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In preclinical tumor models, cyclic fasting and fasting-mimicking diets (FMDs) produce antitumor effects that become synergistic when combined with a wide range of standard anticancer treatments while protecting normal tissues from treatment-induced adverse events. More recently, results of phase 1/2 clinical trials showed that cyclic FMD is safe, feasible, and associated with positive metabolic and immunomodulatory effects in patients with different tumor types, thus paving the way for larger clinical trials to investigate FMD anticancer activity in different clinical contexts. Here, we review the tumor-cell-autonomous and immune-system-mediated mechanisms of fasting/FMD antitumor effects, and we critically discuss new metabolic interventions that could synergize with nutrient starvation to boost its anticancer activity and prevent or reverse tumor resistance while minimizing toxicity to patients. Finally, we highlight potential future applications of FMD approaches in combination with standard anticancer strategies as well as strategies to implement the design and conduction of clinical trials. Vernieri et al. review the molecular mechanisms of fasting/FMD antitumor effects, and they discuss new low-toxicity metabolic interventions that could synergize with nutrient starvation to boost its anticancer activity. Finally, they highlight potential clinical future applications of fasting/FMD approaches. [ABSTRACT FROM AUTHOR]

For the monitoring of chimeric antigen receptor (CAR) T-cell therapies, antigen-based CAR detection methods are usually applied. However, for each target-antigen, a separate detection system is required. Furthermore, when monitored CAR T-cells in the blood of patients treated with bispecific antibodies or T-cell engagers (bsAbs/BiTEs) recognize the same antigen, these methods produce false-positive results in clinical diagnostics. Anti-CAR-linker monoclonal antibodies (mAbs) targeting the linker sequence between the variable domains of the antigen binding CAR fragment promise a universal and unbiased CAR detection. To test this, we analyzed clinical specimens of all BCMA- and CD19-targeting CAR T-cell products currently approved for clinical use. We found a highly specific and sensitive CAR detection using anti-CAR-linker mAb in blood cells from patients treated with Ide-cel, Tisa-cel, Axi-cel, Brexu-cel, and Liso-cel. For Ide-cel and Tisa-cel, the sensitivity was significantly lower compared to that for antigen-based CAR detection assays. Strikingly, the specificity of anti-CAR linker mAb was not affected by the simultaneous presence of bispecific blinatumomab or teclistamab for Axi-cel, Brexu-cel, Liso-cel, or Ide-cel, respectively. Cilta-cel (containing a monomeric G4S-CAR linker) could not be detected by anti-CAR linker mAb. In conclusion, anti-CAR-linker mAbs are highly specific and useful for CAR T-cell monitoring but are not universally applicable. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer. Currently, standard treatment options for TNBC are limited to surgery, adjuvant chemotherapy, and radiotherapy. However, these treatment methods are associated with a higher risk of intrinsic or acquired recurrence. Antibody–drug conjugates (ADCs) have emerged as a useful and promising class of cancer therapeutics. ADCs, also known as "biochemical missiles", use a monoclonal antibody (mAb) to target tumor antigens and deliver a cytotoxic drug payload. Currently, several ADCs clinical studies are underway worldwide, including sacituzumab govitecan (SG), which was recently approved by the FDA for the treatment of TNBC. However, due to the fact that only a small portion of TNBC patients respond to ADC therapy and often develop resistance, growing evidence supports the use of ADCs in combination with other treatment strategies to treat TNBC. In this review, we described the current utilization of ADCs and discussed the prospects of ADC combination therapy for TNBC. [ABSTRACT FROM AUTHOR]

For the monitoring of chimeric antigen receptor (CAR) T-cell therapies, antigen-based CAR detection methods are usually applied. However, for each target-antigen, a separate detection system is required. Furthermore, when monitored CAR T-cells in the blood of patients treated with bispecific antibodies or T-cell engagers (bsAbs/BiTEs) recognize the same antigen, these methods produce false-positive results in clinical diagnostics. Anti-CAR-linker monoclonal antibodies (mAbs) targeting the linker sequence between the variable domains of the antigen binding CAR fragment promise a universal and unbiased CAR detection. To test this, we analyzed clinical specimens of all BCMA- and CD19-targeting CAR T-cell products currently approved for clinical use. We found a highly specific and sensitive CAR detection using anti-CAR-linker mAb in blood cells from patients treated with Ide-cel, Tisa-cel, Axi-cel, Brexu-cel, and Liso-cel. For Ide-cel and Tisa-cel, the sensitivity was significantly lower compared to that for antigen-based CAR detection assays. Strikingly, the specificity of anti-CAR linker mAb was not affected by the simultaneous presence of bispecific blinatumomab or teclistamab for Axi-cel, Brexu-cel, Liso-cel, or Ide-cel, respectively. Cilta-cel (containing a monomeric G4S-CAR linker) could not be detected by anti-CAR linker mAb. In conclusion, anti-CAR-linker mAbs are highly specific and useful for CAR T-cell monitoring but are not universally applicable.

Simple Summary: New forms of cancer treatment are needed to target resistant cancers or reduce severe side effects associated with some treatments. Cold Atmospheric Plasma (CAP) has demonstrated promising anti-cancer effects in several types of cancer, not only by direct application onto cancer cells, but also by indirect treatment using activation of liquids, such as water. Although the exact mechanism of action and underlying signaling pathways are yet to be discovered, CAP has the potential to be combined with traditional therapies, such as chemotherapy. This study investigates a new approach for treating brain cancer by combining a conventional cancer drug with plasma-activated water, which is produced by exposing water to plasma. The reactive chemical species in these solutions may help to kill the cancer cells and reduce the amount of drug that is needed. Not only were the combined treatments able to interfere with cell metabolism and increase cell death, but they also reduced the long-term cell proliferation. This study provides evidence that indirect CAP-derived approaches could be used in combination with chemotherapeutics for prospective treatment of brain cancer. The increase in cancer diagnoses and cancer deaths, severe side effects of existing treatments and resistance to traditional treatments have generated a need for new anticancer treatments. Glioblastoma multiforme (GBM) is the most common, malignant and aggressive brain cancer. Despite many innovations regarding GBM treatment, the final outcome is still very poor, making it necessary to develop new therapeutic approaches. Cold atmospheric plasma (CAP) as well as plasma-activated liquids (PAL) are being studied as new possible approaches against cancer. The anticancer activity of PAL such as "plasma-activated water" (PAW) is dependent on the reactive chemical compounds present in the solution. Possible combinatory effects with conventional therapies, such as chemotherapeutics, may expand the potential of PAL for cancer treatment. We aim to explore the therapeutic properties of a combination of PAW and topotecan (TPT), an antineoplastic agent with major cytotoxic effects during the S phase of the cell cycle, on a GBM cancer cell line (U-251mg). Combined treatments with PAW and TPT showed a reduction in the metabolic activity and cell mass, an increase in apoptotic cell death and a reduction in the long-term survival. Single applications of PAW+TPT treatments showed a cytotoxic effect in the short term and an antiproliferative effect in the long term, warranting future exploration of combining PAW with chemotherapeutic agents as new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Simple Summary: Uveal Melanoma (UM) is a rare and malignant intraocular tumor with dismal prognosis. Despite efficient control of the primary tumor by radiation or surgery, up to 50% of patients subsequently develop metastases, mainly in the liver. The treatment of UM metastases is challenging and the patient survival is very poor. Today, most of the tested treatments including inhibitors of protein kinase C (PKC), mitogen-activated protein kinase (MEK) or immune checkpoint blockade have been largely ineffective in patients with metastatic UM. Given that single-agent targeted therapies often activate compensatory mechanisms, combination strategies are relevant to evaluate in UM in preclinical and clinical settings. Our study confirms the previously described synergy of the dual inhibition of focal adhesion kinase (FAK) and MEK, and identifies a novel combination of drugs (FAK and PKC inhibitors) as a promising strategy for therapeutic intervention in metastatic UM. Uveal Melanoma (UM) is a rare and malignant intraocular tumor with dismal prognosis. Even if radiation or surgery permit an efficient control of the primary tumor, up to 50% of patients subsequently develop metastases, mainly in the liver. The treatment of UM metastases is challenging and the patient survival is very poor. The most recurrent event in UM is the activation of Gαq signaling induced by mutations in GNAQ/11. These mutations activate downstream effectors including protein kinase C (PKC) and mitogen-activated protein kinases (MAPK). Clinical trials with inhibitors of these targets have not demonstrated a survival benefit for patients with UM metastasis. Recently, it has been shown that GNAQ promotes YAP activation through the focal adhesion kinase (FAK). Pharmacological inhibition of MEK and FAK showed remarkable synergistic growth-inhibitory effects in UM both in vitro and in vivo. In this study, we have evaluated the synergy of the FAK inhibitor with a series of inhibitors targeting recognized UM deregulated pathways in a panel of cell lines. The combined inhibition of FAK and MEK or PKC had highly synergistic effects by reducing cell viability and inducing apoptosis. Furthermore, we demonstrated that these combinations exert a remarkable in vivo activity in UM patient-derived xenografts. Our study confirms the previously described synergy of the dual inhibition of FAK and MEK and identifies a novel combination of drugs (FAK and PKC inhibitors) as a promising strategy for therapeutic intervention in metastatic UM. [ABSTRACT FROM AUTHOR]

Current treatments for advanced hepatocellular carcinoma (HCC) have limited success in improving patients' quality of life and prolonging life expectancy. The clinical need for more efficient and safe therapies has contributed to the exploration of emerging strategies. Recently, there has been increased interest in oncolytic viruses (OVs) as a therapeutic modality for HCC. OVs undergo selective replication in cancerous tissues and kill tumor cells. Strikingly, pexastimogene devacirepvec (Pexa-Vec) was granted an orphan drug status in HCC by the U.S. Food and Drug Administration (FDA) in 2013. Meanwhile, dozens of OVs are being tested in HCC-directed clinical and preclinical trials. In this review, the pathogenesis and current therapies of HCC are outlined. Next, we summarize multiple OVs as single therapeutic agents for the treatment of HCC, which have demonstrated certain efficacy and low toxicity. Emerging carrier cell-, bioengineered cell mimetic- or nonbiological vehicle-mediated OV intravenous delivery systems in HCC therapy are described. In addition, we highlight the combination treatments between oncolytic virotherapy and other modalities. Finally, the clinical challenges and prospects of OV-based biotherapy are discussed, with the aim of continuing to develop a fascinating approach in HCC patients. [ABSTRACT FROM AUTHOR]

Novel oncology treatment strategies increasingly use medicines with distinct but complementary mechanisms of action in combination or in close sequence. Payers, when confronted with higher total cost of providing combination regimens involving multiple therapies and usually longer treatment durations, are reluctant to reimburse them, particularly when they perceive the expected incremental benefits from adding a new medicine (the add-on) to a currently reimbursed medicine (the backbone) not to represent value for money to the health system. Nevertheless, depending on how value is attributed to the add-on versus the backbone, a clinically effective medicine used as part of a regimen that increases treatment duration might be found "not cost-effective at zero price." This phenomenon, signaling a policy problem not a pricing issue, first needs to be better understood before a generalizable and transparent solution can be presented. This article sets out when this policy challenge arises and describes general principles that any proposed solution to the value attribution problem must satisfy. We develop a simplified conceptual framework and use this to address 2 topics. The first is to understand the origin of problems posed by the current approach for attributing value in incremental cost-effectiveness analyses of combination regimens. The second is to discuss 2 new approaches in the literature designed to address the challenge. We find that neither meets our criteria, meaning that further work is needed to resolve the issue. Finally, we briefly discuss the implications of relaxing the simplifying assumptions in our conceptual framework. • The root cause of the "not-cost-effective-at-zero-price" phenomenon in combination regimens is that most combinations have an increase in overall survival relative to treatment duration that is proportionately the same or less than that of the monotherapy. • A new approach to address the value attribution problem is required to overcome challenges faced by attributing combination value, while accepting the price of the backbone as given. • Any proposed value attribution approach should produce plausible and reasonable attribution of value regardless of whether the outcomes of the combination regimen are equal, smaller, or greater than the sum of its parts. [ABSTRACT FROM AUTHOR]

Often, the neck and décolletage are forgotten treatment areas, as most people concentrate on the face's appearance. Photodamage is the primary cause of ageing, leading to loss of skin elasticity and dyschromia. Fat loss and redistribution also occurs, which leads to the familiar pattern of ageing. Treatment of the neck and décolletage differ, as the later has minimal fat to act as a buttress for deeper treatments. Effective intervention relies on a good history, examination, management of expectations and sensible treatment choice. The options are extensive, and it is usually a combination of treatments that provide the best outcomes. [ABSTRACT FROM AUTHOR]

Objectives: Valuing and pricing the components of combination therapies can be difficult because of competition law issues, difficulty implementing different prices for the same product in alternative uses, and attributing value to each component of the combination. We propose a value attribution solution that allows all combination components to be priced according to their relative value in the combination., Methods: We developed a value attribution solution that is universal, symmetrical, and neutral to each combination constituent, regardless of whether it is the backbone or the add-on, and complete, meaning that it will always attribute the full value of the combination between the component parts. Moreover, it can be applied to any number of components in the combination (eg, triplets or quadruplets). We compared this solution with 2 other existing approaches., Results: The results of the proposed value attribution solution sit between those of the 2 other value attribution approaches as it combines elements of each. As the degree of additivity moves further away from one in either direction, then our general approach ratios also move, reflecting the impact of the incremental value., Conclusions: The proposed value attribution solution for combination therapies differs from 2 existing approaches by being universally applicable and allowing for symmetry when neutral to the constituent components of the combination. To optimally contribute to policy debate and practice, various requirements for its implementation need to be well understood, including how to overcome (1) partial information, (2) whether its assumptions can be relaxed, and (3) implementation issues., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Simple Summary: Chronic myeloid leukaemia (CML) is a type of blood cancer that is currently well-managed with drugs that target cancer-causing proteins. However, a significant proportion of CML patients do not respond to those drug treatments or relapse when they stop those drugs because the cancer cells in those patients stop relying on that protein and instead develop a new way to survive. Therefore, new treatment strategies may be necessary for those patients. In this review, we discuss those additional survival pathways and outline combination treatment strategies to increase responses and clinical outcomes, improving the lives of CML patients. Tyrosine kinase inhibitors (TKIs) have revolutionised the management of chronic myeloid leukaemia (CML), with the disease now having a five-year survival rate over 80%. The primary focus in the treatment of CML has been on improving the specificity and potency of TKIs to inhibit the activation of the BCR:ABL1 kinase and/or overcoming resistance driven by mutations in the BCR:ABL1 oncogene. However, this approach may be limited in a significant proportion of patients who develop TKI resistance despite the effective inhibition of BCR:ABL1. These patients may require novel therapeutic strategies that target both BCR:ABL1-dependent and BCR:ABL1-independent mechanisms of resistance. The combination treatment strategies that target alternative survival signalling, which may contribute towards BCR:ABL1-independent resistance, could be a successful strategy for eradicating residual leukaemic cells and consequently increasing the response rate in CML patients. [ABSTRACT FROM AUTHOR]

Oncolytic virotherapy (OVT) is a novel type of immunotherapy that induces anti-tumor responses through selective self-replication within cancer cells and oncolytic virus (OV)-mediated immunostimulation. Notably, talimogene laherparepvec (T-Vec) developed by the Amgen company in 2015, is the first FDA-approved OV product to be administered via intratumoral injection and has been the most successful OVT treatment. However, the systemic administration of OVs still faces huge challenges, including in vivo pre-existing neutralizing antibodies and poor targeting delivery efficacy. Recently, state-of-the-art progress has been made in the development of systemic delivery of OVs, which demonstrates a promising step toward broadening the scope of cancer immunotherapy and improving the clinical efficacy of OV delivery. Herein, this review describes the general characteristics of OVs, focusing on the action mechanisms of OVs as well as the advantages and disadvantages of OVT. The emerging multiple systemic administration approaches of OVs are summarized in the past five years. In addition, the combination treatments between OVT and traditional therapies (chemotherapy, thermotherapy, immunotherapy, and radiotherapy, etc.) are highlighted. Last but not least, the future prospects and challenges of OVT are also discussed, with the aim of facilitating medical researchers to extensively apply the OVT in the cancer therapy. [ABSTRACT FROM AUTHOR]

Facial rejuvenation treatments include any injectables or skin interventions that make the face appear younger. This article aims to improve treatment outcomes by assisting practitioners in selecting optimum treatment for patients depending on their individual needs, whether that is wrinkle reduction, long-term improvement of skin elasticity, reduction in pigmentation, tightening or all of these. This review includes clinical analyses of botulinum toxin, microneedling, hyaluronic acid dermal filler and intense pulsed light, including evidence and arguments for the benefits and limitations in each case. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) results in multiple pathophysiological processes, including blood–spinal cord barrier disruption, hemorrhage/ischemia, oxidative stress, neuroinflammation, scar formation, and demyelination. These responses eventually lead to severe tissue destruction and an inhibitory environment for neural regeneration.cAMP signaling is vital for neurite outgrowth and axonal guidance. Stimulating intracellular cAMP activity significantly promotes neuronal survival and axonal regrowth after SCI.However, neuronal cAMP levels in adult CNS are relatively low and will further decrease after injury. Targeting cAMP signaling has become a promising strategy for neural regeneration over the past two decades. Furthermore, studies have revealed that cAMP signaling is involved in the regulation of glial cell function in the microenvironment of SCI, including macrophages/microglia, reactive astrocytes, and oligodendrocytes. cAMP-elevating agents in the post-injury milieu increase the cAMP levels in both neurons and glial cells and facilitate injury repair through the interplay between neurons and glial cells and ultimately contribute to better morphological and functional outcomes. In recent years, combination treatments associated with cAMP signaling have been shown to exert synergistic effects on the recovery of SCI. Agents carried by nanoparticles exhibit increased water solubility and capacity to cross the blood–spinal cord barrier. Implanted bioscaffolds and injected hydrogels are potential carriers to release agents locally to avoid systemic side effects. Cell transplantation may provide permissive matrices to synergize with the cAMP-enhanced growth capacity of neurons. cAMP can also induce the oriented differentiation of transplanted neural stem/progenitor cells into neurons and increase the survival rate of cell grafts. Emerging progress focused on cAMP compartmentation provides researchers with new perspectives to understand the complexity of downstream signaling, which may facilitate the clinical translation of strategies targeting cAMP signaling for SCI repair. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) results in multiple pathophysiological processes, including blood–spinal cord barrier disruption, hemorrhage/ischemia, oxidative stress, neuroinflammation, scar formation, and demyelination. These responses eventually lead to severe tissue destruction and an inhibitory environment for neural regeneration.cAMP signaling is vital for neurite outgrowth and axonal guidance. Stimulating intracellular cAMP activity significantly promotes neuronal survival and axonal regrowth after SCI.However, neuronal cAMP levels in adult CNS are relatively low and will further decrease after injury. Targeting cAMP signaling has become a promising strategy for neural regeneration over the past two decades. Furthermore, studies have revealed that cAMP signaling is involved in the regulation of glial cell function in the microenvironment of SCI, including macrophages/microglia, reactive astrocytes, and oligodendrocytes. cAMP-elevating agents in the post-injury milieu increase the cAMP levels in both neurons and glial cells and facilitate injury repair through the interplay between neurons and glial cells and ultimately contribute to better morphological and functional outcomes. In recent years, combination treatments associated with cAMP signaling have been shown to exert synergistic effects on the recovery of SCI. Agents carried by nanoparticles exhibit increased water solubility and capacity to cross the blood–spinal cord barrier. Implanted bioscaffolds and injected hydrogels are potential carriers to release agents locally to avoid systemic side effects. Cell transplantation may provide permissive matrices to synergize with the cAMP-enhanced growth capacity of neurons. cAMP can also induce the oriented differentiation of transplanted neural stem/progenitor cells into neurons and increase the survival rate of cell grafts. Emerging progress focused on cAMP compartmentation provides researchers with new perspectives to understand the complexity of downstream signaling, which may facilitate the clinical translation of strategies targeting cAMP signaling for SCI repair.

The investigation was carried out to study the phenotypic reaction of seeds of CO 6 blackgram variety exposed to Gamma rays doses at 200 Gy, 300 Gy, 400 Gy and combination treatments with 200 Gy + 20 mM EMS, 200 Gy + 30 mM EMS, 300 Gy + 20 mM EMS, 300 Gy + 30 mM EMS, 400 Gy + 20 mM EMS, 400 Gy +30 mM EMS. It was observed that different mutation frequencies and span of mutation spectra were induced under the action of different concentrations of the applied mutagens in the M2 generation of blackgram. Five different types of chlorophyll mutants namely albino, xantha, chlorina, viridis, and maculata type were observed in the M2 populations and chlorophyll mutation frequency was calculated on a plant population basis. In Gamma treated population, the frequency of xantha mutants was high followed by chlorina whereas in combination treatments of Gamma ray + EMS, the highest frequency was observed in chlorina followed by xanthan mutants. Maculata type of chlorophyll mutant was observed in the treatment 200 Gy + 20 mM EMS. The combination treatments of Gamma ray + EMS were found to be more efficient than gamma rays alone in inducing chlorophyll mutations. The frequency of chlorophyll mutations (2.51%) was high in the combination treatment 400 Gy+ 30 mM EMS.

Abstract The recent years saw the advent of promising preclinical strategies that combat the devastating effects of a spinal cord injury (SCI) that are progressing towards clinical trials. However, individually, these treatments produce only modest levels of recovery in animal models of SCI that could hamper their implementation into therapeutic strategies in spinal cord injured humans. Combinational strategies have demonstrated greater beneficial outcomes than their individual components alone by addressing multiple aspects of SCI pathology. Clinical trial designs in the future will eventually also need to align with this notion. The scenario will become increasingly complex as this happens and conversations between basic researchers and clinicians are required to ensure accurate study designs and functional readouts.

Abstract Background Engineered inorganic nanoparticles (NPs) are essential components in the development of nanotechnologies. For applications in nanomedicine, particles need to be functionalized to ensure a good dispersibility in biological fluids. In many cases however, functionalization is not sufficient: the particles become either coated by a corona of serum proteins or precipitate out of the solvent. We show that by changing the coating of magnetic iron oxide NPs using poly-l-lysine (PLL) polymer the colloidal stability of the dispersion is improved in aqueous solutions including water, phosphate buffered saline (PBS), PBS with 10% fetal bovine serum (FBS) and cell culture medium, and the internalization of the NPs toward living mammalian cells is profoundly affected. Methods A multifunctional magnetic NP is designed to perform a near-infrared (NIR)-responsive remote control photothermal ablation for the treatment of breast cancer. In contrast to the previously reported studies of gold (Au) magnetic (Fe3O4) core–shell NPs, a Janus-like nanostructure is synthesized with Fe3O4 NPs decorated with Au resulting in an approximate size of 60 nm mean diameter. The surface of trisoctahedral Au–Fe3O4 NPs was coated with a positively charged polymer, PLL to deliver the NPs inside cells. The PLL–Au–Fe3O4 NPs were characterized by transmission electron microscopy (TEM), XRD, FT-IR and dynamic light scattering (DLS). The unique properties of both Au surface plasmon resonance and superparamagnetic moment result in a multimodal platform for use as a nanothermal ablator and also as a magnetic resonance imaging (MRI) contrast agent, respectively. Taking advantage of the photothermal therapy, PLL–Au–Fe3O4 NPs were incubated with BT-474 and MDA-MB-231 breast cancer cells, investigated for the cytotoxicity and intracellular uptake, and remotely triggered by a NIR laser of ~ 808 nm (1 W/cm2 for 10 min). Results The PLL coating increased the colloidal stability and robustness of Au–Fe3O4 NPs (PLL–Au–Fe3O4) in biological media including cell culture medium, PBS and PBS with 10% fetal bovine serum. It is revealed that no significant (

Meatballs are widely consumed ready-to-cook meat products due to their favourable tastes and flavours. They can be contaminated with several saprophyte and pathogenic bacteria due to their ingredients. The aim of this study was to investigate the effect of nisin and EDTA treatments in combination with modified atmosphere packaging (ambient air, 80:20:0/O2:CO2:N2 and 0.4:30:69.60/CO:CO2:N2 gas mixtures) on the survival of Salmonella Enteritidis in Turkish type meatballs stored at 4°C. Shelf-life of meatballs containing nisin and/or EDTA was extended compared to control. The efficient inhibition of Salmonella Enteritidis was enhanced with increasing concentrations of EDTA when applied together with nisin (1000 µg/g nisin and 50 mM EDTA). In conclusion, combined effects of nisin and EDTA incorporation with low level of CO packaging appears to be an important strategy to increase food safety; thus, this application can contribute to minimize the incidence of foodborne diseases originated from Salmonella spp.

Spinal cord injury (SCI) is a debilitating neurologic condition with tremendous socioeconomic impact on affected individuals and the health care system. The treatment of SCI principally includes surgical treatment and marginal pharmacologic and rehabilitation therapies targeting secondary events with minor clinical improvements. This unsuccessful result mainly reflects the complexity of SCI pathophysiology and the diverse biochemical and physiologic changes that occur in the injured spinal cord. Once the nervous system is injured, cascades of cellular and molecular events are triggered at varying times. Although the cascade of tissue reactions and cell injury develops over a period of days or weeks, the most extensive cell death in SCI occurs within hours of trauma. This situation suggests that early intervention is likely to be the most promising approach to rescue the cord from further and irreversible cell damage. Over the past decades, a wealth of research has been conducted in preclinical and clinical studies with the hope to find new therapeutic strategies. Researchers have identified several targets for the development of potential therapeutic interventions (e.g., neuroprotection, replacement of cells lost, removal of inhibitory molecules, regeneration, and rehabilitation strategies to induce neuroplasticity). Most of these treatments have passed preclinical and initial clinical evaluations but have failed to be strongly conclusive in the clinical setting. This narrative review provides an update of the many therapeutic interventions after SCI, with an emphasis on the underlying pathophysiologic mechanisms. [ABSTRACT FROM AUTHOR]

A field experiment was conducted to study the effect of mycorrhizal inoculation and seed priming with plant growth regulators on yield and yield components of lentil as factorial base on the randomized complete block design in four replications at the research farm of Gonbad Kavous University of Iran during 2013-2014. First factor included application of the mycorrhiza at three levels (control, inoculated soil using Glomus intraradices and Glomus mosseae) and seed priming at five levels (hydro-priming with distilled water, seed priming with GA3 100 ppm, priming with SA 100 ppm, priming with GA3 100 ppm + SA 100 ppm and non-primed seed as control was the second factor. On the basis of results, days to 50% flowering was significantly decreased with the application of mycorrhizal inoculation along whole treatments of priming except G. mosseae in combination with both hormones level. It was also observed that combined treatments of Glomus intraradical inoculation with hydro priming caused most early flowering, the number of pods in the plant, ratio of the filled pod, grain weight of lentil eventually higher yields and harvest index of lentil over other treatments. Thus mycorrhizal inoculation can help to minimize synthetic herbicides and develop biofertilizer in sustainable agriculture. [ABSTRACT FROM AUTHOR]

The recent years saw the advent of promising preclinical strategies that combat the devastating effects of a spinal cord injury (SCI) that are progressing towards clinical trials. However, individually, these treatments produce only modest levels of recovery in animal models of SCI that could hamper their implementation into therapeutic strategies in spinal cord injured humans. Combinational strategies have demonstrated greater beneficial outcomes than their individual components alone by addressing multiple aspects of SCI pathology. Clinical trial designs in the future will eventually also need to align with this notion. The scenario will become increasingly complex as this happens and conversations between basic researchers and clinicians are required to ensure accurate study designs and functional readouts. [ABSTRACT FROM AUTHOR]

Synthetic textile dyes have considerable molecular complexity, which makes these compounds highly stable and resistant to different types of treatments. Azo dyes represent the most commonly used group of dyes in textile industry. Azo dye contaminants in wastewater are recalcitrant, and microbiological treatments and oxidative processes have been widely studied to remedy this problem. These treatments can transform recalcitrant substances into substances with low toxicity. Therefore, microbiological and electrochemical/microbiological discoloration treatments were performed with the azo textile dye Acid Blue 161 in aqueous solution. The microbiological discoloration treatments were carried out using the filamentous fungus Aspergillus terreus and the yeast Saccharomyces cerevisiae. Discoloration treatments were performed with and without electrochemical pretreatment. The acute toxicity of the solutions was analyzed before and after the treatments using a vegetable test system (Lactuca sativa seeds). Adsorption treatment with white clay was performed to remove intermediate metabolites with high toxicological potential. At the end, all treatments tested were effective at discoloring the Acid Blue 161 dye solution. Moreover, the systems composed of the fungus A. terreus were more efficient and exhibited lower acute toxicity to L. sativa seeds at the end of 288 h of exposure to fungal biomass before and after adsorption treatment with white clay. [ABSTRACT FROM AUTHOR]

Objective: Inspired by the traditionally clinical application of herb pair Zhimu-Huangbo to treat diabetes, a combination of plant ingredients, timosaponin B2 (TB-2) and berberine (BBR), was evaluated for their anti-diabetic efficacy and cooperative mechanisms.Methods: The efficacy and pharmacokinetics of orally administered TB-2 (33.3 mg/kg/day), BBR (66.7 mg/kg/day), and TB-2+BBR (100 mg/kg/day) were evaluated in spontaneously non-obese diabetic Goto-Kakizaki (GK) rats, and metformin (200 mg/kg/day) was used as a positive control. The comparative exposure of the parent drugs, timosaponin A3 (TB-2 metabolite), and M1–M5 (BBR metabolites) was quantified in the portal vein plasma (before hepatic disposition), liver, and systemic plasma (after hepatic disposition) of normal rats on single and combination treatments. Cooperative mechanism of TB-2 and BBR on intestinal absorption and hepatic metabolism was investigated in Caco-2 cells and primary hepatocytes, respectively.Results: After a 6-week experiment, non-fasting and fasting blood glucose levels and oral glucose tolerance test results showed that TB-2+BBR treatments (100 mg/kg/day) displayed significantly anti-diabetic efficacy in GK rats, comparable to that on metformin treatments. However, no significant improvement was observed on TB-2 or BBR treatments alone. Compared to single treatments, combination treatments led to the increased circulating levels of BBR by 107% in GK rats. In normal rats, the hepatic exposure of BBR, timosaponin A3, and M1–M5 was several hundred folds higher than their circulating levels. Co-administration also improved the levels in the plasma and liver by 41–114% for BBR, 141–230% for TB-2, and 12–282% for M1–M5. In vitro, the interaction between TB-2 and BBR was mediated by intestinal absorption, rather than hepatic metabolism.Conclusion: Combining TB-2 and BBR enhanced the anti-diabetic efficacy by increasing the in vivo variety of effective substances, including the parent compounds and active metabolites, and improving the levels of those substances through intestinal absorption. This study is a new attempt to assess the effects of combined plant ingredients on diabetes by scientifically utilizing clinical experience of an herb pair.

A growing body of literature reports on the combined use of peptide receptor radionuclide therapy (PRRT) with other anti-tumuor therapies in order to anticipate synergistic effects with perhaps increased safety issues. Combination treatments to enhance PRRT outcome are based on improved tumour perfusion, upregulation of somatostatin receptors (SSTR), radiosensitization with DNA damaging agents or targeted therapies. Several Phase 1 or 2 trials are currently recruiting patients in combined regimens. The combination of PRRT with cytotoxic chemotherapy, capecitabine and temozolomide (CAPTEM), seems to become clinically useful especially in pancreatic neuroendocrine tumours (pNETs) with acceptable safety profile. Neoadjuvant PRRT prior to surgery, PRRT combinations of intravenous and intraarterial routes of application, combinations of PRRT with differently radiolabelled (alpha, beta, Auger) SSTR-targeting agonists and antagonists, inhibitors of immune checkpoints (ICIs), poly (ADP-ribose) polymerase-1 (PARP1i), tyrosine kinase (TKI), DNA-dependent protein kinase, ribonucleotide reductase or DNA methyltransferase (DMNT) are tested in currently ongoing clinical trials. The combination with [ 131 I]I-MIBG in rare NETs (such as paraganglioma, pheochromocytoma) and new non-SSTR-targeting radioligands are used in the personalization process of treatment. The present review will provide an overview of the current status of ongoing PRRT combination treatments., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Accumulating evidence shows that the anti-cancer potential of the immune response that can be activated by modulation of the immunogenicity of dying cancer cells. This regulated cell death process is called immunogenic cell death (ICD) and constitutes a new innovating anti-cancer strategy with immune-modulatory potential thanks to the release of damage-associated molecular patterns (DAMPs). Some conventional clinically-used chemotherapeutic drugs, as well as preclinically-investigated compounds of natural origins such as anthracyclines, microtubule-destabilizing agents, cardiac glycosides or hypericin derivatives, possess such an immune-stimulatory function by triggering ICD. Here, we discuss the effects of ICD inducers on the release of DAMPs and the activation of corresponding signaling pathways triggering immune recognition. We will discuss potential strategies allowing to overcome resistance mechanisms associated with this treatment approach as well as co-treatment strategies to overcome the immunosuppressive microenvironment. We will highlight the potential role of metronomic immune modulation as well as targeted delivery of ICD-inducing compounds with nanoparticles or liposomal formulations to improving the immunogenicity of ICD inducers aiming at long-term clinical benefits. [ABSTRACT FROM AUTHOR]

Objective: Inspired by the traditionally clinical application of herb pair Zhimu - Huangbo to treat diabetes, a combination of plant ingredients, timosaponin B2 (TB-2) and berberine (BBR), was evaluated for their anti-diabetic efficacy and cooperative mechanisms. Methods: The efficacy and pharmacokinetics of orally administered TB-2 (33.3 mg/kg/day), BBR (66.7 mg/kg/day), and TB-2+BBR (100 mg/kg/day) were evaluated in spontaneously non-obese diabetic Goto-Kakizaki (GK) rats, and metformin (200 mg/kg/day) was used as a positive control. The comparative exposure of the parent drugs, timosaponin A3 (TB-2 metabolite), and M1–M5 (BBR metabolites) was quantified in the portal vein plasma (before hepatic disposition), liver, and systemic plasma (after hepatic disposition) of normal rats on single and combination treatments. Cooperative mechanism of TB-2 and BBR on intestinal absorption and hepatic metabolism was investigated in Caco-2 cells and primary hepatocytes, respectively. Results: After a 6-week experiment, non-fasting and fasting blood glucose levels and oral glucose tolerance test results showed that TB-2+BBR treatments (100 mg/kg/day) displayed significantly anti-diabetic efficacy in GK rats, comparable to that on metformin treatments. However, no significant improvement was observed on TB-2 or BBR treatments alone. Compared to single treatments, combination treatments led to the increased circulating levels of BBR by 107% in GK rats. In normal rats, the hepatic exposure of BBR, timosaponin A3, and M1–M5 was several hundred folds higher than their circulating levels. Co-administration also improved the levels in the plasma and liver by 41–114% for BBR, 141–230% for TB-2, and 12–282% for M1–M5. In vitro , the interaction between TB-2 and BBR was mediated by intestinal absorption, rather than hepatic metabolism. Conclusion: Combining TB-2 and BBR enhanced the anti-diabetic efficacy by increasing the in vivo variety of effective substances, including the parent compounds and active metabolites, and improving the levels of those substances through intestinal absorption. This study is a new attempt to assess the effects of combined plant ingredients on diabetes by scientifically utilizing clinical experience of an herb pair. [ABSTRACT FROM AUTHOR]

Abstract The shelf life of quail carcass was examined after imposing separate and combined treatments of spraying with lactic acid (LA, 1% v/v), dipping in chitosan (CH, 1% w/v) and placing the carcass in modified atmosphere package (MAP, 65% CO 2 + 30% N 2 + 5% O 2) at 4 ± 1 °C for 20 days. The control group was packed under similar atmospheric condition but without any antimicrobial agents. Microbiological populations, physicochemical properties and sensory attributes (color, odor and overall appearance) were monitored at 4-day intervals. All antibacterial treatments effectively lowered microbial numbers, compared to the control during chilled storage. The total viable count, as an indicator of meat spoilage, on day 8 of the storage in treated samples was 0.5–3.4 log CFU/g which was lower than the control. The weakest and strongest effects were caused by LA and LA + CH + MAP treatments, respectively. Similar impact intensity occurred in other microbial tests during refrigerated storage. Binary combination treatments of MAP and chitosan showed synergistic effects on controlling microbial growth, and had no significant difference with LA + CH + MAP. Evaluations on days 4 and 8 showed that all treatments significantly controlled microbial growth, pH value, peroxide value and reactive substances of thiobarbituric acid in comparison with the control (P < 0.05). Interestingly, total volatile basic nitrogen (TVB-N) values were sharply increased in all treatments, whereas the CH + MAP and LA + CH + MAP retained the TVB-N content below 30 mg/100 g, which is an indication of meat freshness. The LA + CH + MAP caused the lowest TVB-N value on days 4, 12, 16 and 20 (P < 0.05). On day 8 of storage, the scores of sensory attributes for the control group were less than the minimum score of acceptance (i.e. 5 points). The results of this study indicate that the LA + CH + MAP treatment rendered the samples favorable in terms of overall appearance (>7) during the entire chilled storage. It is noteworthy that organoleptic evaluations correlated well with physicochemical and microbiological data. Based on microbiological data and the overall appearance results of the carcasses, the shelf lives of the control, LA, CH, MAP, LA + MAP, LA + CH, CH + MAP and LA + CH + MAP samples were 6, 7, 11, 12, 12, 15, 20 and 20 days, respectively, under chilled conditions. Highlights • Quail carcass was treated with lactic acid, chitosan and MAP. • Chitosan had a synergistic effect on the anti-microbial properties of LA + MAP. • Synergy among chitosan and MAP showed a high protective effect on chemical changes. • Lactic acid + chitosan + MAP develop a novel method for preserving quail meat. [ABSTRACT FROM AUTHOR]

Meatballs are widely consumed ready-to-cook meat products due to their favourable tastes and flavours. They can be contaminated with several saprophyte and pathogenic bacteria due to their ingredients. The aim of this study was to investigate the effect of nisin and EDTA treatments in combination with modified atmosphere packaging (ambient air, 80:20:0/O2:CO2:N2 and 0.4:30:69.60/CO:CO2:N2 gas mixtures) on the survival of Salmonella Enteritidis in Turkish type meatballs stored at 4°C. Shelf-life of meatballs containing nisin and/or EDTA was extended compared to control. The efficient inhibition of Salmonella Enteritidis was enhanced with increasing concentrations of EDTA when applied together with nisin (1000 µg/g nisin and 50 mM EDTA). In conclusion, combined effects of nisin and EDTA incorporation with low level of CO packaging appears to be an important strategy to increase food safety; thus, this application can contribute to minimize the incidence of foodborne diseases originated from Salmonella spp. [ABSTRACT FROM AUTHOR]

Choroid neovascularization(CNV)is more common in age-related macular degeneration, pathological myopia macular degeneration and central exudative chorioretinopathy and so on, and it is the leading cause of vision loss and even lost. In the treatment, laser photocoagulation, transpupillary thermotherapy(TTT)and photodynamic therapy(PDT)have been widely carried out in our country; And resistance to new blood vessels formation and pathological process of inflammatory reaction of drugs used in clinic were also significantly increased. In recent years, the new methods such as gene therapy, targeted treatment of CNV also get achievements, now we summarize the research status at home and abroad about the treatment of CNV.

Lung cancer is a heterogeneous disease consisting of multiple histological subtypes each driven by unique genetic alterations. Despite the development of targeted therapies that inhibit the oncogenic mutations driving a subset of lung cancer cases, there is a paucity of effective treatments for the majority of lung cancer patients and new strategies are urgently needed. In recent years, the concept of synthetic lethality has been established as an effective approach for discovering novel cancer-specific targets as well as a method to improve the efficacy of existing drugs which provide partial but insufficient benefits for patients. In this review, we discuss the concept of synthetic lethality, the various types of synthetic lethal interactions in the context of oncology and the approaches used to identify these interactions, including recent advances that have transformed the ability to discover novel synthetic lethal combinations on a global scale. Lastly, we describe the specific synthetic lethal interactions identified in lung cancer to date and explore the pharmacological challenges and considerations in translating these discoveries to the clinic. [ABSTRACT FROM AUTHOR]

Current treatments for advanced hepatocellular carcinoma (HCC) have limited success in improving patients' quality of life and prolonging life expectancy. The clinical need for more efficient and safe therapies has contributed to the exploration of emerging strategies. Recently, there has been increased interest in oncolytic viruses (OVs) as a therapeutic modality for HCC. OVs undergo selective replication in cancerous tissues and kill tumor cells. Strikingly, pexastimogene devacirepvec (Pexa-Vec) was granted an orphan drug status in HCC by the U.S. Food and Drug Administration (FDA) in 2013. Meanwhile, dozens of OVs are being tested in HCC-directed clinical and preclinical trials. In this review, the pathogenesis and current therapies of HCC are outlined. Next, we summarize multiple OVs as single therapeutic agents for the treatment of HCC, which have demonstrated certain efficacy and low toxicity. Emerging carrier cell-, bioengineered cell mimetic- or nonbiological vehicle-mediated OV intravenous delivery systems in HCC therapy are described. In addition, we highlight the combination treatments between oncolytic virotherapy and other modalities. Finally, the clinical challenges and prospects of OV-based biotherapy are discussed, with the aim of continuing to develop a fascinating approach in HCC patients., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article., (© 2022 Shenyang Pharmaceutical University. Published by Elsevier B.V.)

Serotonin reuptake inhibiting drugs (SRI) have been used in the treatment of paediatric obsessive-compulsive disorder over the past 30 years. We performed a systematic review and meta-analysis of the literature to discuss the place of and evidence for the use of SRI in paediatric OCD, based on 14 publications of methodologically sound, randomized and controlled studies. Both SRI and specific SRIs were examined and comparisons of SRI, placebo, cognitive behaviour therapy (CBT), combined (COMBO) treatments (SRI+CBT) made to investigate their relative efficacy. Using the Cochrane methodology, and as measures of effect size mean difference and Hedge’s g , SRIs proved to be superior to drug placebo, with a modest effect size. From direct comparisons of CBT and SRI treatments, we conclude that CBT has the superior efficacy. COMBO versus CBT shows that SRI treatment adds little to concomitant CBT, while COMBO shows favourable outcome versus SRI alone. In pre-trial partial treatment responders, those who failed a SRI had better outcome from adding CBT as compared to continuing a SRI. Those who failed CBT treatment did as well with continued CBT as with switching to a SRI. The studies of combinations and sequences of treatments need to be developed further. [ABSTRACT FROM AUTHOR]

Objective To examine the tolerability and antitumor activity of trebananib plus pegylated liposomal doxorubicin (PLD) or topotecan in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. Methods In this open-label phase 1b study, patients received trebananib 10 mg/kg or 15 mg/kg IV QW plus PLD 50 mg/m² (cohorts A1 and A3, respectively) or topotecan 4 mg/m² (cohorts B1 and B3, respectively). Endpoints were dose-limiting toxicity (DLT; primary); treatment-emergent adverse events (AEs), overall response rate, anti-trebananib antibodies, and pharmacokinetics (secondary). Results 103 patients were enrolled. One patient in A1 and B1 had DLTs. Across all cohorts, the most common AEs were nausea, fatigue, and peripheral edema. Across both trebananib plus PLD cohorts (A1/A3), grade 4 AEs were pulmonary embolism, disease progression, and anemia. Two patients had grade 5 intestinal perforation (n = 1) and sudden death (n = 1). Across both trebananib plus topotecan cohorts (B1/B3), grade 4 AEs were neutropenia, hypokalemia, decreased granulocyte count, chest pain, dyspnea, decreased neutrophil count, and pulmonary embolism. Two patients had grade 5 disease progression. One patient had grade 5 pleural effusion associated with progressive disease. Confirmed objective response rates were 36.0% (A1), 34.8% (A3), 16.7% (B1), and 0.0% (B3). Median progression-free survival duration (months) was 7.4 (A1), 7.1 (A3), 3.5 (B1), and 3.1 (B3), respectively. No drug--drug interactions were apparent. Conclusions Trebananib 10 mg/kg and 15 mg/kg IV QW plus PLD or topotecan appear to have acceptable toxicity profiles in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. Antitumor activity was evident across all cohorts. [ABSTRACT FROM AUTHOR]