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Background: It is well-established that specific herbal plants contain natural active ingredients that have demonstrated anti-cancer potential. Therefore, they are considered highly beneficial as a potential adjuvant, alternative or complementary agent in anti-cancer therapy. However, the low chemical stability and limited bioavailability of 3, 3′-Diindolylmethane (DIM), a plant-derived compound used in clinical settings, limit its therapeutic applications. To overcome this challenge, researchers have focused on developing innovative approaches to improve DIM's biological activity, such as utilizing nanoformulations. Here, we investigated the potential benefits of coating DIM nanoparticles (DIM-NPs) with PEG/chitosan in the treatment of breast cancer. Our results demonstrate the molecular mechanism underlying the activity of DIM-NPs, highlighting their potential as an effective therapeutic strategy for breast cancer treatment. Methods: DIM-PLGA-PEG/chitosan NPs were synthesised and characterised using dynamic light scattering (DLS) and evaluated the impact of these NPs on two breast cancer cell models. Results: DIM-NPs had an average diameter of 102.3 nm and a PDI of 0.182. When treated with DIM-NPs for 48 h, both MCF7 and MDA-MB-231 cells displayed cytotoxicity at a concentration of 6.25 g/mL compared to untreated cells. Furthermore, in MDA-MB-231 cells, treatment with 2.5 μg/mL of DIM-NPs resulted in a significant decrease in cell migration, propagation, and angiogenesis which was further enhanced at 10 μg/mL. In chicken embryos, treatment with 5 μg/mL of DIM-NPs on day 2 led to a significant reduction in angiogenesis. Furthermore, this treatment induced cell death through a regulatory pathway involving the upregulation of Bax and p53, as well as the downregulation of Bcl-2. These results were supported by in-silico analysis of DIM's binding affinity to key proteins involved in this pathway, namely Bax, Bcl-2, and p53. Conclusion: Our findings show that DIM-NPs induces apoptosis, inhibit migration, and reduce angiogenesis in breast cancer. However, further research using a preclinical cancer model may be necessary to determine the pharmacokinetics of DIM-NPs and ensure their safety and efficacy in vivo.

Liver cancer (LC) ranks as the second most prevalent cause of cancer-related deaths. Herbaceous plants are valuable sources of complementary, adjuvant, or alternative anti-tumor therapy as they contain natural active ingredients with anti-cancer potential. Although the clinical use of 3, 3′-Diindolylmethane (DIM) has been established, its low chemical stability and bioavailability, limits its therapeutic applications. Increasing effort has been undertaken to improve DIM’s biological activity including nanoformulations. Here, we evaluated the efficacy of DIM nanoparticles (DIM-NPs) coated with PEG/chitosan for the treatment of liver cancer and elucidated the underlying molecular mechanisms contributing to its anti-tumor activity. DIM-PLGA-PEG/chitosan NPs were synthesized and characterized using dynamic light scattering (DLS). The effect of newly synthesized DIM-NPs was evaluated in HepG-2 and HUH-7 hepatocarcinoma cells and compared to THLE-2 immortal normal liver cells and WI-38 (normal lung fibroblast cells). These cells were treated with different non-cytotoxic concentrations of DIM-NPs and MTT assay and other functional assays were performed. Compared to normal cells, DIM-NPs induced cytotoxicity in HepG-2 cells at 6.25 µg/mL after 48 h of treatment. Treatment of HepG-2 cells with the 50 % inhibitory concentration (IC50) 12.5 µg/mL of DIM-NPs inhibited cell migration (p

Cisplatin (CISP) ranks among the most used chemo-therapeutic agents with exceptional efficacy against testicular cancer among other diverse types of cancers. However, it has been associated with nephrotoxicity among other side effects. Pomegranate (PE) is an effective anti-inflammatory and antioxidant compound, protecting against several chemotherapy-linked toxicities. The use of PE are limited due to its low bioavailability and poor solubility. We investigated the potential of a novel nanoparticle (NP) encapsulating PE formulation to surmount its poor solubility, improve its bioavailability, and augment its protective efficacy against CISP-induced testicular toxicity in an Ehrlich solid carcinoma (ESC) mice model. All animals were randomly grouped into four treatment groups: 1) control, 2) tumor, 3) CISP, and 4) CISP + PE-NPs. The results obtained demonstrated that PE-NPs efficiently prevented testicular toxicity induced by CISP in ESC mice and enhanced its functions. PE-NPs effectively improved CISP-induced oxidative stress in testicular tissues by elevating the levels of antioxidants (GSH, SOD and CAT). Importantly, PE-NPs, also, substantially decreased testicular inflammation induced by CISP, via reducing the levels of IL-1β, TNF-α, and NF-kB. PE-NPs did not impede the CISP’s antitumor activity as shown by histological examination data and tumor weight. It is, therefore, conceivable that PE-NPs may serve as an adjuvant therapy to CISP in the treatment of cancer, to ameliorate the associated testicular toxicity and other unwanted effects without compromising the antitumor efficacy of CISP.

Introduction: Incidents of myocardial infarction and sudden cardiac arrest vary with time of the day, but the mechanism for this effect is not clear. We hypothesized that diurnal changes in the ability of cardiac mitochondria to control calcium homeostasis dictate vulnerability to cardiovascular events. Objectives: Here we investigate mitochondrial calcium dynamics, respiratory function, and reactive oxygen species (ROS) production in mouse heart during different phases of wake versus sleep periods. Methods: We assessed time-of-the-day dependence of calcium retention capacity of isolated heart mitochondria from young male C57BL6 mice. Rhythmicity of mitochondrial-dependent oxygen consumption, ROS production and transmembrane potential in homogenates were explored using the Oroboros O2k Station equipped with a fluorescence detection module. Changes in expression of essential clock and calcium dynamics genes/proteins were also determined at sleep versus wake time points. Results: Our results demonstrate that cardiac mitochondria exhibit higher calcium retention capacity and higher rates of calcium uptake during sleep period. This was associated with higher expression of clock gene Bmal1, lower expression of per2, greater expression of MICU1 gene (mitochondrial calcium uptake 1), and lower expression of the mitochondrial transition pore regulator gene cyclophilin D. Protein levels of mitochondrial calcium uniporter (MCU), MICU2, and sodium/calcium exchanger (NCLX) were also higher at sleep onset relative to wake period. While complex I and II-dependent oxygen utilization and transmembrane potential of cardiac mitochondria were lower during sleep, ROS production was increased presumably due to mitochondrial calcium sequestration. Conclusions: Taken together, our results indicate that retaining mitochondrial calcium in the heart during sleep dissipates membrane potential, slows respiratory activities, and increases ROS levels, which may contribute to increased vulnerability to cardiac stress during sleep-wake transition. This pronounced daily oscillations in mitochondrial functions pertaining to stress vulnerability may at least in part explain diurnal prevalence of cardiac pathologies.

Thermoelectric devices are currently being used in many industrial applications for cooling devices and generating electricity. This paper mainly focuses on using thermoelectric for cooling applications, specifically to cool down computer chips. In this study, experimental tests were conducted using a commercial thermoelectric module to investigate its capabilities for cooling hotspot in chip at different heat rates. Two experimental tests were conducted at steady-state condition to cool down hotspot with two different values of heat rates of 10.8 W and 12.1 W. The former heat rate represents the case of hotspot with low heat flux, whereas the latter represents the case of hotspot with high heat flux. The test results showed that at hotspot heat rate of 10.8 W, using thermoelectric current of 5.5 A has resulted in decreasing the hotspot temperature at open circuit condition (111.4 °C) by 54.0 °C. However, at hotspot heat rate of 12.1 W, using thermoelectric current of 6.0 A has resulted in decreasing the hotspot temperature at open circuit condition (138.8 °C) by 61.1 °C. The test results showed that the optimum electrical current at high heat rate was always greater than that at low heat rate. The results provided in this paper is a part of a research project that consists of a number of phases in which the ultimate goal is to develop a simple tool for designing self-cooling framework to cool down chip hotspot at different operating conditions with minimal increase in the overall power requirements. A case study for self-cooling framework is provided in this paper to demonstrate that the chip hotspot at a given operating condition can successfully be cooled at an acceptable temperature with no need for additional power requirements.

Objectives: Cisplatin (CISP) is an effective chemotherapy used in the treatment of various types of cancer, but it causes nephrotoxicity and other adverse effects. Thymoquinone (THY) is an effective anti-inflammatory and antioxidant compound, which might protects against many chemotherapies associated toxicities. However, THY applications are hindered by its poor solubility and low bioavailability. This study evaluated the efficacy of a novel nanoparticle (NP) encapsulting THY to overcome its poor solubility, enhance its bioavilability, efficacy for the protection against CISP-induced nephrotoxicity in an Ehrlich solid carcinoma (ESC) mice model. Methods: Four treatment groups were included: 1) control, 2) tumour, 3) CISP, and 4) CISP + NP THY. Results: The results showed that NP THY was effective in preventing CISP-induced kidney toxicity in ESC mice and improved its function and pathology. NP THY effectively ameliorated CISP-induced oxidative stress conditions in the kidney tissue via increasing the levels of antioxidants both non-enzymatic (GSH) and enzymatic (SOD and CAT). NP THY, also, significantly reduced CISP-induced kidney inflammation by reducing TNF-α, IL-1β, and NF-kB levels. NP THY didn’t hinder the antitumor activity of CISP as shown by tumour weight and histological examination data. Conclusions: In conclusion, NP THY could be an adjuvant therapy to CISP cancer treatment to prevent associated nephrotoxicity and other adverse effects without compromising CISP antitumor efficacy.

Alginate is a natural polysaccharide obtained from brown seaweeds and having advantageous health usefulness, was employed extensively in nutraceutical sectors and the pharmaceutical industry. This research was devoted for optimization of alginate extraction from different brown seaweeds. A Box-Behnken Design (BBD) was used for the optimization of alginate extraction from Padina pavonica by analyzing the influence of temperature (30, 40, and 50 °C), time (60, 120, and 180 min), and alkaline concentration (1 %, 2 %, and 3 %) on extraction yield and uronic acid content. The optimal conditions recorded to maximize the alginate yield and its uronic content were an alkali concentration of 2.5 % and a temperature of 39.95 °C for 102.5 min. The optimized parameters achieved from BBD were used to compare alginate extraction from P. pavonica, Sargassum cinereum, Turbinaria turbinata, and Dictyota dichotoma. FTIR, 1 H NMR, and HPLC were used to characterize the extracted alginate. The bioactivity of alginate against free radicals, breast cancer cells (MCF-7), some pathogenic microbes, and SARS-CoV-2 viruses was tested. Under the optimized conditions, alginate was extracted from P. pavonica at a rate of 21.13 ± 2.47 % DW, S. cinereum at 24.08 ± 0.33 % DW g/L, T. turbinata at 17.47 ± 0.26 % DW, and D. dichotoma at a rate of 19.57 ± 3.60 % DW. The alginate extracted from D. dichotoma showed the highest antioxidant, anticancer, and antiviral activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fucoidan is a sulfated polysaccharide that occurs naturally in the cell wall of brown seaweeds and has substantial biological efficacy. Optimizing the extraction of fucoidan from different brown seaweeds was the primary goal of this research. The optimization of fucoidan extraction was applied on the brown macroalga Turbinaria turbinata using a Box-Behnken Design (BBD) to inspect the impacts of different pH (3, 5, 7), temperature (70, 80, 90 °C) and extraction duration (60, 120, 180 min) on both the yield and sulfate content of fucoidan. The optimized parameters recorded to maximize the fucoidan yield and its sulfate content were a pH of 3.44 and a temperature of 82.26 °C for 60 min. The optimal conditions obtained from BBD were used for fucoidan extraction from T. turbinata, Sargassum cinereum, Padina pavonica, and Dictyota dichotoma. The highest average of fucoidan yield was derived from P. pavonica (40.76 ± 4.04 % DW). FTIR, 1 H NMR, and HPLC were used to characterize extracted fucoidan. The extracted fucoidan's Physical characteristics, biochemical composition, antioxidant potential, antitumor effect against breast cancer cells (MCF-7), and antimicrobial and anticoagulant activity were assessed. The extracted fucoidan from D. dichotoma, followed by that extracted from S. cinereum, which had the highest sulphate content, depicted the highest antioxidant, anticancer, and anticoagulant activities. Fucoidan has demonstrated a strong antimicrobial action against some pathogenic microorganisms; Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia, and Candida albicans. The anticoagulant properties of fucoidan from D. dichotoma were stronger than those of fucoidan from S. cinereum, T. turbinata, and P. pavonica due to its higher sulphate content. These findings could be used for various biomedical applications to improve the pharmaceutical industry., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pharmacokinetic (PK) models are increasingly submitted to the FDA to support first-in-human (FIH) dose selection of immune-oncology products. To examine whether a simple PK modeling (SPM) using clearance for scaling was acceptable for dose estimation, FIH (SPM) doses were computed and compared to doses that were safely administered to patients. We concluded that the SPM approach is acceptable in FIH dose estimation, but the variables should be carefully selected for CD3 constructs. For CD3 constructs, use of 60 kg BW h , a clearance exponent of 0.75, and a targeted plasma concentration based on relevant and/or sensitive activity assays was an acceptable approach for FIH dose selection; use of 0.85 as the scaling factor is questionable at this time as it resulted in a FIH dose that was too close to the AHD for one product (7%). Immune activating mAbs were not sensitive to changes in the clearance exponent (0.75-0.85) or body weight (60-70 kg). For PD-1/PD-L1 mAbs, using products' in vitro EC50 in the model resulted in suboptimal FIH doses and clinical data of closely related products informed FIH dose selection. PK models submitted by sponsors were diverse in methods, assumptions, and variables, and the resulting FIH doses were not always optimal., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Protein-rich seaweeds are regarded as having commercial significance due to their numerous industrial applications. The green seaweed Halimeda opuntia was used during this study for the preparation of bioplastic film. A thin bioplastic film with better physical and mechanical properties was produced by optimizing the ratio of polyvinyl alcohol (PVA) to seaweed biomass. The films obtained were characterized by their thickness, tensile strength, elongation at break, Young's modulus, moisture absorption resistance, and solubility. To evaluate the composition and potential for chemical reactions of the films, an FTIR spectroscopy examination was conducted. Whereas TG-DTA and AFM were performed on films with high mechanical properties. The bioplastic film produced when algae percent was tripled in PVA concentration had better physical and mechanical characteristics, and the bioplastic films degraded in the environment within a short time. According to the current study, seaweed might serve as an alternative source for the production of bioplastic, which could help minimize the use of non-biodegradable plastics., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Synthetic magnetic resonance imaging (MRI) offers a scanning paradigm where a fast multi-contrast sequence can be used to estimate underlying quantitative tissue parameter maps, which are then used to synthesize any desirable clinical contrast by retrospectively changing scan parameters in silico. Two benefits of this approach are the reduced exam time and the ability to generate arbitrary contrasts offline. However, synthetically generated contrasts are known to deviate from the contrast of experimental scans. The reason for contrast mismatch is the necessary exclusion of some unmodeled physical effects such as partial voluming, diffusion, flow, susceptibility, magnetization transfer, and more. The inclusion of these effects in signal encoding would improve the synthetic images, but would make the quantitative imaging protocol impractical due to long scan times. Therefore, in this work, we propose a novel deep learning approach that generates a multiplicative correction term to capture unmodeled effects and correct the synthetic contrast images to better match experimental contrasts for arbitrary scan parameters. The physics inspired deep learning model implicitly accounts for some unmodeled physical effects occurring during the scan. As a proof of principle, we validate our approach on synthesizing arbitrary inversion recovery fast spin-echo scans using a commercially available 2D multi-contrast sequence. We observe that the proposed correction visually and numerically reduces the mismatch with experimentally collected contrasts compared to conventional synthetic MRI. Finally, we show results of a preliminary reader study and find that the proposed method statistically significantly improves in contrast and SNR as compared to synthetic MR images., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Optimal management of acute ischemic stroke (AIS) secondary to intracranial atherosclerotic disease (ICAD) refractory to conventional mechanical thrombectomy remains unclear. We aimed to investigate the clinical outcome of patients undergoing rescue intracranial balloon angioplasty with or without stent placement in the setting of AIS in our institution., Methods: This is a retrospective single-arm observational study to evaluate the efficacy and safety of rescue balloon angioplasty with or without stent placement in emergent large vessel occlusion (EVLO) strokes with underlying ICAD. We included all patients undergoing such rescue intervention within 24 hours of AIS presentation with EVLO between 2017 and 2021. We further evaluated stent or vessel reocclusion., Results: Of 20 patients undergoing rescue intervention, 3 cases achieved adequate recanalization of artery using balloon angioplasty alone. Seventeen patients required stent placement. Fourteen (70%) procedures resulted in National Institutes of Health Stroke Scale improvement in postprocedure and upon discharge. Among 6 (30%) procedures with worsening neurological measures, 3 had reoccluded stent 24-48 hours after procedure, 2 had symptomatic hemorrhagic conversion, and 1 had perforator occlusion. Nine patients (45%) had favorable functional outcome (modified Rankin Scale ≤2) at discharge, unchanged or improved at 3-month follow-up. The median modified Rankin Scale score was 4 (Interquartile range: 1.75-4) at discharge, improving to 3 (Interquartile range: 0-4) at 3-month follow-up. Two patients (10%) died during hospital stay., Conclusions: Rescue angioplasty with or without stenting can lead to significant clinical improvement in patients with ICAD presenting with ELVO and refractory to thrombectomy; however, this procedure is associated with a high rate of morbidity in acute setting., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Although still recommended, using intravenous tissue plasminogen activator (IV-tPA) for large vessel occlusions (LVOs) has been questioned in the era of mechanical thrombectomy (MT). We sought to determine the impact of IV-tPA if used before MT., Methods: We used a single-institution, prospectively maintained stroke database from July 2017 through June 2019. All patients undergoing MT with or without IV-tPA treatment for LVO with pretreatment computed tomography angiography (CTA) head and neck were included. We compared the initial CTA images of clot location and morphology to the angiographic findings visualized on the first injection before mechanical intervention., Results: Eighty patients were included. About a third (33%) received IV-tPA before thrombectomy. Among patients receiving IV-tPA, significantly more, 29% versus 5.6% without IV-tPA, experienced distal clot migration or changes in morphology between first CTA acquisition and first angiographic run before thrombectomy (P = 0.006). On logistic regression IV-tPA was the only significant predictor of clot migration (P = 0.024). Of note, clot migration due to IV-tPA use was not associated with superior recanalization rates or outcomes in this analysis (P = 0.27). Original site clot resolution was noted in 8% (2/24) of patients who received IV-tPA; however, distal M4/5 embolic cutoffs were noted in both patients., Conclusions: IV-tPA administration for LVO has a low rate of primary recanalization with risk of distal embolic phenomenon often still requiring MT. No significant changes in patient outcomes were noted in this study due to clot migration. Larger studies will be necessary to determine if IV-tPA plus MT truly benefits entire clot removal versus MT alone., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A systematic analysis of new commercial investigational new drug applications (IND) submitted to the FDA's Office of Hematology and Oncology Products (OHOP) in the Center for Drug Evaluation and Research was conducted to quantify the most common reasons INDs for oncology indications go on clinical hold. In OHOP, less than 10% of INDs went on hold or were withdrawn within the 30-day safety review period. Of INDs that were placed on hold, deficiencies were mainly clinical, followed by concerns related to pharmaceutical quality and nonclinical development. INDs were also characterized based on phase of development, product type, sponsors' regulatory experience, and occurrence of a pre-IND meeting. INDs that were placed on hold were mostly for first-in-human trials or submitted by sponsors with limited regulatory experience. INDs that went on hold or were safe-to-proceed had pre-IND meetings with comparable rates but sponsors with substantial experience appeared to benefit more from pre-IND meetings compared to those with limited experience. The time interval between the pre-IND meeting and the IND submission was longer for INDs that went on hold. To obtain useful FDA feedback on product development, it is essential to provide focused questions and supporting information in pre-IND meeting packages., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Signal integration has a crucial role in the cell fate decision and dysregulation of the cellular signaling pathways is a primary characteristic of cancer. As a signal integrator, mTOR shows a complex dynamical behavior which determines the cell fate at different cellular processes levels, including cell cycle progression, cell survival, cell death, metabolic reprogramming, and aging. The dynamics of the complex responses to rapamycin in cancer cells have been attributed to its differential time-dependent inhibitory effects on mTORC1 and mTORC2, the two main complexes of mTOR. Two explanations were previously provided for this phenomenon: 1-Rapamycin does not inhibit mTORC2 directly, whereas it prevents mTORC2 formation by sequestering free mTOR protein (Le Chatelier's principle). 2-Components like Phosphatidic Acid (PA) further stabilize mTORC2 compared with mTORC1. To understand the mechanism by which rapamycin differentially inhibits the mTOR complexes in the cancer cells, we present a mathematical model of rapamycin mode of action based on the first explanation, i.e., Le Chatelier's principle. Translating the interactions among components of mTORC1 and mTORC2 into a mathematical model revealed the dynamics of rapamycin action in different doses and time-intervals of rapamycin treatment. This model shows that rapamycin has stronger effects on mTORC1 compared with mTORC2, simply due to its direct interaction with free mTOR and mTORC1, but not mTORC2, without the need to consider other components that might further stabilize mTORC2. Based on our results, even when mTORC2 is less stable compared with mTORC1, it can be less inhibited by rapamycin., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: In patients who have failed systemic anticoagulation therapy, various endovascular approaches may assist in emergent recanalization., Methods: We searched the PubMed database from January 1999 to August 2018 for studies that reported endovascular treatment modalities and associated clinical outcomes including recanalization, functional independence, mortality, or intracranial complications. Random-effect models were used to pool estimates across studies using R software., Results: Overall, 393 patients with cerebral venous thrombosis from 21 studies were included in the study. Transvenous local chemolysis treatment results were as follows: good outcome rate. 0.88 (95% confidence interval [CI], 0.80-0.93), mortality, 0.08 (95% CI, 0.04-0.16), postprocedural hemorrhagic rate, 0.11 (95% CI, 0.06-0.19), and complete recanalization rate, 0.59 (95% CI, 0.48-0.70). Transvenous mechanical thrombectomy results were as follows: good outcome rate, 0.66 (95% CI, 0.41-0.84), mortality, 0.09 (95% CI, 0.03-0.26), postprocedural hemorrhagic rate, 0.03 (95% CI, 0-0.16), and complete recanalization rate, 0.60 (95% CI, 0.35-0.80). Combined approach treatment results were as follows: good outcome rate, 0.80 (95% CI, 0.70-0.87), mortality, 0.10 (0.04-0.22), postprocedural hemorrhagic rate, 0.17 (95% CI, 0.10-0.27), and complete recanalization rate, 0.75 (95% CI, 0.64-0.84). Mixed approach to treatment results were as follows: good outcome rate, 0.61 (95% CI, 0.51-0.70), mortality, 0.23 (95% CI, 0.16-0.32), postprocedural hemorrhagic rate, 0.46 (95% CI, 0.33-0.59), and complete recanalization rate, 0.48 (95% CI, 0.37-0.58)., Conclusions: The combination approach treatment tended to have better outcomes, although this meta-analysis did not achieve statistical significance in all outcome parameters. Future studies are needed to establish the best treatment options with tailoring to specific clinical or angiographic scenarios., (Copyright © 2019 Elsevier Inc. All rights reserved.)

With a new generation of antibody-drug conjugates (ADCs) that contain a drug-to-antibody ratio (DAR) of 2, the question remains whether advances in technology have resulted in more stable and tumor-specific ADCs. These ADCs are anticipated to cause minimal systemic exposures of payloads, with toxicities being evident mainly at tumor sites. We examined 15 ADCs with PBD-dimer payloads and a DAR of 2 and concluded that dose limiting toxicities in animals and in humans are generally related to the payload. Both the payloads and the ADCs had pro-inflammatory responses causing severe toxicities that were at times of low incidence, making it difficult to assess a cause-effect relationship. Due to their low incidence, single-patient cohorts may not detect these events and such design may not be suitable in first-in-human (FIH) trials. The commonly proposed approach by the sponsors for FIH dose selection was 1/6 th highest non-severely toxic dose (HNSTD) in monkeys. This approach resulted in an acceptable balance of safety and efficient dose escalation in phase 1 trials, when using data from repeat-dose toxicology studies and body surface area for scaling. No sponsor used the data generated in rodents or proposed novel approaches for FIH dose selection., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We retrospectively examined the nonclinical studies conducted with 17 CD3 bispecific constructs in support of first-in-human (FIH) trials in oncology. We also collected information on the design of dose-finding clinical trials. Sponsors have used different MABEL approaches for FIH dose selection. To better assess acceptable approaches, FIH doses were computed from nonclinical studies and compared to the maximum tolerated doses (MTDs) in patients, to the highest human doses (HHDs) when an MTD was not identified, or to the recommended human dose (RHD) for blinatumomab. We concluded that approaches based on receptor occupancy, highest non-severely toxic dose, or no-observed adverse effect level are not acceptable for selecting the FIH dose as they resulted in doses close to or above the MTDs, HHDs, or the RHD. A FIH dose corresponding to 10%-30% pharmacologic activity (PA) was an acceptable approach. A FIH dose corresponding to 50% PA was acceptable for all except one construct, potentially due to its biological or structural properties. The most common toxicities in animals and patients were those related to cytokine release. Doses were better tolerated when intra-animal or intra-patient dose escalation was used. Exposing naïve patients to an MTD achieved with intra-patient dose escalation design may be unsafe., (Published by Elsevier Inc.)

As sub-therapeutic doses are not medically justifiable in patients with cancer, we retrospectively analyzed data on immune activating products, to assess approaches used in first-in-human (FIH) dose selection, the utility of animal toxicology studies in dose selection, and the length of time to complete FIH trials. The information collected included pharmacology and toxicology data, FIH dose and rationale, and dose-finding trial design. We used the principles of the Hill equation to estimate the FIH doses for antibodies and compared them to the doses administered to patients with acceptable toxicities. For approximately half the antibodies (44%) examined, the FIH doses were at least a hundred-fold lower than the doses safely administered to patients, indicating optimization of FIH dose selection and/or optimization of dose-finding trial design is needed to minimize patient exposure to sub-therapeutic doses. However, selection of the FIH dose for antibodies based on animal toxicology studies using 1/6th the HNSTD or 1/10th the NOAEL resulted in human doses that were unsafe for several antibodies examined. We also concluded that antibodies with Fc-modifications for increased effector function may be less tolerated, resulting in toxicities at lower doses than those without such modifications. There was insufficient information to evaluate CD3 bispecific products., (Published by Elsevier Inc.)

Glutamate decarboxylase (GAD) is an enzyme that converts l-glutamate to gamma amino butyric acid (GABA) that is a widely used drug to treat mental disorders like Alzheimer's disease. In this study for the first time point mutation was performed virtually in the active site of the E. coli GAD in order to increase thermal stability and catalytic activity of the enzyme. Energy minimization and addition of water box were performed using GROMACS 5.4.6 package. PoPMuSiC 2.1 web server was used to predict potential spots for point mutation and Modeller software was used to perform point mutation on three dimensional model. Molegro virtual docker software was used for cavity detection and stimulated docking study. Results indicate that performing mutation separately at positions 164, 302, 304, 393, 396, 398 and 410 increase binding affinity to substrate. The enzyme is predicted to be more thermo- stable in all 7 mutants based on ΔΔG value., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Antibody-drug conjugates (ADCs) are complex molecules composed of monoclonal antibodies conjugated to potent cytotoxic agents through chemical linkers. Because of this complexity, sponsors have used different approaches for the design of nonclinical studies to support the safety evaluation of ADCs and first-in-human (FIH) dose selection. We analyzed this data with the goal of describing the relationship between nonclinical study results and Phase 1 study outcomes. We summarized the following data from investigational new drug applications (INDs) for ADCs: plasma stability, animal study designs and toxicities, and algorithms used for FIH dose selection. Our review found that selecting a FIH dose that is 1/6th the highest non-severely toxic dose (HNSTD) in cynomolgus monkeys or 1/10th the STD10 in rodents scaled according to body surface area (BSA) generally resulted in the acceptable balance of safety and efficient dose-escalation in a Phase 1 trial. Other approaches may also be acceptable, e.g. 1/10th the HNSTD in monkeys using BSA or 1/10th the NOAEL in monkeys or rodents using body weight for scaling. While the animal data for the vc-MMAE platform yielded variable range of HNSTDs in cynomolgus monkeys, MTDs were in a narrow range in patients, suggesting that for ADCs sharing the same small molecule drug, linker and drug:antibody ratio, prior clinical data can inform the design of a Phase 1 clinical trial., (Published by Elsevier Inc.)

Heat shock proteins (Hsps) comprise several families of proteins expressed by a number of cell types following exposure to stressful environmental conditions that include heat, free radicals, toxins and ischemia, and are particularly involved in the recognition and renaturation of mis-folded proteins. Heat shock protein-27 (Hsp27) is a member of the small Hsp (sHsp) family with a molecular weight of approximately 27 KDa. In addition to its chaperoning functions, Hsp27 also appears to be involved in a diverse range of cellular functions, promoting cell survival through effects on the apoptotic pathway and plays important roles in cytoskeleton dynamics, cell differentiation and embryogenesis. Over the past two decades there has been an increasing interest in the relationship between Hsp27 and cardiovascular disease. Hsp27 is thought to exert an important role in the atherosclerotic process. Serum Hsp27 concentrations appear to be a biomarker of myocardial ischemia. In this review, we will focus on the possible protective and immuno-modulatory roles of Hsp27 in atherogenesis with special emphasis on their changes following acute coronary events and their potential as diagnostic and therapeutic targets., (Copyright © 2011 Elsevier B.V. All rights reserved.)