Multimodal Agents Research Articles

Effects of shell-integrated Sudan Black dye on the acoustic activity and ultrasound imaging properties of lipid-shelled nanoscale ultrasound contrast agents.

.Significance: An effective contrast agent for concurrent multimodal photoacoustic (PA) and ultrasound (US) imaging must have both high optical absorption and high echogenicity. Integrating a highly absorbing dye into the lipid shell of gas core nanobubbles (NBs) adds PA contrast to existing US contrast agents but may impact agent ultrasonic response.Aim: We report on the development and ultrasonic characterization of lipid-shell stabilized NBs with integrated Sudan Black (SB) B dye in the shell as dual-modal PA-US contrast agents.Approach: Perfluoropropane NBs stabilized with a lipid shell including increasing concentrations of SB B dye were formulated by amalgamation (SBNBs). Physical properties of SBNBs were characterized using resonant mass measurement, transmission electron microscopy and pendant drop tensiometry. Concentrated bubble solutions were imaged for 8 min to assess signal decay. Diluted bubble solutions were stimulated by a focused transducer to determine the response of individual NBs to long cycle (30 cycle) US. For assessment of simultaneous multimodal contrast, bulk populations of SBNBs were imaged using a PA and US imaging platform.Results: We produced high agent yield () with a mean diameter of to 300 nm depending on SB loading. A 40% decrease in bubble yield was measured for solutions with 0.3 and SB. The addition of SB to the shell did not substantially affect NB size despite an increase in surface tension by up to . The bubble decay rate increased after prolonged exposure (8 min) by dyed bubbles in comparison to their undyed counterparts (2.5-fold). SB in bubble shells increased gas exchange across the shell for long cycle US. PA imaging of these agents showed an increase in power (up to 10 dB) with increasing dye.Conclusions: We added PA contrast function to NBs. The addition of SB increased gas exchange across the NB shell. This has important implications in their use as multimodal agents.

Targeted PET/MRI Imaging Super Probes: A Critical Review of Opportunities and Challenges.

Recently, the demand for hybrid PET/MRI imaging techniques has increased significantly, which has sparked the investigation into new ways to simultaneously track multiple molecular targets and improve the localization and expression of biochemical markers. Multimodal imaging probes have recently emerged as powerful tools for improving the detection sensitivity and accuracy—both important factors in disease diagnosis and treatment; however, only a limited number of bimodal probes have been investigated in preclinical models. Herein, we briefly describe the strengths and limitations of PET and MRI modalities and highlight the need for the development of multimodal molecularly-targeted agents. We have tried to thoroughly summarize data on bimodal probes available on PubMed. Emphasis was placed on their design, safety profiles, pharmacokinetics, and clearance properties. The challenges in PET/MR probe development using a number of illustrative examples are also discussed, along with future research directions for these novel conjugates.

The association of multimodal analgesia and high-risk opioid discharge prescriptions in opioid-naive surgical patients

BackgroundOpioids and multimodal analgesia are widely administered to manage postoperative pain. However, little is known on how improvements in inpatient pain control are correlated with high-risk (> 90 daily OME) discharge opioid prescriptions for opioid naïve surgical patients.MethodsWe conducted a retrospective observational study of adult opioid-naïve patients undergoing surgery from June 2012 through December 2018 at a large academic medical center. We used multivariate logistic regression to assess whether multimodal analgesic drugs consumed in the 24 h prior to discharge was associated with a reduction in high-risk opioid discharge prescriptions. We identified other risk factors for receiving a high-risk discharge opioid prescription.ResultsAmong the 32,511 patients, 83% of patients were discharged with an opioid prescription. In 2013, 34.1% of patients with a discharge opioid prescription received a high-risk prescription and this declined to 17.7% by 2018. Use of multimodal analgesic agents during the final 24 h of hospitalization increased each year, with over 80% receiving at least one multimodal analgesic agent by 2018. The median OME consumed in the 24 h prior to discharge peaked in 2013 at 31 and steadily decreased to 19.8 by 2018. There was a significant association between the use of acetaminophen in the 24 h prior to discharge and a high-risk prescription at discharge (p < 0.01). OMEs consumed in the 24 h prior to discharge was a significant predictor of receiving a high-risk discharge prescription, even at low doses. Other factors associated with receipt of a high-risk discharge opioid prescription included male gender, race, history of anxiety disorder, and discharge service.DiscussionUse of multimodal analgesia regimens in hospitalized surgical patients in the 24 h prior to hospital discharge increased between 2012 and 2018. Simultaneously, opioid use prior to hospital discharge decreased. Despite these gains, approximately one in five discharge prescriptions was high-risk (> 90 daily OME). In addition, we found that prescribing of discharge opioids above inpatient opioid requirements remains common in opioid naive surgical patients.ConclusionProviders should account for pre-discharge opioid consumption and use of multimodal analgesia when considering the total and daily OME’s that may be appropriate for an individual surgical patient on the discharge opioid prescription.

Introducing the Tellurophene-Appended BODIPY: PDT Agent with Mass Cytometry Tracking Capabilities.

The synthesis and characterization of the first BODIPY appended to the five-membered heterocylic tellurophene [Te] moiety is reported. By incorporating tellurophene at the meso position, the tellurophene-appended boron-dipyrromethene dye (BODIPY) acts as a multimodal agent, becoming a potent photosensitizer with a mass cytometry tag. To synthesize the compound, we developed a method to enable late-stage Suzuki-Miyaura coupling by preparing and isolating tellurophene-2-BPin in a one-step procedure from the parent tellurophene. Coupling to a meso-substituted BODIPY functionalized with a pendant aryl bromide provides the desired tellurophene-appended BODIPY. This compound demonstrated a singlet oxygen quantum yield of 0.26 ± 0.01 and produced a light dose-dependent cytotoxicity with nanomolar IC50 values against 2D cultured HeLa cells and high efficacy against 3D cultured HeLa tumor spheroids, proving to be a strong photosensitizer. The presence of the tellurophene moiety could be detected using mass cytometry, thus showcasing the ability of a tellurophene-appended BODIPY as a novel photodynamic-therapy-mass-cytometry theranostic agent.

Nanoscale covalent organic framework for the low-temperature treatment of tumor growth and lung metastasis

Photothermal therapy (PTT) has shown promising applications in tumor therapies. However, due to laser-induced nonspecific heating and heat diffusion, high levels of hyperthermia (>50°C) in tumor tissues often increase the risk of cancer recurrence and metastasis, which causes the patient pain and destroys the surrounding normal cells and tissues. It is therefore important to develop photothermal strategies that have excellent therapeutic efficiencies under low-temperature conditions (≤45°C). In addition, the heterogeneity and complexity of tumors require the development of combinatorial antitumor treatments as the therapeutic efficiency of monomodal PTT is not currently sufficient. Herein, we have adopted a stepwise synthetic approach to develop a highly efficient multimodal therapeutic agent GA@PCOF@PDA by successive bonding defect functionalization (BDF), guest encapsulation, and surface modification steps. The covalently grafted porphyrinic photosensitizers (Por), encapsulated gambogic acid (GA), and surface-modified PDA film are independently responsible for photodynamic therapy (PDT), heat-shock protein 90 (HSP90) down-regulation and chemotherapy (CT), and low-temperature PTT. This proof-of-concept study illustrates an efficient, generalized approach to design high-performance covalent organic framework (COF)-based nanoagents that can be easily tailored to combine different therapeutic modalities for improved cancer theranostics at low temperatures.

Crystallization of the Multi-Receptor Tyrosine Kinase Inhibitor Sorafenib for Controlled Long-Term Drug Delivery Following a Single Injection.

A major challenge in cancer medicine is the safe and effective delivery of drugs to the right tissue at the right time. Despite being designed for greater target specificity, many drugs still result in side effects and lack of safety in patients following global dissemination. Therefore, to develop new, more effective formulations capable of improving specificity and reducing off-target effects, here we describe formulation of drug crystals, from even a very hydrophobic and otherwise difficult to solubilize small molecule chemical compound, capable of providing constant drug release for weeks following a single injection. We chose to utilize the multi-tyrosine kinase inhibitor and multi-modal (anti-angiogenic and tumor cell cytotoxic) agent sorafenib, to combat aberrant angiogenesis and tumor growth which contribute to metastasis, ultimately responsible for poor patient outcomes. We tuned crystal size (surface area:volume ratios), imaged by SEM, to display controllability of drug delivery kinetics in in vitro drug release assays. Single and powder crystal X-ray diffraction (XRD) established that all crystals were the same polymorph and drug form. When utilized against an orthotopic triple negative breast cancer (TNBC) mouse model (4T1 in syngeneic BALB/c mice), we established anti-tumor activity from a single local, subcutaneous injection of crystalline sorafenib. From our findings, we support that engineering crystalline drug delivery systems has implications in the treatment of cancer or other diseases where high enough constitutive drug levels are needed to maintain target saturation and inhibition while also preventing emergence of drug resistance, which is a consequence often seen with suboptimal dosing. The online version contains supplementary material available at 10.1007/s12195-021-00708-6.

First-in-Class Isonipecotamide-Based Thrombin and Cholinesterase Dual Inhibitors with Potential for Alzheimer Disease.

Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer’s disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The N-phenyl-1-(pyridin-4-yl)piperidine-4-carboxamide derivative 1, which has already been experimentally shown to inhibit thr with a Ki value of 6 nM, has been flagged by a new, upcoming release of MuSSeL as a binder of cholinesterase (ChE) isoforms (acetyl- and butyrylcholinesterase, AChE and BChE), as well as thr, fXa, and other enzymes and receptors. Interestingly, the inhibition potency of 1 was predicted by the MuSSeL platform to fall within the low-to-submicromolar range and this was confirmed by experimental Ki values, which were found equal to 0.058 and 6.95 μM for eeAChE and eqBChE, respectively. Thirty analogs of 1 were then assayed as inhibitors of thr, fXa, AChE, and BChE to increase our knowledge of their structure-activity relationships, while the molecular determinants responsible for the multiple activities towards the target enzymes were rationally investigated by molecular cross-docking screening.

Sentiment-influenced trading system based on multimodal deep reinforcement learning

Owing to advancements in deep learning, studies involving the use of deep learning techniques to solve investment decision-making problems are increasing. However, although numerous aspects of the stock market may affect trends in financial data, previous studies have only considered price fluctuations. Therefore, investors may lose out on profits because of the complicated financial market condition. In this study, a multimodal reinforcement trading system is developed, which makes use of three techniques: reinforcement learning, sentiment analysis, and multimodal learning. The agent considers not only the price fluctuations but also news information when making a trading decision. Multimodal learning which can merge different modalities of data to enhance the performance of the model, and sentiment analysis for understanding the sentiment of news are introduced. In addition, an influence model is proposed to enable our agents to gain special insights on the impact that news has on the market. The influence model considers the relationship between sentiment of news and time. The experimental results show that multimodal agents outperform price-concerned agents by at least 13.26%. Our experimental results also indicate that the proposed influence model has the ability to shape the impact of news on the stock market. The model can aid the multimodal agents in evaluating the status of the market. The proposed multimodal reinforcement trading system is demonstrated to be robust in an experiment involving different sectors and evaluations by using various measures. In addition, because the data used are public, investors seeking to profit can easily implement the results of this paper. Therefore, it can be used in advanced research and financial applications.

Vortioxetine mitigates neuronal damage by restricting PERK/eIF2α/ATF4/CHOP signaling pathway in rats subjected to focal cerebral ischemia-reperfusion

AimsStroke has risen to the fifth and third most common causes of death in the United States and the rest of the world, respectively. Vortioxetine (VTX) is a multimodal antidepressant agent that balances 5-HT receptors and represses the serotonin transporter. Our study aimed to examine the neuroprotective impacts of VTX against cerebral ischemia caused by occluding the middle cerebral artery (MCA). Main methodsUntil the middle cerebral artery occlusion (MCAO) induction, VTX (10 mg/kg/day) was taken orally for 14 days. Behavioral assessments were carried out 24 h after the MCAO technique. The hippocampal and cortical tissues of the brain were isolated to assess the histological changes and the levels of the biochemical parameters. Key findingsMCAO damage led to severe neurological deficits and histopathological damage. However, VTX improved MCAO-induced neurological deficits and ameliorated histopathological changes in both hippocampal and cortical tissues of MCAO rats. Western blot analysis showed increments of p-PERK, CHOP, ASK-1, NICD, HES-1, HES-5, and p-eIF2α expression levels in MCAO rats. Moreover, ELISA revealed an increase in the levels of ATF4, IRE1, Apaf-1, and HIF-1α, while VTX administration ameliorated most of these perturbations induced after MCAO injury. SignificanceThis research suggests that VTX could be a potent neuroprotective agent against ischemic stroke by inhibiting a variety of oxidative, apoptotic, inflammatory, and endoplasmic reticulum stress pathways.

Chiral Benzothiazole Monofluoroborate Featuring Chiroptical and Oxygen-Sensitizing Properties: Synthesis and Photophysical Studies

Advances in personalized medicine are prompting the development of multimodal agents, that is, molecules that combine properties promoting various diagnostic and therapeutic applications. General approaches exploit chemical conjugation of therapeutic agents with contrast agents or the design of multimodal nanoplatforms. Herein, we report the design of a single molecule that exhibits potential for different diagnostic modes as well as the ability to sensitize oxygen, thus offering potential for photodynamic therapy. Exceptionally, this work involves the synthesis and chiral resolution of an enantiomeric pair of chiral monofluoroborates that contain a stereogenic boron atom. Combining experimental and theoretical chiroptical studies allowed the unambiguous determination of their absolute configuration. Photophysical investigations established the ability of this compound to sensitize oxygen even in the absence of heavy atoms within its structure. The synthesis of a chiral benzothiazole monofluoroborate paves a way to multimodal diagnostic tools (fluorescence and nuclear imaging) while also featuring potential therapeutic applications owing to its ability to activate oxygen to its singlet state for use in photodynamic therapy.

Porphyrin-lipid nanovesicles (Porphysomes) are effective photosensitizers for photodynamic therapy

Porphysomes (PS) are liposome-like nanoparticles comprising pyropheophorbide-conjugated phospholipids that have demonstrated potential as multimodal theranostic agents for applications that include phototherapies, targeted drug delivery and in vivo fluorescence, photoacoustic, magnetic resonance or positron emission imaging. Previous therapeutic applications focused primarily on photothermal therapy (PTT) and suggested that PSs require target-triggered activation for use as photodynamic therapy (PDT) sensitizers. Here, athymic nude mice bearing subcutaneous A549 human lung tumors were randomized into treatment and control groups: PS-PDT at various doses, PS-only and no treatment negative controls, as well as positive controls using the clinical photosensitizer Photofrin. Animals were followed for 30days post-treatment. PS-PDT at all doses demonstrated a significant tumor ablative effect, with the greatest effect seen with 10mg/kg PS at a drug-light interval of 24h. By comparison, negative controls (PS-only, Photofrin-only, and no treatment) showed uncontrolled tumor growth. PDT with Photofrin at 5mg/kg and PS at 10mg/kg demonstrated similar tumor growth suppression and complete tumor response rates (15 vs. 25%, p=0.52). Hence, porphysome nanoparticles are an effective PDT agent and have the additional advantages of multimodal diagnostic and therapeutic applications arising from their intrinsic structure. Porphysomes may also be the first single all-organic agent capable of concurrent PDT andPTT.

Efficacy and safety of Cerebrolysin after futile recanalisation therapy in patients with severe stroke

IntroductionGolden standard of acute stroke treatment is recanalisation therapy. However, opening the occluded blood vessel sometimes does not show the expected clinical result or leads to haemorrhagic complications. As neuroinflammation and neurotoxicity play an important role in the pathophysiology of stroke, neuroprotective agents might preserve brain tissue after futile recanalisation. Patients and methodsAfter recanalisation therapy and not later than 24 h after symptoms onset, patients with initial NIHSS of ≥ 8 were assigned to the investigational and control group. The investigational group received intravenous Cerebrolysin as add-on therapy. The primary objective was to assess the clinical efficacy of Cerebrolysin. The secondary objective was to investigate its effect on haemorrhagic transition and to confirm its safety profile. ResultsBaseline characteristics of patients showed no significant differences between the two groups. No difference could be detected between the two groups in the mRS scale though the Cerebrolysin group showed descriptive superiority over the control group. We found a statistically significant difference considering haemorrhagic transition and mortality rate in favour of the Cerebrolysin group. DiscussionThe multimodal neurotrophic agent Cerebrolysin holds promise to impact on the late consequences of a reperfusion syndrome. Its influence on reducing neuroinflammation, promoting neuronal cell viability and neurogenesis as well as the stabilising effect on the blood-brain barrier suggests a protective effect on the neurovascular unit even when no recanalisation occurs. We confirmed the excellent safety profile of Cerebrolysin. ConclusionCerebrolysin as add-on therapy might be beneficial and safe for patients with acute stroke in terms of lowering risk for haemorrhagic complications after recanalisation therapy.

One-for-all phototheranostics: Single component AIE dots as multi-modality theranostic agent for fluorescence-photoacoustic imaging-guided synergistic cancer therapy

Construction of single component theranostic agent with one-for-all features to concurrently afford both multi-modality imaging and therapy is an appealing yet significantly challenging task. Herein, a type of luminogens with aggregation-induced emission (AIE) characteristics are tactfully designed and facilely synthesized. These AIE luminogens (AIEgens) exhibit long emission wavelengths, good photostability, remarkable biocompatibility, good reactive oxygen species (ROS) generation performance and excellent photothermal conversion efficiency, which allow them to be powerfully utilized for in vitro and in vivo cancer phototheranostics. The results show that one of the AIEgens is capable of precisely diagnosing solid tumors of mice by means of combined near-infrared-I/II (NIR-I/II) fluorescence-photoacoustic imaging, meanwhile this AIEgen can activate photodynamic and photothermal synergistic therapy (PDT-PTT) upon laser irradiation, resulting in excellent tumor elimination efficacy with only once injection and irradiation. This study thus provides a versatile platform for practical cancer theranostics.

The rationale for methylene blue utility against SARS-CoV-2 infection complications

Context: Almost one year after the onset of COVID-19 pandemic in Wuhan, China and still no specific therapy has emerged, counting millions of dead worldwide. The association of an uncontrolled SARS-CoV-2 replication and host-dependent mechanisms in COVID-19 pathogenesis suggest that any therapeutic strategy must combine antiviral drugs and adjuvant therapy to modulate the host’s responses. Owing to the multiplicity of mechanisms involved in COVID-19 pathogenic expressions, such as severe hypoxia, excessive inflammatory reaction and impaired immune response, an emerging therapeutic paradigm is the searching for agents acting as multifunctional drugs. Methylene blue (MB), the antique medication, seems to meet the above criterion. Aims: To summarize the probable beneficial effects of MB against COVID-19 supported by a discussion of the drug mechanisms of action counteracting the pathogenic mechanisms of the disease. Methods: PubMed, Google Scholar, and Scopus databases were used to collect the biomedical research on MB, and the discussed dataset finally included 150 published articles. Those COVID-19 pathogenic pathways possibly targeted by MB were critically appraised. Results: It was found that MB may act as multimodal agent by targeting simultaneously several pathogenic mechanisms of COVID-19 as hypoxic damage, hyper-inflammatory reaction and death signaling activation. It also may act as a virucidal agent by preventing virus-induced metabolic re-orientation. Its high safety profile, low cost, along with the mechanisms discussed herein might be essential criteria to test MB as an adjuvant therapy against COVID-19. Conclusions: Overall, this critical review provides theoretical grounds for MB clinical evaluation in the therapeutic management of SARS-CoV-2 infection.

Gadolinium-chelate functionalized magnetic CuFeSe2 ternary nanocrystals for T1-T2 dual MRI and CT imaging in vitro and in vivo

CuFeSe2 nanomaterial with high thermal conversion efficiency, well superparamagnetism, effective x-ray attenuation ability, multifunctional groups and excellent biocompatibility is beneficial to the construction of multimodal imaging probes which can combine various imaging modes to provide a synergistic advantage over a single imaging mode. This study aimed to develop a novel multimodal nanocontrast agent CuFeSe2@diethylenetriaminepentaacetic acid (DTPA)-Gd to obtain imaging information with high specificity, high sensitivity and high contrast. The morphology and physical characteristics of CuFeSe2@DTPA-Gd were detected by transmission electron microscope, scanning electron microscope, x-ray single crystal diffraction, vibrating sample magnetometer and fourier transform infrared spectrometer. The toxicity of CuFeSe2@DTPA-Gd in vivo was evaluated by hematoxylin-eosin staining. The imaging capability of CuFeSe2@DTPA-Gd in vitro and in vivo was evaluated by magnetic resonance imaging (MRI) and computed tomography (CT). This study successfully prepared nanoparticles CuFeSe2@DTPA-Gd, and experimental results in this study demonstrated CuFeSe2@DTPA-Gd is expected to be a useful CT and MRI T1-weighted imaging/T2-weighted imaging three-modal contrast agent in clinic.

Monodentately-coordinated bioactive moieties in multimodal half-sandwich organoruthenium anticancer agents

• Metal-based drugs are widely used in the treatment of cancer. • Synergistic activity between ruthenium centers and bioactive ligands. • Multimodal anticancer agents formed from bioactive ligands and ruthenium. • Bioactivity of Ru complexes is often determined by monodentate ligands. • Donor atoms of ligands determine the stability of the Ru complexes. Metallodrugs have a central role in the treatment and diagnosis of diseases. To overcome potential toxicity and equip metal-based anticancer agents with biological activity, the choice of the ligands coordinated to the metal center is essential. A recent strategy to address the shortcomings of current drugs and improve their targeted properties, is to introduce bioactive ligands, which may result in synergistic activity between the metal center and the ligand system. In this review, we discuss such efforts in the development of Ru half-sandwich compounds, a class of promising anticancer agents which have been widely studied. We explore here strategies to introduce monodentately-coordinated bioactive moieties into such metal complexes by a variety of design concepts and review their potential as multimodal anticancer agents.

Dual laser activatable brominated hemicyanine as a highly efficient and photostable multimodal phototherapy agent

Dual phototherapy agents have attracted great interest in recent years as they offer enhanced cytotoxicity on cancer cells due to the synergistic effect of photodynamic and photothermal therapies (PDT/PTT). In this study, we demonstrate a brominated hemicyanine (HC-1), which is previously shown as mitochondria targeting PDT agent, can also serve as an effective photosensitizer for PTT for the first time under a single (640 nm or 808 nm) and dual laser (640 nm + 808 nm) irradiation. Generation of reactive oxygen species and photothermal conversion as a function of irradiation wavelength and power were studied. Both single wavelength irradiations caused significant phototoxicity in colon and cervical cancer cells after 5 min of irradiation. However, co-irradiation provided near-complete elimination of cancer cells due to synergistic action. This work introduces an easily accessible small molecule-based synergistic phototherapy agent, which holds a great promise towards the realization of local, rapid and highly efficient treatment modalities against cancer.

Twisted Intramolecular Charge Transfer—Aggregation-Induced Emission Fluorogen with Polymer Encapsulation-Enhanced Near-Infrared Emission for Bioimaging

Fluorescence probes with strong near-infrared (NIR) emission and water solubility are considered useful visualization tools for localization marking as well as investigating cell migration and tran...

Therapy of Established Tumors with Rationally Designed Multiple Agents Targeting Diverse Immune-Tumor Interactions: Engage, Expand, Enable.

Immunotherapy of immunologically cold solid tumors may require multiple agents to engage immune effector cells, expand effector populations and activities, and enable immune responses in the tumor microenvironment (TME). To target these distinct phenomena, we strategically chose five clinical-stage immuno-oncology agents, namely, (i) a tumor antigen-targeting adenovirus-based vaccine (Ad-CEA) and an IL15 superagonist (N-803) to activate tumor-specific T cells, (ii) OX40 and GITR agonists to expand and enhance the activated effector populations, and (iii) an IDO inhibitor (IDOi) to enable effector-cell activity in the TME. Flow cytometry, T-cell receptor (TCR) sequencing, and RNA-sequencing (RNA-seq) analyses showed that in the CEA-transgenic murine colon carcinoma (MC38-CEA) tumor model, Ad-CEA + N-803 combination therapy resulted in immune-mediated antitumor effects and promoted the expression of costimulatory molecules on immune subsets, OX40 and GITR, and the inhibitory molecule IDO. Treatment with Ad-CEA + N-803 + OX40 + GITR + IDOi, termed the pentatherapy regimen, resulted in the greatest inhibition of tumor growth and protection from tumor rechallenge without toxicity. Monotherapy with any of the agents had little to no antitumor activity, whereas combining two, three, or four agents had minimal antitumor effects. Immune analyses demonstrated that the pentatherapy combination induced CD4+ and CD8+ T-cell activity in the periphery and tumor, and antitumor activity associated with decreased regulatory T-cell (Treg) immunosuppression in the TME. The pentatherapy combination also inhibited tumor growth and metastatic formation in 4T1 and LL2-CEA murine tumor models. This study provides the rationale for the combination of multimodal immunotherapy agents to engage, enhance, and enable adaptive antitumor immunity.

Panic disorder: A review of treatment options.

Panic disorder (PD) is a devastating illness, with numerous patients experiencing significant functional disability and many not achieving full remission with first-line pharmacologic and psychotherapeutic treatments. A search of PubMed, Cochrane Library, and PsychINFO databases was used to identify publications focused on evidence-based treatment of PD. Selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines are standard first-line pharmacologic treatments for PD. Many other antidepressants can be considered as alternatives to SSRIs, including serotonin-norepinephrine reuptake inhibitors, serotonin multimodal agents, tricyclic antidepressants, monoamine oxidase inhibitors, and mirtazapine. Certain anticonvulsants and antipsychotics may be helpful; however, the evidence base is limited. Buspirone, beta blockers, and hydroxyzine can be considered third-line agents. Currently, there is minimal data supporting the use of electroconvulsive therapy or repetitive transcranial magnetic stimulation (rTMS). There is very little evidence justifying the use of medical cannabis or over-the-counter supplements for PD, and these treatments have risk for adverse effects. Research strongly supports the use of cognitive-behavioral therapy (CBT) for PD. Many options exist for the management of PD. Treatments with the strongest evidence include SSRIs, other antidepressants, and CBT. Newer interventions approved for the treatment of depression, such as serotonin multimodal agents, esketamine, and rTMS, merit further investigation for use in PD.