High Side Research Articles

Repurposing simvastatin in cancer treatment: an updated review on pharmacological and nanotechnological aspects.

Management of cancer is challenging due to non-targeting and high side effect issues. Drug repurposing is an innovative method for employing medications for other disease therapy in addition to their original use. Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor, is a lipid-lowering drug that is being studied for the treatment of cancer in various in vitro and in vivo models. Nanotechnology offers a potential platform for incorporation of drugs with enhanced pharmaceutical (solubility, release characteristics, stability, etc.) and biological characteristics (targeting, pharmacokinetic, pharmacodynamic). Utilizing a variety of resources such as Scopus, Springer, Web of Science, Elsevier, Bentham Science, Taylor & Francis, and PubMed, a thorough literature search was carried out by looking through electronic records published between 2003 and 2024. The keywords used were simvastatin, drug repurposing, anti-cancer simvastatin, pharmaceutical properties of simvastatin, simvastatin nanoformulations, simvastatin patents, clinical trials, etc. Numerous articles were looked for, filtered, checked out, and incorporated. Pure simvastatin has been researched as a repurposed medication for the treatment of cancer in several in vitro and in vivo models, such as carcinoma of the lung, colon, liver, prostate, breast, and skin. Simvastatin also incorporated into different nanocarriers (nanosuspensions, microparticles/nanoparticles, liposomes, and nanostructured lipid carriers) and showed improvement in solubility, bioavailability, drug loading, release kinetics, and targeting. Clinical trial and patent reports suggest potential of simvastatin in cancer therapy. The preclinical studies of pure simvastatin in in vitro and in vivo models showed the potential for its ability to inhibit cancer cell growth and further incorporation into nanoformulations strengthened its preclinical and pharmaceutical characteristics.

Numerical simulation of neutral gas dynamics in the W7-X sub-divertor

Abstract The present work presents a 2D and 3D modelling of the neutral gas flow in the sub-divertor region of the W7-X. The investigations have been done using the DIVGAS code. The complex 2D and 3D geometries of the divertor components in the sub-divertor region have been considered and the Standard and High-Iota magnetic configurations have been numerically simulated. The main objective of this study is to investigate the dynamics of neutral particles in the sub-divertor region including the effects due to geometry and toroidal and poloidal leakages located at the divertor targets and baffles on the achieved pumping efficiency. A sensitivity analysis has been performed for the effect of various geometrical and flow parameters on the pumping performance, under different plasma scenarios. The considered incoming fluxes in the sub-divertor range between 1020 to 1022 (H2/s). The main conclusions, which can be extracted from the present numerical analysis could be summarized as follows; a large fraction of incoming neutral particle flux i.e. > 70% on the low iota side and > 40% for the high iota side is leaked back to the main divertor region, while higher incoming neutral fluxes facilitate the increase of the pumped flux as well as the decrease of the outflux. It has been estimated that a small fraction ~3-4% of the incoming neutral flux is being pumped via the turbo-molecular pumps. The closure of the toroidal leakages as well as the inclination of the pumping gap panel by 9 o facilitate the increase of the pumped flux, but considering the all the engineering constraints, the latter option seems to be more easy to be implemented. For low incoming neutral fluxes (~1020 H2/s) and for the case of AEH section, free molecular flow conditions are estimated and therefore neutral-neutral collisions could be neglected. For higher incoming neutral fluxes and for both AEH and AEP sections neutral-neutral collisions play a significant role in the flow establishment. A comparison with available experimental measurements of the neutral pressure in the sub-divertor has been performed for Standard and High-Iota plasma discharges. The 3D DIVGAS simulations predict qualitatively the experimental data with relative deviation between 25 and 63%. All the above numerical findings will actively support the optimization of the W7-X particle exhaust, in view of the experimental campaign OP2.

Optimization of the N∥ Upshift in the DIII-D high field side lower hybrid current drive experiment

High field side lower hybrid current drive (LHCD) is one potential candidate for efficient non-inductive current drive in tokamak power plants, and the first test of this technology will occur on the DIII-D tokamak during the 2024 campaign. Previous LFS launch experiments operated in the multi-pass regime and relied on scrape-off layer interactions to close the spectral gap. In the DIII-D experiment, single-pass damping is achievable via an upshift in the parallel refractive index N∥ caused by mode converting twice (slow → fast → slow). This mode conversion affects the ray trajectories and can lead to enhanced N∥ upshift depending on where mode conversion occurs. Compared to multi-pass absorption experiments, the optimization of launched N∥ and plasma parameters can be counter-intuitive: increased density may increase efficiency and smaller N∥,launch tend to damp closer to the separatrix. A hard x-ray camera installed to measure the bremsstrahlung (50–250 keV) radiation from LHCD-generated fast electrons is capable of verifying the trends reporting in this paper through comparison to the ray-tracing/Fokker–Planck codes GENRAY/CQL3D.

Application and progress of new technologies and new materials in the treatment of pathological scar

Pathological scars (PS), including hypertrophic scars (HTS) and keloids, are a common complication of poor wound healing that significantly affects patients’ quality of life. Currently, there are several treatment options for PS, including surgery, drug therapy, radiation therapy, and biological therapy. However, these treatments still face major challenges such as low efficacy, high side effects, and a high risk of recurrence. Therefore, the search for safer and more effective treatments is particularly urgent. New materials often have less immune rejection, good histocompatibility, and can reduce secondary damage during treatment. New technology can also reduce the side effects of traditional treatments and the recurrence rate after treatment. Furthermore, derivative products of new materials and biomaterials can improve the therapeutic effect of new technologies on PS. Therefore, new technologies and innovative materials are considered better options for enhancing PS. This review concentrates on the use of two emerging technologies, microneedle (MN) and photodynamic therapy (PDT), and two novel materials, photosensitizers and exosomes (Exos), in the treatment of PS.

Functional outcome of mini external fixator in hand injuries: an observational study in a tertiary care hospital

Background: Metacarpal and phalangeal fractures are one of the common fractures of the upper extremity that account for about 10% of total body fractures. The distal parts of the hand are the most common parts to be injured. Outcome is also influenced by other factors such as patient’s age, occupation, socio economic status, systemic illness, surgeon’s skill and the patient’s compliance. Methods: We are doing an observational study with 40 patients included according to the inclusion and exclusion criteria for a period of six months with age group between 20 and 60 years. We use mini external fixators with JESS clamps, 1.8 mm threaded pins and k wires. Patients were followed up periodically with required radiograph for the union of the fracture. Results: Out 40 patients, most of the patients were between the age of 21 to 40 years with male preponderance, open fractures were more when compared with closed fractures. Functional outcome was excellent and good on the higher side which was analysed with Strickland score. Radiological union were also in greater side with 17.5% of them with delayed union. Conclusions: Simple surgical technique will minimize complications and an aggressive rehabilitation will ensure best result. In general, mini external fixator is a good treatment for management of fractures with best functional outcome.

A Bioinspired Copper-Pair Catalyst in Metal-Organic Frameworks for Molecular Dioxygen Activation and Aerobic Oxidative C-N Coupling.

Open Cu sites were loaded to the UiO-67 metal-organic framework (MOF) skeleton by introduction of flexible Cu-binding pyridylmethylamine (pyma) side chains to the biphenyldicarboxylate linkers. Distance between Cu centers in the MOF pores was tuned by controlling the density of metal-binding side chains. "Interacted" Cu-pair or "isolated" monomeric Cu sites were achieved with high and low (pyma)Cu side chain loading, respectively. Spectroscopic and theoretical studies indicate that "interacted" Cu pairs can effectively bind and activate molecular dioxygen to form Cu2O2 clusters, which showed high catalytic activity for aerobic oxidative C-N coupling. On the contrary, MOF catalyst bearing isolated monomeric Cu sites only showed modest catalytic activity. Enhancement in catalytic performance for the Cu-pair catalyst is attributed to the remote synergistic effect of the paired Cu site, which binds molecular dioxygen and cleaves the O═O bond in a collaborative manner. This work demonstrates that noncovalently interacted metal-pair sites can effectively activate inert small molecules and promote heterogeneous catalytic processes.

Contribution of different electron-capture mechanisms in the fragmentation of CO23+ upon slow ion-molecule collision

Abstract We present recoil ion - projectile ion coincidence study on the three body fragmentation of CO23+ ion into C+ + O+ + O+ fragments upon impact with
Ar3+, Ar6+ and Ar8+ projectile ions having the same velocity of vp = 0.49 a.u. (atomic units) using recoil ion momentum imaging technique. The kinetic energy
release (KER) distributions are presented and effect of different electron-capture associated processes such as pure capture, electron capture followed by target ionization or projectile auto-ionization is discussed based on the analysis of KER corresponding to different final projectile charge state post collision. As the capture stabilization increased the relative yields in the KER distribution are found to decrease in the high KER side for low charged Ar3+ impact, while an increase is observed for Ar6+ and Ar8+ impacts. We discussed the interplay between electron-capture, projectile auto-ionization and target ionization for the dominance of particular process. We also observed a low-KER feature around 15 eV which was observed for electron
and proton impacts, which was not yet observed for highly charged ion impacts

Fuelling of deuterium-tritium plasma by peripheral pellets in JET experiments

Abstract A baseline scenario of deuterium-tritium (D-T) plasma with peripheral high field side fuelling pellets has been produced on JET in order to mimic the situation in ITER. The isotope mix ratio is controlled in order to target the value of 50%-50% by combination of tritium gas puffing and deuterium pellet injection. Multiple factors controlling the fuelling efficiency of individual pellets are analysed with following findings: (1) prompt particle losses due to pellet triggered ELMs are detected, (2) plasmoids drift velocity might be smaller than predicted by simulation, (3) post-pellet particle loss is controlled by transient ELMy phases. Overall pellet particle flux normalised to heat flux is similar to that in previous pellet fuelling experiments on AUG and JET.

Improvement of Phased Antenna Array Applied in Focused Microwave Breast Hyperthermia.

Focused microwave breast hyperthermia (FMBH) employs a phased antenna array to perform beamforming that can focus microwave energy at targeted breast tumors. Selective heating of the tumor endows the hyperthermia treatment with high accuracy and low side effects. The effect of FMBH is highly dependent on the applied phased antenna array. This work investigates the effect of polarizations of antenna elements on the microwave-focusing results by simulations. We explore two kinds of antenna arrays with the same number of elements using different digital realistic human breast phantoms. The first array has all the elements' polarization in the vertical plane of the breast, while the second array has half of the elements' polarization in the vertical plane and the other half in the transverse plane, i.e., cross polarization. In total, 96 sets of different simulations are performed, and the results show that the second array leads to a better focusing effect in dense breasts than the first array. This work is very meaningful for the potential improvement of the antenna array for FMBH, which is of great significance for the future clinical applications of FMBH. The antenna array with cross polarization can also be applied in microwave imaging and sensing for biomedical applications.

High voltage electrochemical performance of single crystal LiNi0.8Co0.1Mn0.1O2 cathode materials with Al-Mg dual doping

Single-crystal materials have high structural stability and low parasitic side reactions for nickel-rich cathodes due to the absence of grain boundaries. However, they suffer challenges such as the complex synthesis route, sluggish lithium-ion diffusion kinetics, and microcracking evolution at high voltage. Bulk co-doping of Al and Mg into the precursors is first employed by a co-precipitation method, and then the Al-Mg dual-doped single-crystal NCM811 cathode is successfully prepared using a straightforward one-step method to reduce production cost. The cycle retention of the corresponding optimized single-crystal material is notably increased by 24.36% compared to the commercial counterpart at 1 C and a high voltage of 4.5 V. Additionally, the discharge capacity at 0.1 C is improved by 4.64% compared to the commercial one with an appropriate annealing temperature and lithium salt ratio. Some advances in the synthesis approach and modification strategy for developing commercial single-crystal material are provided.

Impact of Catalysis-Relevant Oxidation and Annealing Treatments on Nanostructured GaRh Alloys.

In this study, we examine the surface-derived electronic and chemical structures of nanostructured GaRh alloys as a model system for supported catalytically active liquid metal solutions (SCALMS), a novel catalyst candidate for dehydrogenation reactions that are important for the petrochemical and hydrogen energy industry. It is reported that under ambient conditions, SCALMS tends to form a gallium oxide shell, which can be removed by an activation treatment at elevated temperatures and hydrogen flow to enhance the catalytic reactivity. We prepared a 7 at. % Rh containing the GaRh sample and interrogated the evolution of the surface chemical and electronic structure by photoelectron spectroscopy (complemented by scanning electron microscopy) upon performing surface oxidation and (activation treatment mimicking) annealing treatments in ultrahigh vacuum conditions. The initially pronounced Rh 4d and Fermi level-derived states in the valence band spectra disappear upon oxidation (due to formation of a GaOx shell) but reemerge upon annealing, especially for temperatures of 600 °C and above, i.e., when the GaOx shell is efficiently being removed and the Ga matrix is expected to be liquid. At the same temperature, new spectroscopic features at both the high and low binding energy sides of the Rh 3d5/2 spectra are observed, which we attribute to new GaRh species with depleted and enriched Rh contents, respectively. A liquefied and GaOx-free surface is also expected for GaRh SCALMS at reaction conditions, and thus the revealed high-temperature properties of the GaRh alloy provide insights about respective catalysts at work.

Light‐Driven Multi‐Core/Shell Microdroplets as a Targeted Drug Delivery System

AbstractTargeted drug delivery system (DDS) holds exciting prospects in biomedical clinical research and drug development. However, it faces a significant challenge in achieving stable and safe targeted transportation without drug leakage while obtaining precise and controllable drug dosing with a high drug utilization rate and low side effects. Herein, an optical tweezers‐based light‐driven technique is proposed to transport and construct multi‐core/shell microdroplets enveloping drug carriers and target cells as a novel, safe, and efficient targeted DDS. Drug‐loaded microdroplets with core/shell structures are first fabricated by a new and simple injection extrusion method and then it is transported to a target cell by a dynamic optical trap with a low optical power, which ensures no drug leakage, exogenous materials, and biothermal damage are introduced during the drug delivery process. Next, precise drug dosing is realized by pushing the target cell into the drug‐loaded microdroplet under the actions of optical forces, which constructs a multi‐core/shell microdroplet structure with a pure drug environment to improve the drug action efficiency. Moreover, quantitative drug dosing with a high drug utilization rate can also achieved by controlling the sizes/number of drug droplets inside the microdroplets. This light‐driven DDS is of great interest to frontier medical research and disease treatment fields.

Poly-l-lysine modified MOF nanoparticles with pH/ROS sensitive CIP release and CUR triggered photodynamic therapy against drug-resistant bacterial infection

The challenge of drug resistance in bacteria caused by the over use of biotics is increasing during the therapy process, which has attracted great attentions of the clinicians and scientists around the world. Recently, photodynamic therapy (PDT) triggered by photosensitizer (PS) has become a promising treatment method because of its high efficacy, easy operation, and low side effect. Herein, the poly-l-lysine (PLL) modified metal-organic framework (MOF) nanoparticles, ZIF/PLL-CIP/CUR, were synthesized to allow both reactive oxygen species (ROS) responsive drug release and photodynamic effect for synergistic therapy against drug resistant bacterial infections. The PLL was modified on the shell of the zeolite imidazole framework (ZIF) by the ROS-responsive thioketal linker for controllable CIP release. CUR were encapsulated in ZIF as the photosensitizer for blue light mediated photodynamic effect to produce singlet oxygen (1O2) and superoxide anion radical (O2−) for efficient inhibition towards methicillin-resistant Staphylococcus aureus (MRSA). The charge conversion from negative charge (−4.6 mV) to positive charge (2.6 mV) was observed at pH 7.4 and pH 5.5, and 70.9 % CIP was found released at pH 5.5 in the presence of H2O2, which suggests the good biosafety at physiological pH and ROS-responsive drug release of the as-prepared nanoparticle in the bacterial microenvironment. The as-prepared nanoparticles could effectively kill MRSA and disrupt bacterial biofilm by combination of chemo- and photodynamic therapy. In mice model, the as-prepared nanoparticles exhibited excellent biosafety and synergistic effect with 98.81 % healing rate in treatment of MRSA infection, which is considered as a promising candidate in combating drug resistant bacterial infection.

Terpenoids and Triterpenoid Saponins: Future Treatment for Depression

Background: Depression is a crippling mental disorder with high prevalence around the world. The available clinical antidepressants have been effective to a certain degree, and different side effects have limited their application. This leads to the necessity of finding new treatments. Herbal plants are a substantial source of new drug leads. Terpenoid compounds are secondary metabolites representing an enormous category of structures found commonly in plants either as aglycones or attached to sugar moieties. These phytochemicals have been extensively studied for their various biological effects, and several have been investigated for potential therapeutic effects in the treatment of depression. Aim: This review aims to highlight the current knowledge on some terpenoids and triterpenoid saponins as potential antidepressant agents and their mechanisms of action, which may provide a better understanding of the potential antidepressant-like effects of these compounds and lead to the development of auspicious molecules with high efficiency and low side effects for depressive disorders treatment. Methods: A total of 16 plants containing antidepressant agents are reviewed in this article. 9 terpenoids and 23 triterpenoid saponins compounds have been reported to becommonly found in plant extracts, indicating potential use for depression. To enhance the datum of this review, the mechanism of action for the candidate compounds has been predicted via functional enrichment analysis. Results: The behavioural and neurochemical effects, as well as the possible mechanisms of action, have been evaluated in rodents by different predictive models of depression, mainly the acute stress models of the forced swimming test (FST) and tail suspension test (TST). The involved mechanisms include enhancing monoamine neurotransmitters, ameliorating brain-derived neurotrophic factor (BDNF), and normalizing the hypothalamus-pituitary-adrenal (HPA) axis. Preclinical studies support the potential antidepressant activities of some terpenoid compounds. Furthermore, the functional enrichment analysis has confirmed the previous pre-clinical findings and predicted further mechanisms of action, including cellular calcium ion homeostasis, cellular response to dopamine, endocrine resistance, and regulating GABAergic, serotonergic, glutamatergic, and dopaminergic synapse, bedsides neurotransmitter reuptake. Conclusion: Terpenoids and triterpenoid saponins provide a large number of natural compounds. This review sheds light on terpenoids and triterpenoid saponins compounds with antidepressantlike activity and their potential mechanisms of action. However, more evaluations are required to confirm that these compounds are promising for discovering antidepressant drugs.

Development of an efficient liposomal DOX delivery formulation for HCC therapy by targeting CK2α.

Hepatocellular carcinoma (HCC) is a digestive tract cancer with high mortality and poor prognosis, especially in China. Current chemotherapeutic drugs lead to poor prognosis, low efficacy, and high side effects due to weak targeting specificity and rapidly formed multidrug resistance (MDR). Based on the previous studies on the doxorubicin (DOX) formulation for cancer targeting therapy, we developed a novel DOX delivery formulation for the targeting chemotherapy of HCC and DOX resistant HCC. HCSP4 was previously screened and casein kinase 2α (CK2α) was predicted as its specific target on HCC cells in our lab. In the study, miR125a-5p was firstly predicted as an MDR inhibiting miRNA, and then CK2α was validated as the target of HCSP4 and miR125a-5p using CK2α-/-HepG2 cells. Based on the above, an HCC targeting and MDR inhibiting DOX delivery liposomal formulation, HCSP4/Lipo-DOX/miR125a-5p was synthesized and tested for its HCC therapeutic efficacy in vitro. The results showed that the liposomal DOX delivery formulation targeted to HCC cells specifically and sensitively, and presented the satisfied therapeutic efficacy for HCC, particularly for DOX resistant HCC. The potential therapeutic mechanism of the DOX delivery formulation was explored, and the formulation inhibited the expression of MDR-relevant genes including ATP-binding cassette subfamily B member 1 (ABCB1, also known as P-glycoprotein), ATP-binding cassette subfamily C member 5 (ABCC5), enhancer of zeste homolog 2 (EZH2), and ATPase Na+/K+ transporting subunit beta 1 (ATP1B1). Our study presents a novel targeting chemotherapeutic drug formulation for the therapy of HCC, especially for drug resistant HCC, although it is primarily and needs further study in vivo, but provided a new strategy for the development of novel anticancer drugs.

Stock status indicators for Cobia Rachycentron canadum in the Indian EEZ

Regional fisheries for cobia (Rachycentron canadum) along the Indian coast was assessedusing length-based stock status indicators. Drift gill nets-cum-hook and line fisheries landedbigger sized cobia as bycatch while multi-day mid-water trawls landed juveniles. Dominantsize groups in the landings along the west coast were 40–160 cm and 60-120 cm on theeast coast. Gear selectivity operating at regional levels because of the multi-gear fisheriesand fishing grounds of the Indian EEZ affects the size distribution of fish caught. Comparedto drift gill net-cum-hooks and line units targeting large pelagics in deeper waters, smallersize groups of cobia dominated as bycatch in trawls. The length at first capture (Lc50) beingsmaller than the estimated length at first maturity of about 60 cm, implementing size-basedoutput controls such as Minimum Legal Size (MLS) is suggested. The indicators for fishingmortality rates (Fmax) on the cobia stocks were on the higher side in certain locations only,but being part of the multi-species bycatch mix, there is little scope to introduce fishinggear regulations solely for cobia. However, the option of short-term, targeted spatiotemporaleffort regulations with fishers’ participation can be explored, based on the stockassessments made at local or regional levels. Keywords:Cobia, Fishery indicators, Length-based indicators,Minimum Legal Size, Rachycentron canadum, Stockstatus

The Relationship Between Teachers' Self-Efficacy and Attitudes Towards Supervision

Self-efficacy is the individual's self-awareness in reaching the intended performance and the individual judgment that he forms for his success. Supervision is the process of involving the teacher in the educational background in order to improve teaching and increase student achievement. The attitude towards the supervision, on the other hand, is a factor that will determine the reaction and subsequent behaviors of the supervisor towards the supervision process and the supervisor after the supervison. This study aims to reveal the relationship between teachers' self-efficacy and their attitudes toward supervision. In the study, a relational survey methodology was employed. 2316 teachers who worked in various districts around the province of Samsun made up the study's population, and 747 of those instructors were chosen at random to represent the sample. Data collection techniques included the "Teachers' Self-Efficacy Scale" created by Schmitz and Schwarzer (2000), translated into Turkish by Yılmaz, Köseoğlu, Gerçek, and Soran (2004) as well as the "Attitude Toward Supervision Scale" created by Gündüz, Elma, and Aslan (2018). The methods utilized to evaluate the data included arithmetic mean, t-test, one-way analysis of variance (ANOVA), Pearson product-moment correlation coefficient, and multiple linear regression. The analysis' findings showed that while instructors' views regarding monitoring were on the medium side, their levels of self-efficacy and efficacy were on the high side. Regarding education level and marital status, there was no discernible variation in teachers' self-efficacy; nevertheless, there was a discernible difference when it came to gender, professional seniority, branch, and school type. While there was no significant difference in teachers' views about supervision when branch type, school type, or marital status were taken into account, there was a significant difference when professional seniority, gender, and educational status were taken into account. The association between instructors' attitudes about supervision and their sense of self-efficacy was shown to be both favorable and substantial. Also, it was found that instructors' views toward monitoring were significantly predicted by their level of self-efficacy.

Takhar Province Morphometric Analysis for the Watershed Management of Amu River Basin in Afghanistan by using Remote Sensing & GIS

The drainage characteristics are basic information for watershed management. The morphometric analysis carried the slope contribution and linear, areal, and relief aspects. Takhar province is 390 km distance from Kabul. Located in the North Eastern Region of the country, the capital of Takhar province is Taluqan (Provincial Center). Badakhshan borders Takhar in the North-East, Panjsher in the south, Baghlan in the South-West and Kunduz in the North-West. Takhar is situated at an elevation of 801 meters above sea level and covers a land area of 12328.684 Km2, representing 1.91 percent of the total Afghan territory. The SRTM (90 m) Digital Elevation Model (DEM), in conjunction with SOI toposheets, have been used to delineate the hydrological boundaries of the study area. The finding variation in the elongated shapes of the basins is due to the guiding effect of faulting and thrusting in the basin. The Rc of the basins is fewer than 1. It indicates that the infiltration rate varies throughout the basin. The Bangi, Farkhar, and Warsaj districts have low Fs, which indicates that there is less side flow for a shorter duration and high main flow for a longer duration. High Fs in Khwaja ghar, Taluqan, and Darqad districts with high side flow for a longer duration and low main flow for a shorter duration causing high peak flows in a shorter duration.

Phase-locked dual-frequency microwave signal generation in an optoelectronic oscillator based on frequency mixing mutual injection

An approach to generating stable phase-locked dual-frequency microwave signals is proposed and demonstrated based on a dual-passband optoelectronic oscillator (OEO). Mode gain competition is broken by employing frequency mixing mutual injection effect to realize phase locking between the two oscillation signals, which is achieved by applying a single-tone signal to a microwave mixer in the OEO cavity. In addition, a dual-loop configuration with balanced detection is utilized to ensure a high side mode suppression ratio (SMSR) and ultra-low phase noise, which also enhances the stability of the generated signal. In the experiment, a phase-locked dual-frequency microwave signal at 9.9982 GHz and 10.1155 GHz is generated by using the proposed OEO scheme. The SMSR and the phase noise are 75 dB and –141 dBc/Hz@10 kHz, respectively. Additionally, the Allan deviation of the generated signal is in the order of 10−11@1 s. These parameters are superior to those based on the same OEO but with a single-loop configuration, which are also compared in detail.

Abstract 2071: Pre-clinical evidence for new camptothecin-peptide conjugates in the treatment of sortilin-positive colorectal cancers

Abstract Limitations in current colorectal cancer (CRC) camptothecin (CPT)-based chemotherapy have mostly been attributed to low specificity and high systemic cytotoxic side effects. More effective therapies are therefore required to improve the clinical outcomes of patients with CRC. Here, we developed a selective and better anticancer drug delivery of CPT through conjugation to a peptide (TH19P01) that targets Sortilin (SORT1), a scavenging receptor expressed in various tumor tissues including CRC. In the current study, significant SORT1 expression was detected in various CRC cell lines as well as that of irinotecan analogs efflux pump (ABCG2) in LoVo and HT-29 cells. Considering this result, we used our proprietary peptide conjugation SORT1 technology to increase cell targeting selectivity and cell delivery efficacy of CPT analogs. Different peptide drug conjugates (PDCs) were generated linking the TH19P01 peptide to SN-38 (an irinotecan metabolite) or exatecan, which are two main CPT derivatives used in recent antibody drug conjugates (ADC) as payloads. In vitro, immunonofluorescent microscopy revealed that TH19P01 was rapidly internalized (<15 min) in a SORT1-positive human HT-29 CRC cell model. These PDCs also inhibited CRC cell proliferation at low nM concentrations (3-90 nM). In vivo, weekly administration of TH2101 (SN-38) and of TH2303 (exatecan) conjugates were well tolerated as they had little impact on mouse body weight but caused a more potent growth inhibition of the HT-29 CRC tumor xenograft model than did either unconjugated irinotecan or exatecan molecules. In fact, at their maximum tolerable dose, irinotecan and exatecan caused a tumor growth inhibition of only 48% and 45% whereas TH2101 and TH2303 inhibited the growth of HT-29 tumors by 83% and 91%, respectively. These results provide strong pre-clinical evidence for the future development of novel CPT PDCs therapeutics with targeting of SORT1-positive CRC cells. Citation Format: Sanjoy Das, Jean-Christophe Currie, Michel Demeule, Cyndia Charfi, Alain Zgheib, Amit Nayyar, Anh Minh Thao Nguyen, Bogdan Alexandru Danalache, Richard Beliveau, Christian Marsolais, Borhane Annabi. Pre-clinical evidence for new camptothecin-peptide conjugates in the treatment of sortilin-positive colorectal cancers [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 2071.