Unsatisfactory Therapeutic Effect Research Articles

X-ray-triggered fenton-like nanocomposites for passive-activation and non-spontaneous chemodynamic therapy

Currently, many studies focused on the TME-regulating strategies to address the unsatisfactory therapeutic effect of single chemodynamic therapy (CDT). However, most of TME-regulating strategies were nonspecific, the CDT agents with spontaneous CDT activity would result in augmented killing effect not only in tumor but also in normal tissues. Furthermore, CDT efficiency was subject to attenuation due to the gradually exhausted active sites in CDT agents. Herein, the passive-activation and non-spontaneous CDT strategy was proposed by constructing a completely X-ray-triggered CDT agent (F-SCNPs) to target the therapeutic dilemma between the augmented CDT efficacy and high tumor specificity. In this study, the designed F-SCNPs can launch Fe2+ sites generation to initiate CDT activity only when they were exposed to X-ray, which were totally different from the traditional CDT agents including other stimuli-responsive CDT agents that always spontaneously exert CDT activity no matter they had accepted the stimuli or not. The X-ray-activated feature of F-SCNPs endowed their tumor specificity with less affect by nonspecific TME-regulating strategies. Meanwhile, X-ray can promote the Fe2+/Fe3+ cycling of F-SCNPs to enhance the •OH yield. This X-ray-mediated nanosystem with remarkable synergistic therapy of CDT and radiotherapy provided a promising avenue for high-efficiency and precise cancer treatments.

Clinical and genetic analysis of a child with co-morbid progressive IgA nephropathy and COQ8B-associated glomerulopathy

To explore the genetic etiology and clinical outcome of a child with co-morbid progressive IgA nephropathy and COQ8B-associated glomerulopathy. A child who was admitted to Peking University First Hospital on March 2, 2021 was selected as the study subject. Genomic DNA was extracted from peripheral blood samples from the child and his parents and sister. Whole exome sequencing was carried out, and candidate variant was verified by Sanger sequencing. This study was approved by the Peking University First Hospital (Ethics No. 2016[1029]). The child, a 7-year-old boy who had developed proteinuria 8 months before, was diagnosed with IgA nephropathy (M1E1S1T1C1). With steroid, cyclophosphamide, cyclosporine and angiotensin-converting enzyme inhibitor therapy, partial remission of proteinuria was achieved. However, his serum creatinine level had increased from 53.8 mol/L at the onset of disease to 86.7 mol/L after 3.9 years, along with massive proteinuria. Kidney biopsy still indicated IgA nephropathy (M0E0S1T0C0). The child was found to harbor a homozygous c.737G>A (p.Ser246Asn) missense variant of the COQ8B gene, for which his parents and sister were heterozygous carriers. The variant was predicted to be pathogenic (PS1+PM2_Supporting+PM3+PP3+PP4) based on the guidelines from the American College of Medical Genetics and Genomics. The child was treated with high-dose coenzyme Q10 in combination with steroid and/or mycophenolate mofetil, though his serum creatinine level still increased to 286 mol/L after 7.3 years, which conformed to a chronic kidney disorder with glomerular filtration rate category of G3b. The homozygous c.737G>A missense variants of the COQ8B gene probably underlay the progressive kidney dysfunction in this child. For children with IgA nephropathy presenting with atypical clinical manifestations, unsatisfactory therapeutic effect, and/or early onset of kidney function decline, coexistence of other diseases should be suspected.

LncRNA AF117829.1 is correlated with prognosis and immune infiltration and facilitates tumor progression by targeting OR7C1 in colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignant tumors in the digestive system with a high incidence, a poor prognosis and an unsatisfactory therapeutic effect. Long non-coding RNAs (lncRNAs) play crucial roles in various biological processes related to tumor progression. Immune-related lncRNA gene AF117829.1 has been reported to participate in the construction of clinical predictive signature in CRC patients, suggesting that it may be involved in regulating the immune landscape and progression of CRC. However, the clinical and immunological significance and biological function of AF117829.1 in CRC remain unclear. In this study, we aim to explore the roles of AF117829.1 in CRC progression by bioinformatics analysis and experimental studies, thereby providing new targets for CRC treatment. This study collected data from The Cancer Genome Atlas (TCGA) database and explored the role of AF117829.1 in CRC by bioinformatics analysis. Cell-type Identification By Estimating Relative Subsets Of known RNA Transcripts (CIBERSORT) and Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) methods estimated the immune infiltration. Gene Set Enrichment Analysis (GSEA) was performed to evaluate the enrichment of functional pathways and gene signatures. The biological functions and mechanism of AF117829.1 in CRC progression were validated using CRC tissues and in vitro experiments. In our study, high expression of AF117829.1 was found in pan-cancer including CRC and was positively associated with tumor (T) stage and tumor-node-metastasis (TNM) stage in CRC. The survival analysis results showed that CRC patients with high-AF117829.1 expression had significantly shorter overall survival (OS) time than those with low-AF117829.1 expression. Moreover, AF117829.1 expression was negatively associated with microsatellite instability (MSI) in colon adenocarcinoma (COAD). Subsequently, AF117829.1 expression was confirmed to be significantly associated with StromalScore, immune cell infiltration (ICI) levels and immune checkpoints (ICP) genes expression in CRC. The immunophenoscore (IPS) results indicated that immunotherapy could be more effective in CRC patients with low-AF117829.1 expression. Then we confirmed that AF117829.1 was highly expressed in CRC cell lines and tissues. Furthermore, our GSEA results showed that olfactory transduction-related signaling pathways were significantly enriched in the high-AF117829.1 expression group. Finally, in vitro experiments confirmed that AF117829.1 overexpression promoted the proliferation, migration and invasion of CRC cells by targeting olfactory receptor family 7 subfamily C member 1 (OR7C1). LncRNA AF117829.1 is closely related to the prognosis, immunological characteristics and immunotherapy response of CRC patients and promotes malignant progression of CRC by targeting OR7C1. Moreover, AF117829.1 may be a potential therapeutic target for CRC patients.

Impact of Physical Activity and Exercise on Endometriosis Related Symptoms with Particular Emphasis on Pain - Systematic Review

Endometriosis is common chronic condition that can cause acute and chronic pain. It affects 5-10 % of women in their reproductive years. It is characterized by the presence of endometrial- like tissue outside the uterus and it is associated with pelvic pain and infertility. Diagnosis of endometriosis requires laparotomy or laparoscopy. Therefore, there is often a delay from initial symptoms to diagnosis and treatment. There is no effective treatment. Current therapeutic methods aim to reduce pain and treat infertility. It include surgery, hormonal treatments and analgesics in case of a pain. Additionally, this methods have their limitations in form of side effects and unsatisfactory therapeutic effect. [1,2] Wherefore physical activity (PA) and exercise have been suggested as alternative treatments.[3] In this study authors perform a systematic review to evaluate the effect of PA and exercise on endometriosis-related symptoms.

ASC4FIRST, a pivotal phase 3 study of asciminib (ASC) vs investigator-selected tyrosine kinase inhibitors (IS TKIs) in newly diagnosed patients (pts) with chronic myeloid leukemia (CML): Primary results.

LBA6500 Background: We present primary results from ASC4FIRST (NCT04971226), the first study in CML comparing all current standard-of-care frontline TKIs with a novel agent, ASC, in newly diagnosed pts. ASC Specifically Targets the ABL Myristoyl Pocket (STAMP). Methods: Adults with CML were randomly assigned 1:1 to receive ASC 80 mg once daily or an IS TKI at standard label doses, stratified by ELTS risk category and prerandomization selected (PRS) TKI (imatinib [IMA] or second-generation [2G] TKIs), which was selected by investigators before randomization, accounting for pt preference. Pts diagnosed within 3 mo before enrollment with no prior treatment (Tx) except IMA/2G TKIs for ≤2 wk prior to randomization were eligible. Primary objectives were to demonstrate superior major molecular response (MMR) rate at wk 48 with ASC vs IS TKI and ASC vs IS TKI within the stratum of pts with IMA as PRS TKI (ASCIMA vs IS TKIIMA). The study is positive if either objective is met. Comparing MMR rate of ASC vs IS TKI at wk 48 within the stratum of pts with 2G TKIs as PRS TKI (ASC2G vs IS TKI2G) was an unpowered secondary objective. Results: Pts received ASC (n=201: ASCIMA, n=101; ASC2G, n=100) or IS TKI (n=204: IS TKIIMA, n=102; IS TKI2G, n=102 [nilotinib, 48%; dasatinib, 41%; bosutinib, 11%]). Median follow-up was 16.3 and 15.7 mo for ASC and IS TKI, respectively (cutoff: Nov 28, 2023). At cutoff, Tx was ongoing in 86%, 62%, and 75% of pts on ASC, IMA, and 2G TKIs, respectively, with pts most commonly discontinuing due to unsatisfactory therapeutic effect (6%, 21%, 10%) (Tx failure per ELN2020 [5%, 16%, 8%], MMR loss [0.5%, 0%, 0%], physician decision [0.5%, 5%, 2%]) and adverse events (AEs) (5%, 11%, 10%). MMR rate at wk 48 (per ITT) was superior with ASC (67.7%) vs IS TKI (49.0%) and with ASCIMA (69.3%) vs IS TKIIMA (40.2%), meeting both primary objectives with high statistical significance; rate difference was 18.9% [95% CI, 9.6%-28.2%] and 29.6% [95% CI, 16.9%-42.2%], respectively, both with adjusted 1-sided P<.001. MMR rate at wk 48 was higher with ASC2G vs IS TKI2G (66.0% vs 57.8%). BCR::ABL1IS ≤1% rate at wk 48 was 87% with ASC vs 73% with IS TKI and 84% with ASCIMA vs 62% with IS TKIIMA. At wk 48, MR4 and MR4.5 rates were higher with ASC vs IS TKI (39% vs 21%; 17% vs 9%), ASCIMA vs IS TKIIMA (43% vs 15%; 18% vs 5%), and ASC2G vs IS TKI2G (35% vs 26%; 16% vs 13%). ASC had markedly favorable safety and tolerability vs IMA and 2G TKIs, with less grade ≥3 AEs (38%, 44%, 55%), half the rate of AEs leading to Tx discontinuation (5%, 11%, 10%), and less dose adjustments/interruptions to manage AEs (30%, 39%, 53%). Rate of arterial occlusive events was 1%, 0%, and 2%, respectively. Conclusions: ASC is the only agent to show a statistically significant superior efficacy and excellent safety and tolerability vs all current standard-of-care frontline Tx, with potential to be the therapy of choice for CML. Clinical trial information: NCT04971226 .

Application of capsaicin and calcium phosphate-loaded MOF system for tumor therapy involving calcium overload

Calcium overload therapy refers to the condition of intracellular Ca2+ overload, which causes mitochondrial damage and leads to the uncontrolled release of apoptotic factors into the cytoplasm through the open mitochondrial permeability pore. Based on this, it is playing an increasingly important role in the field of oncology due to its good efficacy and small side effects. However, the regulation of calcium homeostasis by cancer cells themselves, insufficient calcium ions (Ca2+) in tumor sites and low efficiency of calcium entering tumor have limited its efficacy, resulting in unsatisfactory therapeutic effect. Therefore, a novel CAP/BSA@TCP-ZIF-8 nanoparticle drug carrier system was constructed that can provide Ca2+ from exogenous sources for pH-controlled degradation and drug release at the same time. Both in vivo and in vitro experiments have proved that the nanomaterial can activate TRPV1 channels and provide exogenous Ca2+ to cause Ca2+ overload and apoptosis, thus achieving anti-tumor effects.

A T-Cell Inspired Sonoporation System Enhances Low-Dose X-Ray-Mediated Pyroptosis and Radioimmunotherapy Efficacy by Restoring Gasdermin-E Expression.

Genome editing has the potential to improve the unsatisfactory therapeutic effect of antitumor immunotherapy. However, the cell plasma membrane prevents the entry of almost all free genome-manipulation agents. Therefore, a system can be spatiotemporally controlled and can instantly open the cellular membrane to allow the entry of genome-editing agents into target cells is needed. Here, inspired by the ability of T cells to deliver cytotoxins to cancer cells by perforation, an ultrasound (US)-controlled perforation system (UPS) is established to enhance the delivery of free genome-manipulating agents. The UPS can perforate the tumor cell membrane while maintaining cell viability via a controllable lipid peroxidation reaction. In vitro, transmembrane-incapable plasmids can enter cells and perform genome editing with the assistance of UPS, achieving an efficiency of up to 90%. In vivo, the UPS is biodegradable, nonimmunogenic, and tumor-targeting, enabling the puncturing of tumor cells under US. With the application of UPS-assisted genome editing, gasdermin-E expression in 4T1 tumor-bearing mice is successfully restored, which leads to pyroptosis-mediated antitumor immunotherapy via low-dose X-ray irradiation. This study provides new insights for designing a sonoporation system for genome editing. Moreover, the results demonstrate that restoring gasdermin expression by genome editing significantly improves the efficacy of radioimmunotherapy.

Biosynthesized tumor acidity and MMP dual-responsive plant toxin gelonin for robust cancer therapy.

Among all kinds of anticancer agents, small molecule drugs produce an unsatisfactory therapeutic effect due to the lack of selectivity, notorious drug resistance and side effects. Therefore, researchers have begun to pay extensive attention to macromolecular drugs with high efficacy and specificity. As a plant toxin, gelonin exerts potent antitumor activity via inhibiting intracellular protein synthesis. However, gelonin lacks a translocation domain, and thus its poor cellular uptake leads to low outcomes of antitumor response. Here, tumor acidity and matrix metalloproteinase (MMP) dual-responsive functional gelonin (Trx-PVGLIG-pHLIP-gelonin, TPpG), composed of a thioredoxin (Trx) tag, a pH low insertion peptide (pHLIP), an MMP-responsive motif PVGLIG hexapeptide and gelonin, was innovatively proposed and biologically synthesized by a gene recombination technique. TPpG exhibited good thermal and serum stability, showed MMP responsiveness and could enter tumor cells under weakly acidic conditions, especially for MMP2-overexpressing HT1080 cells. Compared to low MMP2-expressing MCF-7 cells, TPpG displayed enhanced in vitro antitumor efficacy to HT1080 cells at pH 6.5 as determined by different methods. Likewise, TPpG was much more effective in triggering cell apoptosis and inhibiting protein synthesis in HT1080 cells than in MCF-7 cells. Intriguingly, with enhanced stability and pH/MMP dual responsiveness, TPpG notably inhibited subcutaneous HT1080 xenograft growth in mice and no noticeable off-target side effect was observed. This ingeniously designed strategy aims at providing new perspectives for the development of a smart platform that can intelligently respond to a tumor microenvironment for efficient protein delivery.

Sabatolimab in Combination with Hypomethylating Agents (HMAs) Was Safe in Patients (Pts) with Intermediate-, High-, or Very-High-Risk Myelodysplastic Syndrome (MDS)

CONCLUSIONS Complete remission (CR) with standard-of-care HMAs in pts with intermediate-, high-, and very-high-risk MDS is usually infrequent and transient, and prognosis remains poor for these pts, who have limited second-line treatment options. Sabatolimab is a high-affinity, humanized anti-TIM3 IgG4 monoclonal antibody that blocks the TIM3 immune checkpoint receptor, which is preferentially expressed on leukemic stem cells and blasts and plays a key role in regulating adaptive and innate immune responses. In a phase Ib study, sabatolimab in combination with intravenous (IV) HMA was safe and well tolerated in pts with high-risk MDS with overall response rates of 61.1% and 57.9% with decitabine and azacitidine, respectively. We present an interim analysis of the STIMULUS-MDS US trial (NCT04878432) to assess the safety of sabatolimab in combination with not only parenteral but also oral HMAs in pts with intermediate-, high-, and very-high-risk MDS. This is a multicenter, phase II, open-label, single-arm study of sabatolimab in combination with HMAs. Adults aged ≥18 years with intermediate-, high-, or very-high-risk MDS per Revised International Prognostic Scoring System criteria who were not previously treated with HMAs were eligible. Pts received an HMA of investigator's choice (decitabine/cedazuridine 35 mg/100 mg oral days 1-5, decitabine 20 mg/m 2 IV days 1-5, or azacitidine 75 mg/m 2 IV or subcutaneous [SC] days 1-7 or days 1-5 plus days 8 and 9) with sabatolimab 800 mg IV every 4 weeks starting at day 8 or any day between days 5 to 8. The primary objective of this study was to assess the safety of sabatolimab in combination with oral, IV, and SC HMAs. Secondary objectives included assessing the efficacy of the combination. The study includes a core phase for up to 12 months, an extension phase for efficacy and survival status up to 12 months after the core phase, and a post-treatment safety follow-up for 30 days following the last dose of HMA or 150 days following the last dose of sabatolimab, whichever is later. This interim analysis included 33 pts with intermediate-, high-, and very-high-risk MDS at the data cutoff of 6 months after cycle 1 day 1 of treatment with sabatolimab and an HMA. The median age was 69 years (range, 39-86). At data cutoff, 8 pts were in ongoing treatment, and 25 pts had discontinued the core phase. Reasons for discontinuation included new therapy for study indication (n=6), physician decision (n=6), pt decision (n=5), progressive disease (n=4), unsatisfactory therapeutic effect (n=2), adverse event (AE) (n=1), and death (n=1). Of those who discontinued study treatment, 6 pts were in ongoing evaluation in the extension phase and 3 pts were in ongoing evaluation in the post-treatment follow-up phase. The median duration (range) of exposure was 3.9 (0.92-5.91) months for sabatolimab and 4.2 (1.05-6.08) months for HMAs. Among 33 pts evaluable for safety, most experienced all-grade and grade ≥3 AEs, AEs requiring additional therapy, and serious AEs (Figure). However, the most frequent (≥10%) grade ≥3 AEs were expected hematologic AEs, including febrile neutropenia (42.4%), anemia (39.4%), neutrophil count decrease (39.4%), and platelet count decrease (36.4%). Nonhematologic grades ≥3 AEs occurring in >1 pt included hypertension (18.2%), pneumonia (9.1%), hypoxia (6.1%), and fall (6.1%). Only 1 pt was reported with encephalopathy leading to treatment discontinuation, which was not attributed to study treatment. One pt had a fatal AE for which the cause was not identified but not thought to be related to study treatment by the investigator. The best overall response results in up to 6 months of treatment were available for 22 pts. Marrow CR (mCR) with and without hematologic improvement (HI) was reported in 18.2% and 9.1%, respectively. Partial remission (PR) and stable disease (SD) with HI was reported in 4.5%, each. CR + mCR + PR was 31.8% (95% CI, 13.9%-54.9%), CR + PR + HI was 27.3% (95% CI, 10.7%-50.2%), and CR + mCR + PR + HI was 36.4% (95% CI, 17.2%-59.3%). This interim analysis of the STIMULUS-MDS US study demonstrated that sabatolimab in combination with an oral, IV, or SC HMA was safe and well tolerated, with AEs consistent with previous reports for pts with MDS treated with HMAs. Response rates for the combination are preliminary, and more information will be provided with longer follow-ups.

Ultrasmall PtMn nanoparticles as sensitive manganese release modulator for specificity cancer theranostics

Manganese-based nanomaterials (Mn-nanomaterials) hold immense potential in cancer diagnosis and therapies. However, most Mn-nanomaterials are limited by the low sensitivity and low efficiency toward mild weak acidity (pH 6.4–6.8) of the tumor microenvironment, resulting in unsatisfactory therapeutic effect and poor magnetic resonance imaging (MRI) performance. This study introduces pH-ultrasensitive PtMn nanoparticles as a novel platform for enhanced ferroptosis-based cancer theranostics. The PtMn nanoparticles were synthesized with different diameters from 5.3 to 2.7 nm with size-dominant catalytic activity and magnetic relaxation, and modified with an acidity-responsive polymer to create pH-sensitive agents. Importantly, R-PtMn-1 (3 nm core) presents “turn-on” oxidase-like activity, affording a significant enhancement ratio (pH 6.0/pH 7.4) in catalytic activity (6.7 folds), compared with R-PtMn-2 (4.2 nm core, 3.7 folds) or R-PtMn-3 (5.3 nm core, 2.1 folds), respectively. Moreover, R-PtMn-1 exhibits dual-mode contrast in high-field MRI. R-PtMn-1 possesses a good enhancement ratio (pH 6.4/pH 7.4) that is 3 or 3.2 folds for T1- or T2-MRI, respectively, which is higher than that of R-PtMn-2 (1.4 or 1.5 folds) or R-PtMn-3 (1.1 or 1.2 folds). Moreover, their pH-ultrasensitivity enabled activation specifically within the tumor microenvironment, avoiding off-target toxicity in normal tissues during delivery. In vitro studies demonstrated elevated intracellular reactive oxygen species production, lipid peroxidation, mitochondrial membrane potential changes, malondialdehyde content, and glutathione depletion, leading to enhanced ferroptosis in cancer cells. Meanwhile, normal cells remained unaffected by the nanoparticles. Overall, the pH-ultrasensitive PtMn nanoparticles offer a promising strategy for accurate cancer diagnosis and ferroptosis-based therapy.Graphical

Compact Waist Rehabilitation Robot Inspired by McKenzie Therapy: Design, Analysis and Validation

Aiming at solving the problems of low compliance and unsatisfactory therapeutic effect in most existing waist rehabilitation robots, this letter presents a compact waist rehabilitation robot (CWRR) for patients with low back pain (LBP). First, the CWRR with a rigid pose adjustment mechanism and a soft curvature adjustment mechanism is designed to adapt to the waist movement and adjust lumbar curvature. Then, the kinematic analysis was conducted using the closed-loop vector method and the phenomenological theory model. Finally, unit mechanism tests and a comprehensive prototype test were carried out to validate the rationality of the theoretical models and the adaptability and compliance of the CWRR. The CWRR adjusted the curvature angle within the range of 10–60 degrees with small errors. Under different pose and curvature conditions, the man-machine contact pressure was lower or slightly higher than the low-pressure regime threshold (10 kPa). Experimental results show that the CWRR possesses potential clinical applications for patients with LBP disease and can provide theoretical and technical reserves for the research and development of curvature-adjustment waist rehabilitation robots.

A self-fused hydrogel for the treatment of glottic insufficiency through outstanding durability, extracellular matrix-inducing bioactivity and function preservation.

Injection laryngoplasty with biomaterials is an effective technique to treat glottic insufficiency. However, the inadequate durability, deficient pro-secretion of extracellular matrix (ECM) and poor functional preservation of current biomaterials have yielded an unsatisfactory therapeutic effect. Herein, a self-fusing bioactive hydrogel comprising modified carboxymethyl chitosan and sodium alginate is developed through a dual-crosslinking mechanism (photo-triggered and dynamic covalent bonds). Owing to its characteristic networks, the synergistic effect of the hydrogel for vocal folds (VFs) vibration and phonation is adequately demonstrated. Notably, owing to its inherent bioactivity of polysaccharides, the hydrogel could significantly enhance the secretion of major components (type I/III collagen and elastin) in the lamina propria of the VFs both in vivo and in vitro. In a rabbit model for glottic insufficiency, the optimized hydrogel (C1A1) has demonstrated a durability far superior to that of the commercially made hyaluronic acid (HA) Gel. More importantly, owing to the ECM-inducing bioactivity, the physiological functions of the VFs treated with the C1A1 hydrogel also outperformed that of the HA Gel, and were similar to those of the normal VFs. Taken together, through a simple-yet-effective strategy, the novel hydrogel has demonstrated outstanding durability, ECM-inducing bioactivity and physiological function preservation, therefore has an appealing clinical value for treating glottic insufficiency.

Therapeutic effect of ursodeoxycholic acid-berberine supramolecular nanoparticles on ulcerative colitis based on supramolecular system induced by weak bond

Ulcerative colitis(UC) is a recurrent, intractable inflammatory bowel disease. Coptidis Rhizoma and Bovis Calculus, serving as heat-clearing and toxin-removing drugs, have long been used in the treatment of UC. Berberine(BBR) and ursodeoxycholic acid(UDCA), the main active components of Coptidis Rhizoma and Bovis Calculus, respectively, were employed to obtain UDCA-BBR supramolecular nanoparticles by stimulated co-decocting process for enhancing the therapeutic effect on UC. As revealed by the characterization of supramolecular nanoparticles by field emission scanning electron microscopy(FE-SEM) and dynamic light scattering(DLS), the supramolecular nanoparticles were tetrahedral nanoparticles with an average particle size of 180 nm. The molecular structure was described by ultraviolet spectroscopy, fluorescence spectroscopy, infrared spectroscopy, high-resolution mass spectrometry, and hydrogen-nuclear magnetic resonance(H-NMR) spectroscopy. The results showed that the formation of the supramolecular nano-particle was attributed to the mutual electrostatic attraction and hydrophobic interaction between BBR and UDCA. Additionally, supramolecular nanoparticles were also characterized by sustained release and pH sensitivity. The acute UC model was induced by dextran sulfate sodium(DSS) in mice. It was found that supramolecular nanoparticles could effectively improve body mass reduction and colon shortening in mice with UC(P<0.001) and decrease disease activity index(DAI)(P<0.01). There were statistically significant differences between the supramolecular nanoparticles group and the mechanical mixture group(P<0.001, P<0.05). Enzyme-linked immunosorbent assay(ELISA) was used to detect the serum levels of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6), and the results showed that supramolecular nanoparticles could reduce serum TNF-α and IL-6 levels(P<0.001) and exhibited an obvious difference with the mechanical mixture group(P<0.01, P<0.05). Flow cytometry indicated that supramolecular nanoparticles could reduce the recruitment of neutrophils in the lamina propria of the colon(P<0.05), which was significantly different from the mechanical mixture group(P<0.05). These findings suggested that as compared with the mechanical mixture, the supramolecular nanoparticles could effectively improve the symptoms of acute UC in mice. The study provides a new research idea for the poor absorption of small molecules and the unsatisfactory therapeutic effect of traditional Chinese medicine and lays a foundation for the research on the nano-drug delivery system of traditional Chinese medicine.

Engineering nanoparticles boost TNBC therapy by CD24 blockade and mitochondrial dynamics regulation.

Although cancer immunotherapy has achieved remarkable progress, the clinical treatment of triple-negative breast cancer (TNBC) is still tough to make a breakthrough. The unsatisfactory therapeutic effect may be attributed to the lack of tumor immunogenicity and the strong immunosuppressive tumor microenvironment (ITM). In order to overcome the above shortcomings, engineering nanoparticles (P-aCD24/CEL+P/shMFN1) was designed to deliver anti-CD24 monoclonal antibody (aCD24), celastrol (CEL) and mitofusin 1 shRNA (shMFN1) for synergistic tumor cells-targeted treatment and tumor-associated macrophages (TAMs)-targeted immunomodulation. CD24, highly expressed on tumor cells, interacts with Siglec10 on TAMs to protect tumor cells from phagocytosis by macrophages, and thus has become a novel and dominant immune checkpoint in TNBC. P-aCD24/CEL achieved the release of aCD24 based on the dual response of carrier to pH and MMP2 in tumor microenvironment. Moreover, CEL increased "eat me" signal CRT and induced the immunogenic cell death (ICD) of tumor cells, together with decreased "don't eat me" signal CD24, reactivated macrophage phagocytosis of tumor cells, and ultimately improves the macrophage-based immunotherapy. On the other hand, P/shMFN1 could target TAMs for mitochondrial dynamics regulation via durable MFN1 silencing in TAMs, thereby reversing the phenotype of M2-TAMs. P-aCD24/CEL and P/shMFN1 could synergistically elicit evident antitumor immune responses and long-term immune memory to significantly inhibit tumor progress and postoperative recurrence. Based on remodeling the ITM and increasing antitumor immune response, this combination immunotherapy strategy showed great potential for TNBC treatment.

A pH/GSH dual responsive nanoparticle with relaxivity amplification for magnetic resonance imaging and suppression of tumors and metastases.

Engineered magnetic nanoparticles combining diagnosis and therapy functions into one entity hold great potential to rejuvenate cancer treatment; however, they are still constrained by the "always on" signals and unsatisfactory therapeutic effect. Here, we report an intelligent theranostic probe based on Mn3O4 tetragonal bipyramids (MnTBs), which simultaneously respond to H+ and glutathione (GSH) with high sensitivity and quickly decompose to release Mn2+ in mild acidic and reductive intracellular environments. Mn2+ binds to the surrounding proteins to achieve a remarkable relaxivity amplification and selectively brighten the tumors. Particularly, this MR signal improvement is also effective in the detection of millimeter-sized liver metastases, with an ultrahigh contrast of 316%. Moreover, Mn2+ would trigger chemodynamic therapy (CDT) by exerting the Fenton-like activity to generate ˙OH from H2O2. Subsequently, a significant tumor suppression effect can be achieved by the GSH depletion-enhanced CDT. Besides, MnTBs manifest efficient urinary and hepatic excretions with biodegradability and minimal systemic toxicity. A pH/GSH dual responsive nanoprobe that integrates tumor diagnostic and therapeutic activities was developed to provide a new paradigm for precise diagnosis and treatment of tumors and metastases.

Aggregation-Induced Emission Luminogens for Enhanced Photodynamic Therapy: From Organelle Targeting to Tumor Targeting.

Photodynamic therapy (PDT) has attracted much attention in the field of anticancer treatment. However, PDT has to face challenges, such as aggregation caused by quenching of reactive oxygen species (ROS), and short 1O2 lifetime, which lead to unsatisfactory therapeutic effect. Aggregation-induced emission luminogen (AIEgens)-based photosensitizers (PSs) showed enhanced ROS generation upon aggregation, which showed great potential for hypoxic tumor treatment with enhanced PDT effect. In this review, we summarized the design strategies and applications of AIEgen-based PSs with improved PDT efficacy since 2019. Firstly, we introduce the research background and some basic knowledge in the related field. Secondly, the recent approaches of AIEgen-based PSs for enhanced PDT are summarized in two categories: (1) organelle-targeting PSs that could cause direct damage to organelles to enhance PDT effects, and (2) PSs with tumor-targeting abilities to selectively suppress tumor growth and reduce side effects. Finally, current challenges and future opportunities are discussed. We hope this review can offer new insights and inspirations for the development of AIEgen-based PSs for better PDT effect.

Safety and Effectiveness of Ruxolitinib in Real-World Patients with Myelofibrosis: A 2-Year Observational Study from Taiwan

Introduction Ruxolitinib (RUX) is an approved JAK1/JAK2 inhibitor for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), and post-essential thrombocythemia myelofibrosis (PET-MF), but real-world safety and efficacy of RUX in Taiwan are not well understood. This study was conducted to evaluate the safety and efficacy of treatment with RUX with intermediate-2 or high risk PMF, PPV-MF or PET-MF in routine clinical practice. Method This 2-year, single-arm, multicenter, post-marketing surveillance registry collected data on the safety, tolerability, efficacy, and other clinical information of adult patients (pts) aged ≥20 years with a confirmed diagnosis of intermediate-2 or high-risk PMF, PPV-MF, or PET-MF who either received RUX or starting RUX in accordance with the general clinical practice in Taiwan. Primary endpoint included collection of adverse events (AEs), AE of special interest (AESIs; anemia, thrombocytopenia, leukocytosis, hepatitis B virus (HBV) infection or reactivation, tuberculosis (TB) infection, and other infections), and serious adverse events (SAEs) throughout the study. Key secondary endpoints included treatment duration, discontinuation rates, dosage of prescribed RUX, Myeloproliferative Neoplasm symptom assessment form (MPN-10) score after study entry and change in spleen size, specifically in naïve patients who were eligible for spleen response evaluation. Results A total of 99 (51% PMF, 22.4% PPV-MF, and 26.5% PET-MF) pts were recruited, of which 38 (38.4%) pts discontinued due to consent withdrawal (n=11), death (n=10), discontinued prescription of RUX for 3 months (n=4), AEs (n = 2), unsatisfactory therapeutic effect (n=2), administrative problems (n=1), disease progression (n=1), required immediate stem cell transplantation (n=1), and others (n=6). Median age was 68.1 (range: 38.3-87.2) years and gender ratio was balanced, with 97 Taiwanese pts (98.0%). Median disease duration was 13.9 months (range: 0-967.6 months) and 70.7% and 28.3% of pts were identified with the risk of intermediate-2 or high using IPSS/DIPSS risk assessment, respectively. Majority of the recruited pts were RUX pre-treated (n=75; 75.8%) and 24.2% (n=24) pts were RUX-naïve at baseline. During the study, 88 pts (89.8%) had 673 AEs, and 44 (44.9%) experienced 159 SAEs. Half of the pts (55.1%) had moderate or severe SAEs and 39 pts recovered. Over 80% of SAEs (n=131) were not related to RUX. Major AESIs were anemia (29.6%) and thrombocytopenia (20.4%). There were no HBV infection or reactivation reported; 2% of pts had TB while 3% of pts had herpes zoster infections. The major reported infection was pneumonia (20.4%). Key safety data are summarized in Table 1. Most pts had their AEs resolved (77.6%), while 10 deaths occurred due to AEs (10.2%). Majority of the pts (41.8%) received a daily dose of RUX 20 mg at the enrolment, with an average mean daily dose of 22.7±9.2 mg (Figure 1). For naïve pts, mean initial dose was 18.8 ± 8.50 mg and gradually titrated up to 22.3 ± 8.69 mg at 3 months and to 24.0 ± 9.17 mg at 6 months. Among 98 pts, 13.3% pts whose platelet counts between 100-200×103/μL and 21.4% pts whose platelet counts were >200×103/μL were treated with RUX 5-10 mg twice daily. Among 27 RUX pre-treated patients (mean RUX duration before study entry: 17.0 ± 20.98 months), spleen size by palpation was relatively stable throughout the study period. For the 7 RUX naïve pts, the mean spleen size change from baseline was -15.9 %± 28.72 at 12 weeks, -30.8% ± 31.28 at 24 weeks, -54.2% ± 41.93 at 48 weeks and -52.0% ± 36.41 at 96 weeks. However, it should be interpreted with caution due to the small pt pool. A total of 65 pts (65.7%) had >50% improvement in the symptom response by MPN-10 during 2-year study period. . Conclusion This is the first real-world study in Taiwan to evaluate safety and efficacy with RUX in patients with MF. It was observed that physicians employed a conservative strategy for a lower starting dose with gradual titration resulting in comparable safety profile, but lower incidences of thrombocytopenia compared to published clinical trials. The majority of pts reported continuous symptomatic improvement and a small number of RUX naïve pts had pronounced spleen size reduction. Further investigations are required to evaluate whether optimal dose of RUX or titration speed would improve spleen response. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Metabolic Homeostasis-Regulated Nanoparticles for Antibody-Independent Cancer Radio-Immunotherapy.

The special metabolic traits of cancer cells and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) are promising targets for developing novel cancer therapy strategies, especially the glycolysis and mitochondrial energy metabolism. However, therapies targeting a singular metabolic pathway are always counteracted by the metabolic reprogramming of cancer, resulting in unsatisfactory therapeutic effect. Herein, this work employs poly(ethylene glycol)-coated (PEGylated) liposomes as the drug delivery system for both mannose and levamisole hydrochloride to simultaneously inhibit glycolysis and restrain mitochondrial energy metabolism and thus inhibit tumor growth. In combination with radiotherapy, the liposomes can not only modulate the immunosuppressive TME by cellular metabolism regulation to achieve potent therapeutic effect for local tumors, but also suppress the M2 macrophage proliferation triggered by X-ray irradiation and thus enhance the immune response to inhibit metastatic lesions. In brief, this work provides a new therapeutic strategy targeting the special metabolic traits of cancer cells and immunosuppressive TAMs to enhance the abscopal effect of radiotherapy for cancer.

A Novel Biodegradable Nanoplatform for Tumor Microenvironments Responsive Bimodal Magnetic Resonance Imaging and Sonodynamic/Ion Interference Cascade Therapy

The unsatisfactory therapeutic effect and long-term adverse effect markedly prevent inorganic nanomaterials from clinical transformation. In light of this, we developed a novel biodegradable theranostic agent (MnCO3:Ho3+@DOX/Ca3(PO4)2@BSA, HMCDB) based on the sonosensitizer manganese carbonate (MnCO3) coating with calcium phosphate (Ca3(PO4)2) and simultaneously loaded it with the chemotherapeutic drug doxorubicin (DOX). Due to the mild acidity of the tumor microenvironment (TME), the Ca3(PO4)2 shell degraded first, releasing substantial quantities of calcium ions (Ca2+) and DOX. Meanwhile, with the ultrasound (US) irradiation, MnCO3 produced enough reactive oxygen species (ROS) to cause oxidative stress in the cells, resulting in accumulation of Ca2+. Consequently, the cascade effect significantly amplified the therapeutic effect. Importantly, the nanocomposite can be completely degraded and cleared from the body, demonstrating that it was a promising theranostic agent for tumor therapy. Furthermore, the doped holmium ions (Ho3+) and in situ generation of manganese ions (Mn2+) in TME endow the nanoagent with the ability for tumor-specific bimodality T1/T2-weighted magnetic resonance imaging (MRI). This novel nanoplatform with low toxicity and biodegradability holds great potential for cancer diagnosis and treatment.

Quercetin Alleviates Lipopolysaccharide-Induced Cell Damage and Inflammation via Regulation of the TLR4/NF-κB Pathway in Bovine Intestinal Epithelial Cells.

Acute diarrhoea and intestinal inflammation represent one of the most prevalent clinical disorders of milk production, resulting in enormous annual financial damage for the dairy sector. In the context of an unsatisfactory therapeutic effect of antibiotics, the natural products of plants have been the focus of research. Quercetin is an important flavonoid found in a variety of plants, including fruits and vegetables, and has strong anti-inflammatory effects, so it has received extensive attention as a potential anti-inflammatory antioxidant. However, the underlying basis of quercetin on inflammatory reactions and oxidative tension generated by lipopolysaccharide (LPS) in bovine intestinal epithelial cells (BIECs) is currently unexplained. This research aimed to determine the influence of quercetin on LPS-induced inflammatory reactions, oxidative tension, and the barrier role of BIECs. Our findings demonstrated that BIEC viability was significantly improved in LPS-treated BIEC with 80 μg/mL quercetin compared with the control group. Indicators of oxidative overload and genes involved in barrier role revealed that 80 μg/mL quercetin efficiently rescued BIECs from oxidative and barrier impairment triggered by 5 μg/mL LPS. In addition, the mRNA expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6, as well as chemokines CXCL2, CXCL5, CCL5, and CXCL8, was diminished in LPS-treated BIECs with 80 μg/mL quercetin compared with LPS alone. Furthermore, the mRNA expression of toll-like receptor 4 (TLR4), CD14, myeloid differential protein-2 (MD2), and myeloid differentiation primary response protein (MyD88) genes associated with the TLR4 signal mechanism was markedly reduced by the addition of quercetin to LPS-modulated BIECs, indicating that quercetin can suppress the TLR4 signal mechanism. We performed Western blotting on the NF-κB signalling mechanism and compared it with immunofluorescence to further corroborate this conclusion. The LPS treatment enhanced the proportions of p-IκBα/GAPDH and p-p65/GAPDH. Compared with the LPS-treated group, quercetin administration decreased the proportions of p-IκBα/GAPDH and p-p65/GAPDH. In addition, immunofluorescence demonstrated that quercetin greatly reduced the LPS-induced nuclear translocation of NF-κB p65 in BIECs. The benefits of quercetin on inflammatory reactions in LPS-induced BIECs may be a result of its capacity to inhibit the TLR4-mediated NF-κB signalling mechanism. These findings suggest that quercetin can be used as an anti-inflammatory reagent to treat intestinal inflammation induced by LPS release.