High Side Research Articles

Factors Associated with Readmission within 30 Days of Hospital Discharge of Psychiatric Patients: Case-Control Study

Background: Readmission, defined as any admission after discharge from the same hospital, has negative implications for health outcomes. This study aims to identify the sociodemographic and clinical factors associated with hospital readmission among psychiatric patients. Methodology: This case-control study analyzed 202 clinical records of patients admitted to a psychiatric hospital between 2019–2021. The sample was selected using simple random sampling. Qualitative variables were presented using frequencies, percentages, and chi-square tests for association. Quantitative variables were described using central tendency measures and dispersion of data, investigated with the Kolmogorov-Smirnov test, Student's t-test or Wilcoxon test as appropriate. Regression analysis was conducted to determine factors linked to readmission. p < 0.05 was considered. Results: Women accounted for a higher readmission rate (59%). Patients diagnosed with schizophrenia had a higher readmission rate (63%), experienced longer transfer times to the hospital during readmissions, and had shorter hospital stays. Polypharmacy and pharmacological interactions were associated with readmission. Olanzapine treatment was identified as a risk factor for readmission (ExpB = 3.203, 95% CI 1.405–7.306, p = 0.006). Conclusions: The findings suggest avoiding polypharmacy and medications with high side effect profiles to reduce readmissions. This study offers valuable insights for clinical decision-making from admission to discharge planning, aiming to enhance the quality of care.

Three-dimensional shape of natural riblets in the white shark: relationship between the denticle morphology and swimming speed of sharks.

The ridges of the dermal denticles of migratory sharks have inspired riblets to reduce the frictional drag of a fluid. In particular, the dermal denticles of white sharks (Carcharodon carcharias) are characterized by a high middle ridge and low side ridges. The detailed morphology of their denticles and their variation along the body, however, have never been investigated. Moreover, the hydrodynamic function of high-low combinations of ridges is unknown. In this article, the ridge spacings and heights of the white shark denticles were three-dimensionally quantified using microfocus X-ray computed tomography. Then, the swimming speed at which the ridges would reduce drag was hydrodynamically calculated with a flat plate body model and previous riblet data. High ridges with a large spacing were found to effectively reduce drag at a migration speed of 2.3 m s-1, while adjacent high and low ridges with a small spacing reduced drag at a burst hunting speed of 5.1 m s-1. Moreover, the above hydrodynamic calculation method was also applied to the shortfin mako shark and an extinct giant shark (called megalodon) with known ridge spacings, resulting in the estimated hunting speeds of 10.5 m s-1and 5.9 m s-1, respectively.

Electron cyclotron current start-up using a retarding electric field in the QUEST spherical tokamak

Abstract The plasma current start-up experiment is conducted through electron cyclotron (EC) heating in the QUEST spherical tokamak. During the EC heating, the application of a toroidal electric field in the opposite direction to the plasma current effectively inhibits the growth of energetic electrons. Observations show rapid increases in plasma current and hard X-ray count immediately following the cancellation of the retarding electric field. When a compact tokamak configuration maintains equilibrium on the high field side, along with the retarding field, it leads to effective bulk electron heating. This heating achieved an electron temperature of T e ≈ 1 keV at electron density n e > 1.0 × 1018 m-3. Ray tracing of the EC wave verifies that more power absorption into plasma through a single-pass occurs around the second resonance layer with higher values of electron density and temperature.

A tumor microenvironment-activated near-infrared photosensitizer enable efficient photodynamic therapy of breast tumor

As an emerging cancer therapy with high selectivity, minimally invasive and low side effects, photodynamic therapy (PDT) has become the focus of current researches. The breast cancer is a malignant tumor with the highest incidence in women. Thus, it is valuable for improving its treatment efficiency to construct efficient photosensitizer. To this end, we engineered a high stable near-infrared photosensitizer NPA-NH2 based on “step by step” strategy. By modifying the optically tunable amino group of NPA-NH2, a peroxynitrite (ONOO-) activated NPA-ONOO- theranostic agent with a new trifluoromethylsulfonamide recognization site was designed and synthesized. It possessed a good singlet oxygen-generating ability after ONOO- activation under 660 nm light, and a high sensitivity (limit of detection: 0.038 μM) and selectivity respond toward ONOO- in buffer solution. The theranostic agent was able to specially monitor ONOO- in tumor cells. Furthermore, we have succeeded in applying the NPA-ONOO- for efficient and precise photodynamic therapy of breast cancer cells and tumors in vivo. This work provides a new way for the design of highly stable photosensitizers and a reliable tool for effective treatment of breast tumors.

Safety assessment of Yasmin: Real-world adverse event analysis using the FAERS database

BackgroundThis study aimed to elucidate the scope and nature of adverse events (AEs) associated with Yasmin. MethodsAmong the 17,035,572 AE reports collected from the Food and Drug Administration Adverse Event Reporting System (FAERS) database between January 2004 and September 2023, 25,949 reports involved Yasmin. The demographic details, clinical outcomes, and sources of reports were extracted, and four algorithms were used to evaluate adverse drug reactions. ResultsThe majority of the AE reports involved females aged 18–45 years. Hospitalization was the most frequently reported serious outcome (46.84 %), with death occurring in 292 patients (1.82 %). The highest number of reports originated from the United States. Adverse reactions spanned across 24 system organ categories (SOCs), and hepatobiliary, vascular, and psychiatric disorders were the most frequently reported AEs. A total of 229 Preferred Terms (PTs) were identified for adverse reactions, with high signal strength observed for conditions such as post-cholecystectomy syndrome. In addition, fear of disease, which has not been previously identified as an AE related to Yasmin, was also identified as a high signal strength side effect. ConclusionThe findings of the present study underscore the importance of monitoring and identifying potential AEs in patients receiving Yasmin, including those not currently listed in the medication instructions.

InAs/GaAs SK quantum dots stacking: Impact of spacer layer on optical properties

In this paper, we report the optical properties of vertically stacked multilayers of self-organized InAs/GaAs quantum dots QDs with different GaAs spacer layer thicknesses of 10 and 15 nm, using photoluminescence PL measurement. The 10 K PL spectrum exhibits double-emission peaks ambiguously identified in PL spectra where the excitation power dependence reveals that these emission peaks are attributed to fundamental ground state GS of large quantum dots in the low energy side, and first excited state 1ES transitions of large quantum dots in coincidence with fundamental ground state GS of smaller ones, in the high energy side. Both the excitation power dependence and the temperature dependence measurement results exhibited competition between the latter's optical transitions in the QDs, which becomes more prevalent at higher excitation powers. The main PL peak is quenched above 190 K, giving rise to “a 1D miniband”, ascribed to the electronic coupling between QDs along the stacking direction and tuning the emission wavelength around 1.3 μm.Our results emphasize the Key role of the vertically stacked InAs/GaAs QDs structures with thin GaAs spacer layers in optimizing design for long-wavelength devices.

Ameliorative effect of nodakenin in combating TNBS-induced ulcerative colitis by suppressing NFƙB-mediated NLRP3 inflammasome pathway.

Ulcerative colitis (UC) is an enduring and complex inflammatory bowel disease that is clinically prevalent, progressive, and debilitating. As of now, the few effective medical treatments for UC have unacceptably high side effects. It is crucial to find safer and more effective UC treatments. Nodakenin possesses anti-inflammatory and antioxidant activity by suppressing several pro-inflammatory mediators. In the present study, we aimed to evaluate the colonoprotective effect of nodakenin in combating colitis through the NFƙB-mediated NLRP3 inflammasome pathway. In mice, UC was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). Nodakenin (10, 20, and 40mg/kg) was introduced intragastrically, and disease activity index (DAI) score was calculated. Malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), nitric oxide (NO) levels, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) concentration were evaluated in colon homogenate. Colon samples were used for histopathological investigation and mRNA expression studies involving nuclear factor kappa B (NFƙB), cyclooxygenase-2 (COX-2), inducible nitric oxide (iNOS), nucleotide-binding receptor domain 3 (NLRP3), interleukin-1β (IL-1β), and interleukin-18 (IL-18). Nodakenin treatment was found effective in lowering the DAI score, histological score, MPO, MDA, and NO levels while elevating SOD levels as compared to the model control group, showcasing its anti-inflammatory and antioxidant properties. Nodakenin (40mg/kg) significantly downregulated the expression of TNF-α, IL-6, NFƙB (1.24-fold), iNOS (1.2-fold), COX-2 (1.98-fold), NLRP3 (1.78-fold), IL-1β (1.29-fold), and IL-18 (1.17-fold) conferring its great anti-inflammatory potential in combating colitis. Taking together, nodakenin presumably alleviated TNBS-induced colitis by NFƙB-mediated NLRP3 inflammasome pathway and reduced colon damage by downregulating various transcriptional genes and pro-inflammatory mediators.

Ficus pumila fruit polysaccharide attenuate ovalbumin-induced allergic asthma in mice associated with changes in microbiota involving the lung-intestinal axis

Allergic asthma accounts for more than 50 percent of adult asthma in life. Glucocorticoids and leukotriene receptor antagonists are commonly used to treat asthma, but these drugs not only have high side effects but also cannot cure the disease. In contrast, natural active ingredients are relatively safe to the organism and show great potential for improving the organism. Polysaccharides, as the main active ingredient in aqueous extract, may be equally beneficial for biological activity. The aim of this study is to investigate the alleviating effect and mechanism of action of Ficus pumila fruit polysaccharide (FPP) and aqueous extract of Ficus pumila fruit (FPW) on mice with allergic asthma. The results showed that FPP and FPW could regulate the secretion of the cytokines IL-4, IL-5, IL-13, and IFN-γ. FPP and FPW also reduced the inflammation, mucus secretion, and collagen deposition in mouse lung tissue, and down-regulated the expression of matrix metallopeptidase-9 (MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1), and α-smooth muscle actin (α-SMA) proteins. In addition, FPP and FPW modulated the intestinal microbiota by augmenting the alpha diversity and adjusting the taxonomic composition at the phylum and family levels, thereby ensured the sustenance of regular physiological processes in the body. This study demonstrated that FPP and FPW may attenuate asthma by inducing beneficial microbiota in the gut-lung axis and provide an effective basis for the future clinical treatment of allergic asthma with Ficus pumila and the development and utilization of new anti-asthma drugs.

Comparative analysis of surface roughness level for bearing coating using VMD of vibration signal

Degradation in surface finish of the material is an important concern in engineering applications. However, most of the conventional techniques available to monitor the surface roughness requires dismantling of the machine element. Though in rotary components like bearing, it is practically not feasible. Therefore, in this work, an on-board technique is proposed to compare the level of surface roughness based on vibration signature. To demonstrate, five different industrial standard coatings (Nickel, Copper, Zinc phosphate (ZnP), Silver, and Black oxide) were carried out on raw five ball bearings (NBC6205). Two sets of coated bearing were prepared, where first set was utilised for experimentation and second for the purpose of measuring surface roughness of bearing surface. These coated bearings were tested at five different RPMs ranging from 300 RPM to 1500 RPM and their vibration signals were recorded. The recorded vibration signals must be having characteristics originated from ball rolling on different level of surface roughness and hence distributed in nature. Further, to target distributed characteristics present in the signal, commonly used statistical parameters for vibration signature analysis (RMS, Crest factor, Variance, Skewness, Kurtosis, Shannon entropy and Log energy) were calculated. Then, correlation of the parameters was checked in relation to the different levels of surface roughness but no relation was found. The signals were then decomposed into six intrinsic mode functions (IMFs) using Variational Mode Decomposition (VMD) method. Again, same statistical parameters were calculated for these decomposed levels, it has been noted that Shannon entropy have shown correlation to surface roughness in at least one decomposed level between 900 to 1500 RPM with minimum value of chain index as 176.65. Moreover, in this RPM range, responsive frequency bands found to be shifted towards higher side i.e. from 567 to 4590 Hz.

Ferroptosis: Latest evidence and perspectives on plant-derived natural active compounds mitigating doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is a chemotherapy drug widely used in clinical settings, acting as a first-line treatment for various malignant tumors. However, its use is greatly limited by the cardiotoxicity it induces, including doxorubicin-induced cardiomyopathy (DIC). The mechanisms behind DIC are not fully understood, but its potential biological mechanisms are thought to include oxidative stress, inflammation, energy metabolism disorders, mitochondrial damage, autophagy, apoptosis, and ferroptosis. Recent studies have shown that cardiac injury induced by DOX is closely related to ferroptosis. Due to their high efficacy, availability, and low side effects, natural medicine treatments hold strong clinical potential. Currently, natural medicines have been shown to mitigate DOX-induced ferroptosis and ease DIC through various functions such as antioxidation, iron ion homeostasis correction, lipid metabolism regulation, and mitochondrial function improvement. Therefore, this review summarizes the mechanisms of ferroptosis in DIC and the regulation by natural plant products, with the expectation of providing a reference for future research and development of inhibitors targeting ferroptosis in DIC. This review explores the mechanisms of ferroptosis in doxorubicin-induced cardiomyopathy (DIC) and summarizes how natural plant products can alleviate DIC by inhibiting ferroptosis through reducing oxidative stress, correcting iron ion homeostasis, regulating lipid metabolism, and improving mitochondrial function.

Ion heating/transport characteristics of merging startup plasma scenario in the TS-6 spherical tokamak

Abstract Here we report ion heating/transport characteristics of merging startup scenario in the TS-6 spherical tokamak. In addition to the previously investigated impulsive heating process during magnetic reconnection, here we also focused on a longer time scale response of ion temperature profile both during and after merging including the semi-steady plasma confinement phase. During magnetic reconnection, (i) ion temperature profile forms poloidally asymmetric profile around the X-point at the initiation phase and (ii) radially asymmetric higher deposition is obtained in the high field side. After merging, (iii) the radially asymmetric double-peak structure is affected by parallel heat conduction and is aligned with field lines, but it does not simply become flux function in microsecond time scale: inboard/outboard asymmetry lasts even in the semi-steady confinement phase. (iv) Under the influence of low aspect ratio configuration, there is 2~3 times higher toroidal field in the high field side on a same closed flux surface, characteristic asymmetry of inboard/outboard ion temperature has experimentally been found for the first time.

Rib-on-Pelvis Deformity and Reported Pain in Neuromuscular Early-Onset Scoliosis.

Neuromuscular early-onset scoliosis (N-EOS) often presents with a long sweeping thoracolumbar scoliosis and pelvic obliquity. With severe pelvic obliquity, the ribs come into contact with the high side of the pelvis, termed rib-on-pelvis deformity (ROP). The goal of this study is to evaluate whether ROP is associated with reported pain and other health-related quality of life (HRQOL) measures. We hypothesize that ROP is associated with increased pain and negative HRQOL. A multicenter international registry was queried for all nonambulatory patients with N-EOS from 2012 to 2022. Both surgical and nonsurgical patients were included. ROP was classified as a binary radiographic assessment of preoperative (surgical patients) and most recent follow-up (nonsurgical patients) upright radiographs. Reported pain and other HRQOL measures were assessed through the 24-Item Early Onset Scoliosis Questionnaire (EOSQ-24). Patients with nonupright radiographs or EOSQ-24 questionnaires and corresponding radiographs >4 months apart were excluded. Totally, 225 patients (8.4±3.1y, 55% female) were included. The median major curve was 63.3 (IQR: 40.6 to 81.2) degrees and median pelvic obliquity was 15.5 degrees (IQR: 8.8 to 26.4). Eighty-three patients (37%) had ROP. ROP was associated with both frequency (P<0.001) and severity (P<0.001) of pain. ROP was associated with worse general health (P=0.01), increased difficulty with vocalization (P=0.02), increased frequency of shortness of breath (P=0.002), and increased difficulty sitting upright (P=0.04). Regarding overall EOSQ-24 domains, ROP was associated with worse general health, pain/discomfort, pulmonary function, and physical function (P<0.01). In a subanalysis of 76 patients who underwent surgical intervention with at least 2 years of follow-up, patients with preoperative ROP experienced significantly greater improvements in both frequency (P=0.004) and severity (P=0.001) of pain than the patients without preoperative ROP at 2 years postoperatively. The overall incidence of ROP in N-EOS is about 37%. ROP is associated with greater pain and worse HRQOL through the EOSQ-24 questionnaire. Furthermore, these patients experienced a greater reduction in pain after surgery. Clinicians and parents must be aware that ROP is possibly a pain generator, but responds positively to surgical intervention. Level III.

Studi Evaluasi Kinerja Ruas Jalan MT Haryono Kota Malang

The MT Haryono highway in Malang City is a type 4/2 UD collector road which connects various places in both the economic and educational sectors in Malang City. The large number of activities that occur on this road result in a buildup of vehicles and high side obstacles, causing traffic jams during rush hours. To overcome this problem, an analytical study using the MKJI 1997 method is needed. The results of the analysis are the value of the degree of saturation for current road conditions &gt;0.80, namely 0.94 at the service level (E) of unstable flow. Therefore, 2 (two) alternatives are given to reduce the DS value, the second alternative is recommended, namely changing the road type to a one-way road so that a DS value of 0.67 is obtained at a stable flow service level (C). Analysis of the performance of the MT Haryono Road section after alternative improvements for the next 5 years is still at a stable service level, with a DS value in 2028 of 0.76 at service level (D).

Numerical analysis of fast ions transport induced by magnetic islands in HL-2A

The transport of beam ions in the presence of single/multiple tearing modes (TMs) under HL-2A geometry has been investigated by test particle method. Simulation results show that there exists a threshold behavior in the number of lost beam ions in the plasma under perturbation of a (2,1) TM with amplitude α0 : when the amplitude α0 is over a critical value, the number of lost beam ions increases linearly with α0 at a much faster pace. Further analysis finds that the lost beam ions have relatively higher percentage of high energy at α0 around the critical value. It also finds that the distribution of lost beam ions which is initially concentrated on the high field side expands gradually toward the low field side as the perturbation amplitude α0 increases. From the phase space analysis, it shows that the enhanced outward transport of fast ions in the presence of magnetic islands results from orbit stochasticity, which is due to the overlap of the drift islands in the interaction of fast ions with TMs. When two TMs are simultaneously present, the stochastic threshold of fast ion orbit is found to be lower than that in their individual TM case. The phase space analysis shows that in the presence of two modes with the same toroidal mode number, the modes increase the loss of fast ions when they are out of phase; however, such the effect of strengthening transport of fast ions turns to weaken when they are in phase. In contrast, when two modes each with a different toroidal mode number, their phase difference phase hardly has any effect on the transport of fast ions.

The Etiology, Pathogenesis and Clinical Treatment of Depression Were Analyzed from the Perspective of Traditional Chinese Medicine

As the pace of life quickens, the prevalence of depression rises. Due to the incomplete understanding of depression and various causes, it is still unable to fully effective prevention and treatment in clinical practice. Western medicine treatment of depression has high cost and side effects, while Chinese medicine treatment has advantages, according to different syndromes, different treatment means and Chinese medicine drugs can be used, efficient and targeted. Traditional Chinese medicine believes that the cause of depression lies in the poor operation of Qi and blood, which leads to the dysfunction of multiple viscera, and the symptoms such as emotional depression appear in the light, and the serious phenomena such as loss of survival motivation appear. This article will discuss the causes and treatment methods of depression from the perspective of traditional Chinese medicine, and provide new ideas for clinical treatment.

Uni-directional release of ibuprofen from an asymmetric fibrous membrane enables effective peritendinous anti-adhesion

Drug-loaded porous membranes have been deemed to be effective physicochemical barriers to separate postoperative adhesion-prone tissues in tendon healing. However, cell viability and subsequent tissue regeneration might be severely interfered with the unrestricted release and the locally excessive concentration of anti-inflammatory drugs. Herein, we report a double-layered membrane with sustained and uni-directional drug delivery features to prevent peritendinous adhesion without hampering the healing outcome. A vortex-assisted electrospinning system in combination with ibuprofen (IBU)-in-water emulsion was utilized to fabricate IBU-loaded poly-ʟ-lactic-acid (PLLA) fiber bundle membrane (PFB-IBU) as the anti-adhesion layer. The resultant highly porous structure, oleophilic and hydrophobic nature of PLLA fibers enabled in situ loading of IBU with a concentration gradient across the membrane thickness. Aligned collagen nanofibers were further deposited at the low IBU concentration side of the membrane for regulating cell growth and achieving uni-directional release of IBU. Drug release kinetics showed that the release amount of IBU from the high concentration side reached 79.32% at 14 d, while it was only 0.35% at the collagen side. Therefore, fibroblast proliferation at the high concentration side was successfully inhibited without affecting the oriented growth of tendon-derived stem cells at the other side. In vivo evaluation of the rat Achilles adhesion model confirmed the successful peritendinous anti-adhesion of our double-layered membrane, in that the macrophage recruitment, the inflammatory factor secretion and the deposition of pathological adhesion markers such as α-SMA and COL-III were all inhibited, which greatly improved the peritendinous fibrosis and restored the motor function of tendon.

Target Reprogramming the 3′UTR of Tumor‐Suppressor Genes by a siRNA Composite Nanoparticle for Glioblastoma Therapy

AbstractGlioblastoma multiforme (GBM) is the most aggressive and common adult brain tumor. Current therapies primarily involve surgical resection, followed by chemotherapy and radiotherapy. However, the low survival rate due to high toxicity, side effects, and poor targeting necessitates novel treatments. Post‐transcriptional regulation pathways, particularly the regulation of alternative polyadenylation based on the mRNA 3′UTR, play a critical role in cell growth and development and the progression of tumors. Targeting tumor cells and reprogramming the 3′UTR of tumor suppressor genes to achieve post‐transcriptional regulation is expected to be a new channel for GBM therapy. Herein, a novel siRNA delivery system is developed based on mesoporous silica nanoparticles: siRNA composite nanoparticles (siRNA CNP). Encapsulation in MSNs overcomes siRNA degradation and cellular entry issues, while lipid bilayer coating improves biocompatibility and stability. Surface‐modified nucleic acid aptamer SL1 (Apt‐SL1) significantly enhances GBM targeting, offering therapeutic potential. The findings show that siRNA CNP effectively silences the promoter CFIm25 of distal poly(A) in tumor cells, inducing gene reprogramming, inhibiting tumor growth, and promoting apoptosis in nude mice. The siRNA CNP demonstrates a significant effect in reprogramming tumor suppressor genes and treating GBM. It offers a novel and promising therapeutic avenue for GBM.

Dynamic Covalent Boronate Chemistry Accelerates the Screening of Polymeric Gene Delivery Vectors via In Situ Complexation of Nucleic Acids.

Gene therapy provides exciting new therapeutic opportunities beyond the reach of traditional treatments. Despite the tremendous progress of viral vectors, their high cost, complex manufacturing, and side effects have encouraged the development of nonviral alternatives, including cationic polymers. However, these are less efficient in overcoming cellular barriers, resulting in lower transfection efficiencies. Although the exquisite structural tunability of polymers might be envisaged as a versatile tool for improving transfection, the need to fine-tune several structural parameters represents a bottleneck in current screening technologies. By taking advantage of the fast-forming and strong boronate ester bond, an archetypal example of dynamic covalent chemistry, a highly adaptable gene delivery platform is presented, in which the polycation synthesis and pDNA complexation occur in situ. The robustness of the strategy entitles the simultaneous evaluation of several structural parameters at will, enabling the accelerated screening and adaptive optimization of lead polymeric vectors using dynamic covalent libraries.

Poloidal structure of the edge parallel flow in H-mode, L-mode and I-mode confinement regimes

Impurity profiles have been measured with the edge high field side (HFS) and low field side (LFS) charge exchange recombination spectroscopy suite at ASDEX Upgrade enabling the study of the poloidal structure of the edge parallel flow in H-mode, L-mode and I-mode. In H-mode, asymmetries in the impurity density, toroidal and poloidal rotations are found. In I-mode, only toroidal rotation asymmetries have been measured while in L-mode no asymmetries have been observed. The measured parallel flow can be divided in two components, the Pfirsch–Schlüter (PS) flow and the symmetric flow. Two different methods have been followed to determine both contributions to the parallel flow. The first method is based on the calculation of the PS flow at the HFS and LFS from the radial electric field. The second method directly provides the symmetric flow from the flux surface average (FSA) of the parallel flow. In H-mode, the methods provide different results, while in L-mode and I-mode they agree. The differences observed in H-mode between the two methods could be explained by the existence of asymmetries in the impurity density, by the non-negligible particle sources and radial losses, or by the approximations made in the calculation of the FSA of the parallel flow from measurements in two poloidal positions (midplane HFS and LFS) only.

Hemay181: A novel SDC (sugar linked drug conjugate) for solid tumors targeting tumor microenvironment.

e15006 Background: Hemay181 is a novel broad-spectrum conjugated cytotoxic drug for treating advanced solid tumours. The drug exerts its inhibitory effect on tumour growth by releasing cytotoxic drug SN-38 in tumour tissues via β-glucuronidase (βGU) metabolism to inhibit the activity of topoisomerase I (TOP1). The water solubility of Hemay181 is increased &gt; 5000-fold compared to SN-38. Hemay181 also binds to plasma albumin to form a macromolecular drug transporter, significantly improving the drug's pharmacokinetics. In addition, βGU has low activity in normal tissues, localised to the lysosomes, but is highly expressed in the hypoxic tumour microenvironment. Methods: In vitro and In Vivo studies showed Hemay181 inhibited growth in 29 human tumour cell lines and 16 human tumor Xenograft models, including colorectal cancer, gastric cancer, triple-negative breast cancer, head and neck cancer, pancreatic cancer, lung cancer, prostate cancer and melanoma. Results: In the absence of βGU, Hemay181 showed significantly weaker inhibitory activity than Hemay181+βGU or no significant inhibitory activity. In these In vitro studies with the addition of βGU, the activity was similar to SN-38, ranging from 3.9 nM to 159 nM. Hemay181 showed tumor selectivity with low activity against two normal human cell lines. The IC50 values of Hemay181 against Chang liver (normal liver cells) and MRC 5 (embryonic lung cells) were 318 nM and 14566 nM under non-enzymatic digestion conditions. In vivo, Hemay181 had significant inhibitory effects on the growth of human colorectal cancer, pancreatic cancer, head and neck cancer, triple-negative breast cancer, lung cancer, liver cancer, ovarian cancer and gastric cancer tumour models. The lowest effective dose of Hemay181 was 1.875mg/kg in the human colon cancer HCT116 model. Within the dose range of 3.75~60 mg/kg, the highest inhibitory rate of the above different tumour models could reach more than 90%. Hemay181 significantly reduced tumour volume compared to irinotecan, which only slowed the tumour growth rates. There was no significant decrease in the body weight of Hemay181 in these studies. In the colon cancer PDX model (CR0029) (30mg/kg), the tumour inhibition rate (TGI) was 78%. At 60mg/kg, in triple-negative breast cancer (BR1458) and non-small cell lung cancer (LU3075) PDX models, a TGI was 97% and 98%, respectively. At 60mg/kg, there was a significant tumour suppressive effect on larger tumours treated with irinotecan, with a reduction of tumour volume. In vitro , 1 μM Hemay181 is stable in CD1 mouse and SD rat plasma, with a minor degree of metabolism in beagle dog, cynomolgus monkey and human plasma. Conclusions: In summary, the novel broad-spectrum anti-tumour drug Hemay181 has the characteristics of high water solubility, tumour-targeting ability, low toxicity and side effects on normal tissues. It is under evaluation in ongoing clinical studies.