Complimentary Mechanisms Research Articles

Single-dose and steady-state pharmacokinetics of clomipramine, yohimbine and clomipramine/yohimbine combination: A clinical drug-drug interaction study.

Clomipramine (CLOMI) has shown effectiveness in treating premature ejaculation but is linked to erectile dysfunction and reduced libido. Yohimbine (YOH), by contrast, is effective in treating erectile dysfunction and may improve libido. Combining CLOMI and YOH could potentially leverage the benefits of both drugs. This study aimed to investigate the interactions between these drugs and to evaluate their safety profile. A prospective, open-labelled, single-centre, pharmacokinetic (PK) drug-drug interaction study was performed in 15 healthy male subjects. Single-dose and steady-state PK were investigated using noncompartmental analysis after mono- and combination therapy of the 2 orally applied drugs. Plasma sampling was performed at baseline, 0.5 (YOH), 1, 1.5 (YOH), 2, 3, 4, 5, 6, 8, 12 and 24 h (CLOMI). Differences in the area under the curve after multiple dosing (MD) were determined using an equivalence boundary of 80-125%. The geometric mean ratio of the area under the curve up to 12 h for MD CLOMI (combination vs. monotherapy) was 112% (90% confidence interval: 104-120%), whereas for MD YOH this ratio was 137% (90% confidence interval: 112-168%). The study drugs were safe and well tolerated as mono- and combination therapy, with no major adverse events reported. A PK assessment of clomipramine and yohimbine indicated a clinically significant drug-drug interaction for MD YOH in combination with CLOMI. This might be explained by competitive, CLOMI-related inhibition of YOH metabolism, probably mediated by cytochrome P450 2D6. However, according to European Medicines Agency guidelines, the effect can be classified as interaction absent (<1,25 fold) or minor (>1.25-<2-fold). Given the complimentary mechanisms of action and the favourable safety profiles, the findings pave the way for future efficacy studies.

Antimicrobial activity of curcuma longa and mimosa pudica: a comprehensive review

The active ingredient in turmeric, Curcuma longa, and the traditional medicinal plant, Mimosa pudica, have both been the subject of intensive research due to their wide range of therapeutic applications. The antibacterial, anti-inflammatory, and wound-healing qualities of Mimosa pudica have long been employed, whereas curcumin is well known for its anti-inflammatory, antioxidant, and anticancer benefits. The pharmacological advantages of these two naturally occurring substances are summarized in this article, which also discusses their possible synergistic effects, modes of action, and therapeutic uses. Our goal in examining the complimentary qualities of Mimosa pudica and curcumin is to present a through analysis that bolsters their application in integrative medicine and offers ideas for further research. Curcumin is known for its powerful anti-inflammatory, antioxidant, and anticancer properties. Its therapeutic success is related to its capacity to affect numerous cellular pathways, such as inhibiting NF-KB and activating AREs. These pathways play a vital role in reducing inflammation and oxidative stress, which contribute to chronic diseases like cancer, cardiovascular disease, and neurodegeneration. Curcumin's antibacterial characteristics make it a promising medicinal agent with broad-spectrum applications. Mimosa pudica, often known as the "sensitive plant" for its quick responsiveness to physical stimuli, has a long history in traditional medicine, especially in Ayurvedic and folk treatments. It is used for wound healing,anti-inflammatory, antibacterial, and anti-ulcer properties. The pharmacological actions of Mimosa pudica are primarily due to its rich composition of bioactive compounds, including alkaloids,flavonoids, tannins, and phenolic acids.These compounds collectively contribute to the plant's ability to modulate immune responses, promote tissue regeneration, and inhibit microbial growth.Curcumin and Mimosa pudica have complimentary mechanisms that can lead to synergistic effects. Curcumin modulates intracellular signaling pathways and transcription factors, while Mimosa pudica's bioactive ingredients also interact with extracellular targets and microbial cell walls, indicating a multimodal approach to illness management.

Abstract 1425: Epigenetic modulation synergizes with a novel TCR β chain directed antibody-fusion molecule to suppress checkpoint-refractory tumors irrespective of MHC I status

Abstract Background: Epigenetic silencing of MHC-I, and poor T cell infiltration and function in the tumor microenvironment (TME) are prevalent in solid malignancies and associate with lack of response to immune checkpoint blockade (ICB). Novel combination therapies may overcome these barriers, thereby providing clinical benefit across solid tumors. STAR0602 is a first-in-class bifunctional therapeutic molecule, that simultaneously engages a nonclonal mode of T cell receptor (TCR) activation with costimulation to promote activation and expansion of αβ T cell subsets expressing distinct variable β (Vβ) TCR chains. Here, we examined the tumor-suppressive ability and mode of action of a murine surrogate of STAR0602 (mSTAR1302) in combination with the class I HDAC inhibitor Entinostat, an epigenetic modulator that enhances tumor immune cell recognition, in multiple tumor models, including ICB-refractory. Methods: mSTAR1302 and/or Entinostat were administered to mice bearing ICB-responsive breast EMT6 wild-type (wt) and ICB-refractory EMT6 β2-microglobulin (B2m)-deleted and CT26 (Kras G12Dmut colon) tumors. Anti-tumor efficacy, survival, and protective memory were monitored. Immune cell depletion studies were conducted. Comprehensive proteomic and immune profiling of tumor, tumor-draining lymph node (tdLN), and spleen cell populations was conducted. Antigen-specific IFNg T cell responses were evaluated by ELISpot. Results: Combination therapy demonstrated significant enhancement in tumor suppression and prolonged survival in CT26 (MHC-I+), EMT6 wt (MHC-I+) and EMT6 β2m-deleted (MHC-Inull) tumors relative to single agent therapy, as well as enhanced tumor-specific protective memory responses. Tumor suppression was independent of CD4+ T cell immunity and associated with sustained activation and expansion of Vβ13 CD8+ T cells. Conclusions: Ongoing mechanistic studies indicate combination therapy to elicit complimentary mechanisms of tumor suppression beyond CD8+ T cells. Ongoing proteomic and single-cell transcriptomic investigation of MHC-I competent and null tumors will provide a deeper insight into the mode of action of this combination therapy. Collectively, these data support the use of STAR0602 in combination with Entinostat for the treatment of solid malignancies, including for patients harboring ICB-refractory tumors devoid of MHC class I. Citation Format: Katherine E. Lothstein, Asma S. Khelifa, Masaya Miyamoto, Christine M. Minnar, Lisa Poppe, Nicholas Roller, Andrew Bayliffe, Ke Liu, Jacques Moisan, Madan Katragadda, Zhen Su, Jeffrey Schlom, Sofia R. Gameiro. Epigenetic modulation synergizes with a novel TCR β chain directed antibody-fusion molecule to suppress checkpoint-refractory tumors irrespective of MHC I status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1425.

Effect of specimen size and crystallographic orientation on the nano/microscale mechanical properties and deformation behavior of CrCoNi medium-entropy alloy

CrCoNi medium-entropy alloy (MEA) shows an exceptional combination of macroscale mechanical properties, however, knowledge of its mechanical properties at nano/microscale is lacking. In this paper, nano/microscale single crystal MEA pillars with orientation of 〈116〉, 〈014〉, 〈102〉 were fabricated using focused ion beam milling, and the compressive strength was determined with micropillar compression testing using a flat-end tip in an indentation machine. Results showed that the yield and flow strength of these MEA pillars were orientation-dependent, i.e., the lower the Schmid factor, the higher the strength. At the same time the strength of the pillars was dependent on the pillar’s size, the strength increasing as the pillar diameter reduced. From the results of the micropillar compression testing, the bulk critical resolved shear stress (CRSS) was determined to be 92 MPa, which is the highest value of the group of CrCoNi-based medium and high-entropy alloys. Analysis of transmission electron microscope images and large-scale molecular dynamics simulations revealed a group of complimentary deformation mechanisms, including dislocation slides, dislocation annihilation, dislocation-slip band interaction, formation of nanoscale stacking-faulting networks, and deformation nanotwins.

Degradation of pesticides using hybrid processes based on cavitation and photocatalysis: A review

AbstractThe production of pesticides and its subsequent consumption in agricultural fields have increased significantly also resulting in environmental concerns. The current review discusses the different aspects of two emerging techniques as cavitation and photocatalysis that can be effectively applied for the degradation of toxic pesticides. Governing mechanisms for the degradation have been presented followed by discussion on the effect of different parameters on the extent of degradation, also presenting guidelines for optimum selection. It has been also demonstrated that the obtained degradation can be synergistically intensified by using combined techniques with complimentary mechanisms. The discussion clearly revealed that cavitation and photocatalysis have great potential to degrade pesticides efficiently. Overall, it was demonstrated that combined technique under the optimized set of operating conditions is energy‐efficient, cost‐effective and promising technique for pesticide degradation.

Immunometabolic modulation by targeting UCP2 and IL-17A boost anti-tumor immunity against pancreatic cancer

Abstract Metabolic reprograming of cytotoxic effectors by tumor microenvironment (TME) is one of the key mechanisms by which TME impairs the success of cancer immunotherapy. Therapeutic strategies that mitigate the immunosuppressive TME and selectively enhance bioenergetic fitness of cytotoxic effectors may enhance benefits of immunotherapy, particularly in TME-abundant pancreatic cancer. IL-17 is a key TME cytokine engaged in a feed-forward loop promoting the immunosuppressive milieu that facilitates cancer progression. Mitochondrial uncoupling protein 2 (UCP2) acts as an inhibitor of T cell metabolic fitness and directly promotes tumorigenesis. Therefore, we hypothesized that targeting IL-17 and UCP2 could act additionally to enhance antitumor immune response and directly inhibit pancreatic cancer growth. UCP2 deficiency regulated bioenergetic metabolism and mTOR signaling in cytotoxic T cells to enhance IFN-γ production and anti-tumor immune responses. UCP2 inhibition increased anti-tumor immunity in PBMCs and tumors of patients with PDAC. The dual inhibition of IL-17 and UCP2 boosted antitumor immunity and suppressed tumorigenesis in tumor-bearing mice. Combination of UCP2 and IL-17 blockade may offer additional complimentary and cooperative mechanisms of antitumor immunity against pancreatic cancer. 1. Ministry of Science and Technology (MOST 108-2320-B-039-024-MY3) 2. China Medical University Hospital (DMR-110-186) 3. Chinese Medicine Research Center, China Medical University from the Featured Areas Research 4. Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (CMRC-CHM-2)

The emerging corporate turn in transitional justice

This essay reviews recent developments in transitional justice (TJ) scholarship that represent an emerging corporate turn in TJ. TJ has traditionally focused primarily on states and state-like actors, a movement that has gone hand in hand with the increasing standardization of TJ as a field of practice. Highlighting some of the limits to this model of TJ, scholars have since early 2000s been calling for the need to include economic actors in the TJ system. These four books that have all been published between 2020 and 2022 reflect a new momentum for this movement within TJ scholarship. They all highlight, in different ways, how complimentary innovative mechanisms and creative legal combinations have led and can lead to holding economic actors accountable for past abuse. Corporate accountability has been a blind spot in the increasingly standardized approach to TJ, but this emerging corporate turn represents a possibility to innovating the TJ standard to include “new” actors as subjects of accountability. All books, however, also show that this is far from a straightforward process as it involves transforming the deeply engrained and rigid international law and human rights system, which have usually protected economic elites and focused on states.

Compound Nanoparticle 5HMF-Prodrug Formulations for Optimized Anti-Sickling Therapy

BACKROUND: Sickle cell disease (SCD) pathology stems from deoxygenation-induced hemoglobin (HbS) polymerization; allosteric Hb adducts that increase oxyHbS target this mechanistic trigger. 5-hydroxymethylfurfural (5HMF) binds to Hb αVal1, reducing O2 affinity & sickling and protecting hypoxic SS mice (survival, organ injury). However, 5HMF did not advance beyond PhI/II trials, due to pharmacokinetic/dynamic (PK/PD) limitations. A related molecule (Voxelotor) was approved based on surrogate endpoints (Hb level and hemolytic markers), but without improved vaso-occlusive morbidities. We reformulated 5HMF, a potentially superior agent, to address translation limitations arising from disfavorable PK/PD. 5HMF PK/PD: RBCs from SCD patients were incubated with 5HMF (20% Hct, 37C, HMF: 0-5mM, 0-3 hrs). 5HMF-induced Hb modification was quantified by HPLC (Waters e2695XE, Swift WCX-PEEK); O2 dissociation curves (ODC) were measured in intact RBCs (HEMOX); pO2's at the point of sickling (POS) and point of unsickling (POU) were determined during controlled Hb O2 unloading/loading, respectively (LORRCA Oxygenscan). We observed a dose dependent increase in 5HMF modified Hb, that was maximal (~75%) at 1 hr and 5mM [5HMF], and that resulted in: (1) 35% increase in HbO2 affinity (ODC p50 pH 7.4; 31.1 ± 3.1 Torr vs 20.3 ± 1.5 Torr; 0 vs 5mM 5HMF), (2) 30% POS reduction (56.9 ± 10.1 vs 39.8 ± 11.6 Torr; 0 vs 5mM 5HMF) and (3) 45% POR reduction (38.3 ± 9.1 vs 21.1 ± 5.7 Torr; 0 vs 5mM 5HMF) (p < 0.05 for all, RMANOVA). PRODRUG NPs: We designed two complementary 5HMF (phospholipid and graphitic) prodrugs (Lipid Prodrug; LP and carbon dot (CD)) that were evaluated individually and as an integrated self-assembled compound nanoparticle (CompNP). Phospholipid LP 'pro-HMF' synthesis: 5HMF was treated with NaH and THF (RT, N2), then mixed with 1-Lysophosphatidylcholine (16:0 lysoPC) and 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) and N-hydroxy-succinimide (NHS) (anhydrous chloroform, RT, ON). Graphitic CD 'pro-HMF' synthesis: sucrose in water (0.2 μM, 18 MΩ cm) was heated (270C, 30m), followed by sonication (Q700, 20m: Amp, 1, on: 2s, off: 1s), filtering (0.2 μm) and dialysis (10 kD MWCO, 2d). Simple LNPs (comprised only of LP pro-5HMF) were prepared by combining 5HMF LP (5 mM) with L-α-Phosphatidylcholine (1:1) in chloroform/methanol, then drying (thin film) that was resuspended (PBS), vortexed and sonicated (amp 1, on 2s, off 1s, 10m) and dialyzed (2d, PBS). Compound Nanoparticle (CompNP) self-assembly: CDs in PBS were mixed with the above lipid film, followed by sonication and dialysis (as above) resulting 152±12nm (hydrodynamic size) particles with -34±6mV surface charge. All formulations were extensively characterized (physicochemical features and biodegradation mapping). NP PK/PD: We found that the prodrugs release 5HMF in RBCs through complimentary mechanisms (acutely from the LP shell by phospholipase A2 (PLA2) activity and slowly/sustained from the CD core by enzyme-triggered and peroxide-based degradation). Then, using human SS RBCs, we quantified time- and concentration-dependent in vitro PK/PD parameters (partially presented here): 3h data for the composite NP: Hb-5HMF modification (HPLC, 76.7±8.9% 5HMF modificatied HbS), HbO2 affinity (p50 15.4±3.8Torr) and antisickling potency (LORRCA deformability/elongation index rose by 0.28±3.8.07AU & point of sickling fell by 21.4±8.2Torr); imaging: ~75% reduced hypoxia-induced sickling (p<0.05, ANOVA, all). Notably, PK (5HMF modified SHb) for LNP & CompNP was sustained well beyond that for free 5HMF and was progressive beyond 24h (likely due to increased PLA2 and oxidizing milieu in SRBCs). PD (anti-sickling) for the CompNP formulation exhibited the greatest efficacy for (POS) (eg hypoxia tolerance) and POR (simulating O2 loading during pulmonary circulatory transit); as for our PK data, effect upon POS/POR progressed from 1h to 3h. NB: No produg/NP formulation resulted in hemolysis > 1-2%. SUMMARY: We developed first in class RBC-targeted, protected, biocompatible, self-assembled 5HMF prodrug nanoparticles for SCD therapy that are designed for eventual transdermal delivery. In vitro proof of concept data demonstrates: (1) improved potency, (2) targeted payload delivery and subsequent extended (>24h) prodrug release within RBCs, and (3) with prolonged pharmacodynamic (antisickling) effect.

Musical expertise shapes visual-melodic memory integration.

Music can act as a mnemonic device that can elicit multiple memories. How musical and non-musical information integrate into complex cross-modal memory representations has however rarely been investigated. Here, we studied the ability of human subjects to associate visual objects with melodies. Musical laypersons and professional musicians performed an associative inference task that tested the ability to form and memorize paired associations between objects and melodies ("direct trials") and to integrate these pairs into more complex representations where melodies are linked with two objects across trials ("indirect trials"). We further investigated whether and how musical expertise modulates these two processes. We analyzed accuracy and reaction times (RTs) of direct and indirect trials in both groups. We reasoned that the musical and cross-modal memory demands of musicianship might modulate performance in the task and might thus reveal mechanisms that underlie the association and integration of visual information with musical information. Although musicians showed a higher overall memory accuracy, non-musicians' accuracy was well above chance level in both trial types, thus indicating a significant ability to associate and integrate musical with visual information even in musically untrained subjects. However, non-musicians showed shorter RTs in indirect compared to direct trials, whereas the reverse pattern was found in musicians. Moreover, accuracy of direct and indirect trials correlated significantly in musicians but not in non-musicians. Consistent with previous accounts of visual associative memory, we interpret these findings as suggestive of at least two complimentary mechanisms that contribute to visual-melodic memory integration. (I) A default mechanism that mainly operates at encoding of complex visual-melodic associations and that works with surprising efficacy even in musically untrained subjects. (II) A retrieval-based mechanism that critically depends on an expert ability to maintain and discriminate visual-melodic associations across extended memory delays. Future studies may investigate how these mechanisms contribute to the everyday experience of music-evoked memories.

PB2012: A PHASE 2 MULTIARM STUDY OF MAGROLIMAB COMBINATIONS IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA

Background: Magrolimab is a first-in-class humanized monoclonal antibody that blocks the immune checkpoint CD47, a “do not eat me” signal, overexpressed on tumor cells. Binding of magrolimab to CD47 leads to phagocytosis of cancer cells in human solid tumors and hematologic malignancies. CD47 is highly expressed in multiple myeloma (MM), and overexpression contributes to MM pathogenesis. Blocking of CD47 induces immediate activation of macrophages and elimination of myeloma cells. Hence, a blockade of CD47 with magrolimab may have therapeutic benefit in patients with MM. Additionally, in vitro studies have shown synergy between magrolimab and daratumumab in MM cell line phagocytosis, and complimentary mechanisms suggest potential enhanced efficacy in other combinations. Aims: To evaluate the safety, tolerability, and efficacy of magrolimab in combination with commonly used myeloma therapies in patients with relapsed/refractory MM (RRMM). Methods: This phase 2 open-label multiarm study includes patients aged ≥18 years currently requiring treatment for RRMM; all participants must have received ≥3 previous lines of therapy for MM, including an immunomodulatory drug and a proteasome inhibitor. This study includes safety run-in and corresponding dose-expansion phases with the following combinations: magrolimab + daratumumab, magrolimab + pomalidomide + dexamethasone, magrolimab + carfilzomib + dexamethasone, and magrolimab + bortezomib + dexamethasone (Figure). Magrolimab + bortezomib + dexamethasone may be initiated based on the preliminary safety and efficacy of magrolimab + carfilzomib + dexamethasone, and, if initiated, only requires 1 prior line of therapy. The primary objectives of the safety run-in phase are to evaluate the safety and tolerability of magrolimab and determine the recommended phase 2 dose (RP2D), with incidence of dose-limiting toxicities (DLTs), adverse events, and laboratory abnormalities as the primary endpoint. The dose-expansion phase will evaluate efficacy, with objective response rate as the primary endpoint. Secondary endpoints include duration of response, progression-free survival, and overall survival. Minimal residual disease negativity, biomarker changes from baseline, immune cell signaling alterations, and the mutational profile of myeloma cells will also be explored. Magrolimab will be administered intravenously as an initial priming dose to mitigate on-target anemia, followed by a maintenance dose on days 8, 15, 22, and 29 during cycle 1 (35 days); days 1, 8, 15, and 22 during cycle 2 (28 days); and days 1 and 15 from cycle 3 (28 days) onward (maximum of 8 cycles in patients who previously received bortezomib). Daratumumab, pomalidomide, dexamethasone, carfilzomib, and bortezomib will be administered according to manufacturer’s prescribing information. Dose de-escalation may occur based on DLTs per protocol in the safety run-in cohorts; magrolimab doses will not be reduced in the dose-expansion cohorts. Patients will continue treatment until unacceptable toxicity, progressive disease, or patient/investigator choice to discontinue. Planned enrollment is approximately 153 patients, with up to 27 in each safety run-in cohort and 72 in the dose-expansion cohorts following completion of the safety run-ins. Results: Trial in progress. Image:Summary/Conclusion: Patient recruitment is ongoing. Clinical trial information: NCT04892446.

Impacts of barley root cortical aerenchyma on growth, physiology, yield components, and grain quality under field waterlogging conditions

Waterlogging is a major ecological threat that restricts crop growth and yield in high rainfall zones across the globe. Waterlogging tolerance is conferred by several complimentary mechanisms, with root cortical aerenchyma (RCA) formation being one of the major ones. In this study, three pairs of near-isogenic lines (NILs) of commercial barley varieties which we introgressed a quantitative trait locus (QTL) for RCA formation, and eight other genotypes contrasting in waterlogging tolerance were subjected to growth under waterlogged and control (non-waterlogged) conditions. Field trials were conducted in 2019 and 2020. The waterlogging treatment began at the two-three leaf stage and continued for two months. The water was subsequently drained, and the crops allowed to recover for final grain yield. Under waterlogging conditions, genotypes with RCA-QTL had significantly higher aerenchyma, white adventitious roots, leaf normalised difference vegetation index (NDVI), higher shoot biomass, tiller number, compared with genotypes without RCA-QTL. Across the three commercial varieties in waterlogged conditions, the average boost to yields from the introgression was 1.8 t/ha. The genotype YF225 showed a degree of waterlogging tolerance but had no RCA-QTL. This appears to be an alternate waterlogging tolerance mechanism that is not yet understood. Importantly, the addition of the RCA-QTL to three commercial varieties showed no significant negative effects on plant growth, yield, and grain quality attributes under control conditions. We conclude that the introgression of an RCA-QTL into other varieties is a promising breeding target for mitigating losses caused by waterlogging. • The formation of aerenchyma can significantly increase root survival and final grain yield under waterlogging conditions. • The addition of the QTL for aerenchyma formation showed no significant effects on plant growth under control conditions. • Pyramiding RCA-QTL with other tolerance mechanisms could create varieties with significantly better waterlogging tolerance.

The development of broad-spectrum antiviral medical countermeasures to treat viral hemorrhagic fevers caused by natural or weaponized virus infections.

The Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO-CBRND) began development of a broad-spectrum antiviral countermeasure against deliberate use of high-consequence viral hemorrhagic fevers (VHFs) in 2016. The effort featured comprehensive preclinical research, including laboratory testing and rapid advancement of lead molecules into nonhuman primate (NHP) models of Ebola virus disease (EVD). Remdesivir (GS-5734, Veklury, Gilead Sciences) was the first small molecule therapeutic to successfully emerge from this effort. Remdesivir is an inhibitor of RNA-dependent RNA polymerase, a viral enzyme that is essential for viral replication. Its robust potency and broad-spectrum antiviral activity against certain RNA viruses including Ebola virus and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) led to its clinical evaluation in randomized, controlled trials (RCTs) in human patients during the 2018 EVD outbreak in the Democratic Republic of the Congo (DRC) and the ongoing Coronavirus Disease 2019 (COVID-19) pandemic today. Remdesivir was recently approved by the US Food and Drug Administration (FDA) for the treatment of COVID-19 requiring hospitalization. Substantial gaps remain in improving the outcomes of acute viral infections for patients afflicted with both EVD and COVID-19, including how to increase therapeutic breadth and strategies for the prevention and treatment of severe disease. Combination therapy that joins therapeutics with complimentary mechanisms of action appear promising, both preclinically and in RCTs. Importantly, significant programmatic challenges endure pertaining to a clear drug and biological product development pathway for therapeutics targeting biodefense and emerging pathogens when human efficacy studies are not ethical or feasible. For example, remdesivir’s clinical development was facilitated by outbreaks of Ebola and SARS-CoV-2; as such, the development pathway employed for remdesivir is likely to be the exception rather than the rule.The current regulatory licensure pathway for therapeutics targeting rare, weaponizable VHF agents is likely to require use of FDA’s established Animal Rule (21 CFR 314.600–650 for drugs; 21 CFR 601.90–95 for biologics). The FDA may grant marketing approval based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drug is safe and likely to produce clinical benefit in humans. In practical terms, this is anticipated to include a series of rigorous, well-documented, animal challenge studies, to include aerosol challenge, combined with human safety data. While small clinical studies against naturally occurring, high-consequence pathogens are typically performed where possible, approval for the therapeutics currently under development against biodefense pathogens will likely require the Animal Rule pathway utilizing studies in NHPs. We review the development of remdesivir as illustrative of the effort that will be needed to field future therapeutics against highly lethal, infectious agents.

A Phase 2 Multi-Arm Study of Magrolimab Combinations in Patients with Relapsed/Refractory Multiple Myeloma

A Phase 2 Multi-Arm Study of Magrolimab Combinations in Patients with Relapsed/Refractory Multiple Myeloma

Who cares? Perception of loneliness in patients treated for coronary heart disease

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): University hospital of Copenhagen, Rigshospitalet research grant Background When patients are treated for Coronary heart disease (CHD), social support is known to be essential for them to adapt mentally and behaviourally to this critical event (1, 2). However, a substantial part of the CHD population experience loneliness in their everyday life, which places them in a vulnerable situation in the early rehabilitation period, as this period is characterized by an increased need for practical, informational and emotional support (3, 4) . Aim To provide insight into the nuances and complexity of loneliness, as well as the impact on health behaviour, in the early rehabilitation period following CHD treatment. Method This qualitative study has a philosophical hermeneutic approach. Patients classified as lonely during hospitalization in a social support questionnaire, were interviewed 8-12 weeks following discharge in either focus group (n = 7) or individual interview (n = 10) sessions. The empirical material was analysed using inductive content analysis. Results The analysis of the data produced three themes: i) A life in loneliness, ii) The changed, but unmet, need for social support, iii) Symmetry and asymmetry in relationships. Each theme contained of three sub-themes. A consistent finding was participants’ experience of shock related to the CHD event and the fundamental uncertainty to which it led, which increased the feeling of loneliness as an emotional pain. Participants experienced loneliness, not in relation to the lack of quantity of social network members, but in relation to the deficient quality of the relationships. In this regard, they described mutual and complimentary mechanisms that impacted how and from whom they could receive adequate social support. Participants described how dyadic relational mechanisms could either promote or limit who they could ask for social support as they experienced a need for reciprocity in the relationship, in order to receive practical and emotional support. Furthermore, a main finding was the participants experience on how loneliness affected their abilities to adapt to the critical event and manage health behavioural changes in the rehabilitation period. Conclusion In patients with coronary heart disease, loneliness is experienced as an emotional pain that negatively influenced the ability to adapt to the critical event and manage health behavioural changes. Participants assessed societal, dyadic and psychological mechanisms to impact their access to support from social network members. Perspective Insight into the patients’ experience of loneliness and the mechanisms mediating loneliness can enhance nursing care practice and inform future social support interventions.

SY4-1 Combination immunotherapy using anti-PD-1/PD-L1 plus anti-CTLA-4 antibodies

The combination of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies, two immune checkpoint inhibitors with distinct but complimentary mechanisms of action has shown clinical efficacy across different solid tumors. This concept also has been investigated in a number of randomized trials in patients with advanced NSCLC. In the Mystic trial patients with a PD-L1 expression =/> 25% were randomized to Durvalumab, Durvalumab plus Tremelimumab or platinum based chemotherapy. While clinical efficacy was observed for Durvalumab and the immunotherapy combination no significant improvement for one of the three primary endpoints was reported. In a retrospective analysis a correlation between blood based TMB and efficacy was shown favoring those patients with a high bTMB level. The BR.34 trial compared the combination of Durvalumab/Tremelimumab and chemotherapy with the immunotherapy combination in untreated advanced NSCLC and reported an improvement in PFS but no difference in OS. A prospective evaluation of the combination Nivolumab/Ipilimumab against chemotherapy in two cohorts of untreated patients with PD-L1 expressing or negative tumors was performed in the Checkmate 227 trial. Besides a significant prolongation of PFS in patients with high tissue based TMB also an improvement in the second coprimary endpoint (OS in patients with PD-L1 expressing tumors) was observed. Interestingly the activity of the immunotherapy combination was independent from the PD-L1 expression. In an approach to improve the early tumor control 2 cycles of chemotherapy were added to the combination of Nivolumab/Ipilimumab and were compared to chemotherapy in the Checkmate 9LA trial. OS as the primary endpoint as well as RR and PFS were significantly improved in favor of this combination independent from histology and PD-L1 expression level. The combination of Nivolumab and Ipilimumab with or without chemotherapy represents an active novel first-line treatment opportunity for NSCLC.

In vivo evaluation of laser-induced choroidal neovascularization in rats simultaneously using optical coherence tomography and photoacoustic microscopy

Determination of the precise location and the degree of the Choroidal neovascularization (CNV) lesion is essential for diagnosation Neovascular age-related macular degeneration (AMD) and evaluation the efficacy of treatment. Noninvasive imaging techniques with specific contrast for CNV evaluation are demanded. In this paper, two noninvasive imaging techniques, namely Optical coherence tomography (OCT) and Photoacoustic microscopy (PAM), are combined to provide specific detection of CNV for their complimentary contrast mechanisms. In vivo time-serial evaluation of Laser-induced CNV in rats is present at days 1, 3, 5, 7, 14, 21 after laser photocoagulation is applied to the rat fundus. Both OCT and PAM show that the CNV increases to its maximum at day 7 and decreases at day 14. Quantification of CNV area and CNV thickness is given. The dual-modal information of CNV is consistent with the histologic evaluation by hematoxylin and eosin (H&amp;E) staining.

The role of emotion covariation and psychological flexibility in coping with chronic physical pain: an integrative model

Objective This study focussed on the mutual role of emotion covariation and psychological flexibility in understanding the reciprocal effects of chronic pain and psychological distress. Design A longitudinal design was applied with a sample of 177 adults (mean age = 58.3, 57.1% women) suffering from chronic back/neck pain. Main outcome measures Assessments were conducted at three timepoints: pain and psychological distress upon referral to a pain clinic (T1); emotion covariation (the correlation between daily reports of positive and negative emotions) and psychological flexibility (self-reported ability to withstand unpleasant experiences while acting upon personal values) during the weeks before undergoing an intrusive procedure (T2); pain and psychological distress one day prior to the procedure (T3). Results T2 psychological flexibility and emotion covariation mediated the effect of T1 pain on T3 psychological distress. However, T2 psychological flexibility and emotion covariation did not mediate the effect of T1 psychological distress on T3 pain. Conclusion The findings highlight two complimentary mechanisms – emotion covariation and psychological flexibility – that mediate the relationship between pain and psychological distress for people with chronic back/neck pain. The findings inform future research on the effects of intervening on these mechanisms, which may lead to clinical interventions aimed at improving coping with pain.

An Integrated Approach Exploring the Synergistic Mechanism of Herbal Pairs in a Botanical Dietary Supplement: A Case Study of a Liver Protection Health Food.

Herbal pairs are used as a bridge between single herb and polyherbal formulas in Traditional Chinese Medicine (TCM) to provide rationale for complicated TCM formulas. The effectiveness and rationality of TCM herbal pairs have been widely applied as a strategy for dietary supplements. However, due to the complexity of the phytochemistry of individual and combinations of herbal materials, it is difficult to reveal their effective and synergistic mechanisms from a molecular or systematic point of view. In order to address this question, UPLC-Q-TOF/MS analysis and System Pharmacology tools were applied to explore the mechanism of action, using a White Peony (Paeoniae Radix Alba) and Licorice (Glycyrrhizae Radix et Rhizoma)-based dietary supplement. A total of sixteen chemical constituents of White Peony and Licorice were isolated and identified, which interact with 73 liver protection-related targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then performed along with network analysis. Results showed that the synergistic mechanism of the White Peony and Licorice herbal pair was associated with their coregulation of bile secretion and ABC transporter pathways. In addition, Licorice exhibits a specific response to drug and xenobiotic metabolism pathways, whereas White Peony responds to Toll-like receptor signaling, C-type lectin receptor signaling, IL-17 signaling, and TNF signaling pathways, resulting in the prevention of hepatocyte apoptosis and the reduction of immune and inflammation-mediated liver damage. These findings suggest that a White Peony and Licorice herbal pair supplement would have a liver-protecting benefit through complimentary and synergistic mechanisms. This approach provides a new path to explore herbal compatibility in dietary supplements derived from TCM theory.

The Neuroprotective Effects of Exercise: Maintaining a Healthy Brain Throughout Aging.

Physical activity plays an essential role in maintaining a healthy body, yet it also provides unique benefits for the vascular and cellular systems that sustain a healthy brain. While the benefit of exercise has been observed in humans of all ages, the availability of preclinical models has permitted systematic investigations into the mechanisms by which exercise supports and protects the brain. Over the past twenty-five years, rodent models have shown that increased physical activity elevates neurotrophic factors in the hippocampal and cortical areas, facilitating neurotransmission throughout the brain. Increased physical activity (such as by the voluntary use of a running wheel or regular, timed sessions on a treadmill) also promotes proliferation, maturation and survival of cells in the dentate gyrus, contributing to the process of adult hippocampal neurogenesis. In this way, rodent studies have tremendous value as they demonstrate that an ‘active lifestyle’ has the capacity to ameliorate a number of age–related changes in the brain, including the decline in adult neurogenesis. Moreover, these studies have shown that greater physical activity may protect the brain health into advanced age through a number of complimentary mechanisms: in addition to upregulating factors in pro-survival neurotrophic pathways and enhancing synaptic plasticity, increased physical activity promotes brain health by supporting the cerebrovasculature, sustaining the integrity of the blood–brain barrier, increasing glymphatic clearance and proteolytic degradation of amyloid beta species, and regulating microglia activation. Collectively, preclinical studies demonstrate that exercise initiates diverse and powerful neuroprotective pathways that may converge to promote continued brain health into old age. This review will draw on both seminal and current literature that highlights mechanisms by which exercise supports the functioning of the brain, and aids in its protection.

Bioresponsive peptide-polysaccharide nanogels — A versatile delivery system to augment the utility of bioactive cargo

We report the design, synthesis and efficacy of a new class of gel-like nano-carrier, or ‘nanogel’, prepared via templated electrostatic assembly of anionic hyaluronic acid (HA) polysaccharides with the cationic peptide amphiphile poly-L-lysine (PLL). Small molecules and proteins present during nanogel assembly become directly encapsulated within the carrier and are precisely released by tuning the nanogel HA:PLL ratio to control particle swelling. Remarkably, nanogels exhibit versatile and complimentary mechanisms of cargo delivery depending on the biologic context. For example, in mammalian cells, nanogels are rapidly internalized and escape the endosome to both deliver membrane-impermeable protein cargo into the cytoplasm and improve chemotherapeutic potency in drug resistant cancer cells. In bacteria, nanogels permeabilize microbial membranes to sensitize bacterial pathogens to the action of a loaded antibiotic. Thus, peptide nanogels represent a versatile, readily scalable and bio-responsive carrier capable of augmenting and enhancing the utility of a broad range of biomolecular cargoes.