, however, to have limited cardiotoxicity. (ClinicalTrials.gov ID: NCT01086605).

Combined impact of lipidomic and genetic aberrations on clinical outcomes in metastatic castration-resistant prostate cancer.

BACKGROUND: Both changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). A key question is how the lipid environment and the cancer genome are interrelated in order to exploit this therapeutically. We assessed the association between the poor prognostic 3-lipid signature (3LS), somatic genetic aberrations and clinical outcomes in mCRPC. METHODS: We performed plasma lipidomic analysis and cell-free DNA (cfDNA) sequencing on 106 men with mCRPC commencing docetaxel, cabazitaxel, abiraterone or enzalutamide (discovery cohort) and 94 men with mCRPC commencing docetaxel (validation cohort). Differences in lipid levels between men ± somatic genetic aberrations were assessed with t-tests. Associations between the 3LS and genetic aberrations with overall survival (OS) were examined using Kaplan-Meier methods and Cox proportional hazard models. RESULTS: The 3LS was associated with shorter OS in the discovery (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.4-3.3, p < 0.001) and validation cohorts (HR 2.32, 95% CI 1.59-3.38, p < 0.001). Elevated plasma sphingolipids were associated with AR, TP53, RB1 and PI3K aberrations (p < 0.05). Men with both the 3LS and aberrations in AR, TP53, RB1 or PI3K had shorter OS than men with neither in both cohorts (p ≤ 0.001). The presence of 3LS and/or genetic aberration was independently associated with shorter OS for men with AR, TP53, RB1 and PI3K aberrations (p < 0.02). Furthermore, aggressive-variant prostate cancer (AVPC), defined as 2 or more aberrations in TP53, RB1 and/or PTEN, was associated with elevated sphingolipids. The combination of AVPC and 3LS predicted for a median survival of ~12 months. The relatively small sample size of the cohorts limits clinical applicability and warrants future studies. CONCLUSIONS: Elevated circulating sphingolipids were associated with AR, TP53, RB1, PI3K and AVPC aberrations in mCRPC, and the combination of lipid and genetic abnormalities conferred a worse prognosis. These findings suggest that certain genotypes in mCRPC may benefit from metabolic therapies.

Modulators of Kv3 Potassium Channels Rescue the Auditory Function of Fragile X Mice.

Fragile X syndrome (FXS) is characterized by hypersensitivity to sensory stimuli, including environmental sounds. We compared the auditory brainstem response (ABR) recorded in vivo in mice lacking the gene (Fmr1-/y ) for fragile X mental retardation protein (FMRP) with that in wild-type animals. We found that ABR wave I, which represents input from the auditory nerve, is reduced in Fmr1-/y animals, but only at high sound levels. In contrast, wave IV, which represents the activity of auditory brainstem nuclei is enhanced at all sound levels, suggesting that loss of FMRP alters the central processing of auditory signals. Current-clamp recordings of neurons in the medial nucleus of the trapezoid body in the auditory brainstem revealed that, in contrast to neurons from wild-type animals, sustained depolarization triggers repetitive firing rather than a single action potential. In voltage-clamp recordings, K+ currents that activate at positive potentials ("high-threshold" K+ currents), which are required for high-frequency firing and are carried primarily by Kv3.1 channels, are elevated in Fmr1-/y mice, while K+ currents that activate near the resting potential and inhibit repetitive firing are reduced. We therefore tested the effects of AUT2 [((4-({5-[(4R)-4-ethyl-2,5-dioxo-1-imidazolidinyl]-2-pyridinyl}oxy)-2-(1-methylethyl) benzonitrile], a compound that modulates Kv3.1 channels. AUT2 reduced the high-threshold K+ current and increased the low-threshold K+ currents in neurons from Fmr1-/y animals by shifting the activation of the high-threshold current to more negative potentials. This reduced the firing rate and, in vivo, restored wave IV of the ABR. Our results from animals of both sexes suggest that the modulation of the Kv3.1 channel may have potential for the treatment of sensory hypersensitivity in patients with FXS.SIGNIFICANCE STATEMENT mRNA encoding the Kv3.1 potassium channel was one of the first described targets of the fragile X mental retardation protein (FMRP). Fragile X syndrome is caused by loss of FMRP and, in humans and mice, causes hypersensitivity to auditory stimuli. We found that components of the auditory brain response (ABR) corresponding to auditory brainstem activity are enhanced in mice lacking FMRP. This is accompanied by hyperexcitability and altered potassium currents in auditory brainstem neurons. Treatment with a drug that alters the voltage dependence of Kv3.1 channels normalizes the imbalance of potassium currents, as well as ABR responses in vivo, suggesting that such compounds may be effective in treating some symptoms of fragile X syndrome.

The Frequency Response of Outer Hair Cell Voltage-Dependent Motility Is Limited by Kinetics of Prestin.

The voltage-dependent protein SLC26a5 (prestin) underlies outer hair cell electromotility (eM), which is responsible for cochlear amplification in mammals. The electrical signature of eM is a bell-shaped nonlinear capacitance (NLC), deriving from prestin sensor-charge (Qp) movements, which peaks at the membrane voltage, Vh, where charge is distributed equally on either side of the membrane. Voltage dependencies of NLC and eM differ depending on interrogation frequency and intracellular chloride, revealing slow intermediate conformational transitions between anion binding and voltage-driven Qp movements. Consequently, NLC exhibits low-pass characteristics, substantially below prevailing estimates of eM frequency response. Here we study in guinea pig and mouse of either sex synchronous prestin electrical (NLC, Qp) and mechanical (eM) activity across frequencies under voltage clamp (whole cell and microchamber). We find that eM and Qp magnitude and phase correspond, indicating tight piezoelectric coupling. Electromechanical measures (both NLC and eM) show dual-Lorentzian, low-pass behavior, with a limiting (τ2) time constant at Vh of 32.6 and 24.8 µs, respectively. As expected for voltage-dependent kinetics, voltage excitation away from Vh has a faster, flatter frequency response, with our fastest measured τ2 for eM of 18.2 µs. Previous observations of ultrafast eM (τ ≈ 2 µs) were obtained at offsets far removed from Vh We hypothesize that trade-offs in eM gain-bandwith arising from voltage excitation at membrane potentials offset from Vh influence the effectiveness of cochlear amplification across frequencies.SIGNIFICANCE STATEMENT Of two types of hair cells within the organ of Corti, inner hair cells and outer hair cells, the latter evolved to boost sensitivity to sounds. Damage results in hearing loss of 40-60 dB, revealing amplification gains of 100-1000× that arise from voltage-dependent mechanical responses [electromotility (eM)]. eM, driven by the membrane protein prestin, may work beyond 70 kHz. However, this speed exceeds, by over an order of magnitude, kinetics of typical voltage-dependent membrane proteins. We find eM is actually low pass in nature, indicating that prestin bears kinetics typical of other membrane proteins. These observations highlight potential difficulties in providing sufficient amplification beyond a cutoff frequency near 20 kHz. Nevertheless, observed trade-offs in eM gain-bandwith may sustain cochlear amplification across frequency.

Osteonecrosis of the jaw related to non-antiresorptive medications: a systematic review.

INTRODUCTION: The reporting of osteonecrosis of the jaw (ONJ) related to anticancer agents without known antiresorptive properties (non-antiresorptives), such as antiangiogenics, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, immune checkpoint inhibitors, and cytotoxic chemotherapy is increasing. OBJECTIVE: To review characteristics of ONJ in cancer patients receiving non-antiresorptives. METHODS: A systematic review of the literature between 2009 and 2017 was conducted by the Bone Study Group of MASCC/ISOO. RESULTS: Of 6249 articles reviewed and from personal communication, 42 ONJ cases related to non-antiresorptives were identified. No gender predilection was noted. Median age was 60 years and ONJ stage 2 was most common, with predilection for posterior mandible. Exposed bone, pain, and infection were common at diagnosis. In comparison to bone targeting agents (BTAs), radiology, histology, and management were similar, with medication often discontinued. Delayed diagnosis (median 8 weeks) was noted. Important differences included earlier time to ONJ onset (median 20 weeks), absence of trigger event (40%), and greater likelihood of healing and shorter healing time (median 8 weeks) as compared to BTA-related ONJ. Gastrointestinal cancers predominated, followed by renal cell carcinomas compared to breast, followed by prostate cancers in BTA-related ONJ, reflecting different medications. CONCLUSIONS: Data about non-antiresorptive-related ONJ is sparse. This type of ONJ may have better prognosis compared to the BTA-related ONJ, suggested by greater likelihood of healing and shorter healing time. However, the delay in diagnosis highlights the need for more education. This is the first attempt to characterize ONJ associated with different non-antiresorptives, including BRAF and immune checkpoint inhibitors.

Generation of HER2-specific antibody immunity during trastuzumab adjuvant therapy associates with reduced relapse in resected HER2 breast cancer.

BACKGROUND: Resected HER2 breast cancer patients treated with adjuvant trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induce HER2-specific antibodies which correlate with improved survival in HER2 metastatic breast cancer patients. It remains unclear whether the generation of immunity required trastuzumab and whether endogenous antibody immunity is associated with improved disease-free survival in the adjuvant setting. In this study, we addressed this question by analyzing serum anti-HER2 antibodies from a subset of patients enrolled in the NCCTG trial N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively. METHODS: Pre-and post-treatment initiation sera were obtained from 50 women enrolled in N9831. Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and compared between arms and with disease-free survival. RESULTS: Prior to therapy, across all three arms, N9831 patients had similar mean anti-HER2 IgG levels. Following treatment, the mean levels of antibodies increased in the trastuzumab arms but not the chemotherapy-only arm. The proportion of patients who demonstrated antibodies increased by 4% in Arm A and by 43% in the Arms B and C combined (p = 0.003). Cox modeling demonstrated that larger increases in antibodies were associated with improved disease-free survival in all patients (HR = 0.23; p = 0.04). CONCLUSIONS: These results show that the increased endogenous antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant, in view of its correlation with improved disease-free survival. The findings may have important implications for predicting treatment outcomes in patients treated with trastuzumab in the adjuvant setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00005970 . Registered on July 5, 2000.

Characterisation of cochlear inflammation in mice following acute and chronic noise exposure.

Oxidative stress has been established as the key mechanism of the cochlear damage underlying noise-induced hearing loss, however, emerging evidence suggests that cochlear inflammation may also be a major contributor. This study aimed to improve our understanding of the cochlear inflammatory response associated with acute and chronic noise exposure. C57BL/6 mice were exposed to acute traumatic noise (100 dBSPL, 8-16 kHz for 24 h) and their cochleae collected at various intervals thereafter, up to 7 days. Using quantitative RT-PCR and immunohistochemistry, changes in expression levels of proinflammatory cytokines (TNF-α, IL-1ß), chemokines (CCL2) and cell adhesion molecules (ICAM-1) were studied. All gene transcripts displayed similar dynamics of expression, with an early upregulation at 6 h post-exposure, followed by a second peak at 7 days. ICAM-1 immunoexpression increased significantly in the inferior region of the spiral ligament, peaking 24 h post-exposure. The early expression of proinflammatory mediators likely mediates the recruitment and extravasation of inflammatory cells into the noise-exposed cochlea. The occurrence of the latter expression peak is not clear, but it may be associated with reparative processes initiated in response to cochlear damage. Chronic exposure to moderate noise (90 dBSPL, 8-16 kHz, 2 h/day, up to 4 weeks) also elicited an inflammatory response, reaching a maximum after 2 weeks, suggesting that cochlear damage and hearing loss associated with chronic environmental noise exposure may be linked to inflammatory processes in the cochlea. This study thus provides further insight into the dynamics of the cochlear inflammatory response induced by exposure to acute and chronic noise.

Markers of cochlear inflammation using MRI.

PURPOSE: To quantify spatial and temporal inflammation-induced changes in vascular permeability and macrophage infiltration in guinea-pig (GP) cochlea using MRI. MATERIALS AND METHODS: GPs were injected with lipopolysaccharide (LPS) to induce cochlear inflammation. One group was injected with a gadolinium based contrast agent (GBCA) and dynamic contrast enhanced (DCE)-MRI was performed at 4, 7, and 10 days after LPS treatment. A two-compartment pharmacokinetic model was used to determine the apparent rate constant of GBCA extravasation (K(trans) ). A second group was injected with ultrasmall superparamagnetic iron oxide particles (USPIOs) and studied at 2, 3, and 7 days after LPS treatment to detect tissue USPIO uptake and correlate with histology. For both groups, control GPs were scanned similarly. RESULTS: The signal enhancement increased substantially and more rapidly at day 4 in LPS-treated than in control cochlea shortly following GBCA injection. K(trans) of LPS-treated cochlea was maximum on day 4 at 0.0218 ± 0.0032 min(-1) and then decreased to control level at 0.0036 ± 0.0004 min(-1) by day 10. In the second group, the relative signal intensity and T2 in cochlear perilymphatic spaces on day 2 decreased, on average, by 54% and 45%, respectively, compared with baseline and then remained under control levels by day 7. This suggests the infiltration of inflammatory cells, although unconfirmed by histology. CONCLUSION: This provides the first measurement of cochlear vascular permeability using MRI and a quantitative evaluation of the development of cochlear inflammation. MRI holds considerable potential for the assessment of disease processes such as clinical diagnosis of conditions such as labyrinthitis.

Changing paradigms in management of metastatic Castration Resistant Prostate Cancer (mCRPC).

Recently, the standard of care for metastatic Castration Resistant Prostate Cancer (mCRPC) has changed considerably. Persistent androgen receptor (AR) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer. Androgen receptor gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells, making them extremely sensitive to low levels of circulating androgens. Additionally, prostate cancer cells are able to maintain dihydrotestosterone (DHT) concentration in excess of serum concentrations to support tumor growth. For many years ketoconazole was the only CYP17 inhibitor that was used to treat mCRPC. However, significant toxicities limit its use. Newly approved chemotherapeutic agents such as Abiraterone (an oral selective inhibitor of CYP17A), which blocks androgen biosynthesis both within and outside the prostate cancer cells), and enzalutamide (blocks AR signaling) have improved overall survival. There are also ongoing phase III trials for Orteronel (TAK- 700), ARN- 509 and Galeterone (TOK-001), which targets androgen signaling. In this review, we will present the rationale for the newly approved hormonal treatments, their indications and complications, and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents. Finally, we will talk about the potential upcoming hormonal treatments for mCRPC.

A real-world experience of pembrolizumab monotherapy in microsatellite instability-high and/or tumor mutation burden-high metastatic castration-resistant prostate cancer: outcome analysis.

BACKGROUND: The efficacy of pembrolizumab monotherapy in metastatic castration-resistant prostate cancer patients (mCRPC) when stratified by MSI-H and/or TMB-H is poorly defined. Additionally, outcomes based on sequencing source (i.e., tissue or liquid biopsy) have not been well described. We sought to assess outcomes of pembrolizumab monotherapy in patients with mCRPC and compare efficacy based on MSI-H and/or TMB-H when identified by tissue or liquid biopsy. METHODS: A retrospective analysis was performed of mCRPC patients treated at Mayo Clinic with pembrolizumab monotherapy between 2018 and 2023. Objective response rates (ORR), median progression-free survival (mPFS), and overall survival (mOS), were determined by RECIST v1.1 criteria. RESULTS: Twenty-two patients with mCRPC received pembrolizumab monotherapy for at least 3 cycles for a MSI-H or TMB-H indication. All patients had next generation sequencing (NGS) performed via tissue (n = 11) or liquid (n = 10) biopsy source. The ORR was 50% (27.3% complete response and 22.7% had partial response). The mPFS for TMB 10-14.9 mut/Mb (n = 4), TMB 15-24.9 mut/Mb (n = 6), and TMB ≥ 25 mut/Mb (n = 10) was 2.1, not reached (NR), and NR, respectively (p = 0.0003). The mOS for these same groups was 5.1 months, 20.5 months, and not reached, respectively. Among patients with TMB-H without co-occurring MSI-H or CDK12 (n = 6), none experienced a response and only one patient had stable disease compared to patients with MSI-H (n = 12) for whom the ORR was 75%. Immunotherapy responsive alterations such as ATRX and PTCH1 mutations were frequently noticed among patients who had complete response (CR). CONCLUSIONS: Our hypothesis-generating study suggests that MSI-H drives the efficacy of pembrolizumab in mCRPC with better survival outcomes as TMB increases. Clinicians should consider alternative treatment strategies for advanced prostate cancer when TMB-H is present without co-occurring MSI-H or CDK12.

Patient-Derived Tumor Xenograft Study with CDK4/6 Inhibitor Plus AKT Inhibitor for the Management of Metastatic Castration-Resistant Prostate Cancer.

Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive malignancy with poor outcomes. To investigate novel therapeutic strategies, we characterized three new metastatic prostate cancer patient derived-tumor xenograft (PDTX) models and developed 3D spheroids from each to investigate molecular targeted therapy combinations including CDK4/6 inhibitors (CDK4/6i) with AKT inhibitors (ATKi). Metastatic prostate cancer tissue was collected and three PDTX models were established and characterized using whole-exome sequencing. PDTX 3D spheroids were developed from these three PDTXs to show resistance patterns and test novel molecular-targeted therapies. CDK4/6i's were combined with AKTi's to assess synergistic antitumor response to prove our hypothesis that blockade of AKT overcomes drug resistance to CDK4/6i. This combination was evaluated in PDTX three-dimensional (3D) spheroids and in vivo experiments with responses measured by tumor volumes, PSA, and Ga-68 PSMA-11 PET-CT imaging. We demonstrated CDK4/6i's with AKTi's possess synergistic antitumor activity in three mCRPC PDTX models. These models have multiple unique pathogenic and deleterious genomic alterations with resistance to single-agent CDK4/6i's. Despite this, combination therapy with AKTi's was able to overcome resistance mechanisms. The IHC and Western blot analysis confirmed on target effects, whereas tumor volume, serum PSA ELISA, and radionuclide imaging demonstrated response to therapy with statistically significant SUV differences seen with Ga-68 PSMA-11 PET-CT. These preclinical data demonstrating antitumor synergy by overcoming single-agent CDK 4/6i as well as AKTi drug resistance provide the rational for a clinical trial combining a CDK4/6i with an AKTi in patients with mCRPC whose tumor expresses wild-type retinoblastoma 1.

Role of mitochondrial dysfunction and oxidative stress in sensorineural hearing loss.

Sensorineural hearing loss (SNHL) can either be genetically inherited or acquired as a result of aging, noise exposure, or ototoxic drugs. Although the precise pathophysiological mechanisms underlying SNHL remain unclear, an overwhelming body of evidence implicates mitochondrial dysfunction and oxidative stress playing a central etiological role. With its high metabolic demands, the cochlea, particularly the sensory hair cells, stria vascularis, and spiral ganglion neurons, is vulnerable to the damaging effects of mitochondrial reactive oxygen species (ROS). Mitochondrial dysfunction and consequent oxidative stress in cochlear cells can be caused by inherited mitochondrial DNA (mtDNA) mutations (hereditary hearing loss and aminoglycoside-induced ototoxicity), accumulation of acquired mtDNA mutations with age (age-related hearing loss), mitochondrial overdrive and calcium dysregulation (noise-induced hearing loss and cisplatin-induced ototoxicity), or accumulation of ototoxic drugs within hair cell mitochondria (drug-induced hearing loss). In this review, we provide an overview of our current knowledge on the role of mitochondrial dysfunction and oxidative stress in the development of SNHL caused by genetic mutations, aging, exposure to excessive noise, and ototoxic drugs. We also explore the advancements in antioxidant therapies for the different forms of acquired SNHL that are being evaluated in preclinical and clinical studies.

Pharmacological Modulation of Energy and Metabolic Pathways Protects Hearing in the Fus1/Tusc2 Knockout Model of Mitochondrial Dysfunction and Oxidative Stress.

Tightly regulated and robust mitochondrial activities are critical for normal hearing. Previously, we demonstrated that Fus1/Tusc2 KO mice with mitochondrial dysfunction exhibit premature hearing loss. Molecular analysis of the cochlea revealed hyperactivation of the mTOR pathway, oxidative stress, and altered mitochondrial morphology and quantity, suggesting compromised energy sensing and production. Here, we investigated whether the pharmacological modulation of metabolic pathways using rapamycin (RAPA) or 2-deoxy-D-glucose (2-DG) supplementation can protect against hearing loss in female Fus1 KO mice. Additionally, we aimed to identify mitochondria- and Fus1/Tusc2-dependent molecular pathways and processes critical for hearing. We found that inhibiting mTOR or activating alternative mitochondrial energetic pathways to glycolysis protected hearing in the mice. Comparative gene expression analysis revealed the dysregulation of critical biological processes in the KO cochlea, including mitochondrial metabolism, neural and immune responses, and the cochlear hypothalamic-pituitary-adrenal axis signaling system. RAPA and 2-DG mostly normalized these processes, although some genes showed a drug-specific response or no response at all. Interestingly, both drugs resulted in a pronounced upregulation of critical hearing-related genes not altered in the non-treated KO cochlea, including cytoskeletal and motor proteins and calcium-linked transporters and voltage-gated channels. These findings suggest that the pharmacological modulation of mitochondrial metabolism and bioenergetics may restore and activate processes critical for hearing, thereby protecting against hearing loss.

Social communication pathways to COVID-19 vaccine side-effect expectations and experience.

OBJECTIVE: Negative beliefs about medication and vaccine side-effects can spread rapidly through social communication. This has been recently documented with the potential side-effects from the COVID-19 vaccines. We tested if pre-vaccination social communications about side-effects from personal acquaintances, news reports, and social media predict post-vaccination side-effect experiences. Further, as previous research suggests that side-effects can be exacerbated by negative expectations, we assessed if personal expectations mediate the relationships between social communication and side-effect experience. METHOD: In a prospective longitudinal survey (N = 551), COVID-19 vaccine side-effect information from three sources-social media posts, news reports, and first-hand accounts from personal acquaintances-as well as side-effect expectations, were self-reported pre-vaccination. Vaccination side-effect experience was assessed post-vaccination. RESULTS: In multivariate regression analyses, the number of pre-vaccination social media post views (ß = 0.17) and impressions of severity conveyed from personal acquaintances (ß = 0.42) significantly predicted an increase in pre-vaccination side-effect expectations, and the same variables (ßs = 0.11, 0.14, respectively) predicted post-vaccination side-effect experiences. Moreover, pre-vaccination side-effect expectations mediated the relationship between both sources of social communication and experienced side-effects from a COVID-19 vaccination. CONCLUSIONS: This study identifies links between personal acquaintance and social media communications and vaccine side-effect experiences and provides evidence that pre-vaccination expectations account for these relationships. The results suggest that modifying side-effect expectations through these channels may change the side-effects following a COVID-19 vaccination as well as other publicly discussed vaccinations and medications.