Sorafenib Encapsulated Poly(ester amide) Nanoparticles for Efficient and Biosafe Prostate Cancer Therapy.

Prostate cancer (PCa) with a high incidence worldwide is a serious threat to men's health. Despite the continuous development of treatment strategies for PCa in recent years, the long-term prognosis of patients is still poor. Hence, the discovery and development of novel, secure, and efficient therapeutic approaches hold significant clinical significance. Although sorafenib (SOR) displays potential as a therapeutic option for PCa, its clinical efficacy is hindered by drug resistance, limited water solubility, and rapid metabolism. Therefore, we proposed to prepare nanoparticles (named SOR@8P4 NPs) utilizing the phenylalanine-based poly(ester amide) polymer (8P4) as the drug carrier to enhance the solubility and drug stability of SOR and improve the therapeutic targeting and bioavailability. SOR@8P4 NPs had high stability and showed acid-responsive drug release at the acidic tumor microenvironment. Additionally, SOR@8P4 NPs demonstrated more remarkable anticancer, antimetastatic, and antiproliferative abilities in vitro, compared with those of free drugs. SOR@8P4 NPs showed high tumor targeting and significantly inhibited tumor growth in vivo. In summary, the drug delivery system of SOR@8P4 NPs provides new ideas for the clinical treatment of PCa.

Network Pharmacology Based Elucidation of Molecular Mechanisms of Laoke Formula for Treatment of Advanced Non-Small Cell Lung Cancer.

OBJECTIVE: To explore the specific pharmacological molecular mechanisms of Laoke Formula (LK) on treating advanced non-small cell lung cancer (NSCLC) based on clinical application, network pharmacology and experimental validation. METHODS: Kaplan-Meier method and Cox regression analysis were used to evaluate the survival benefit of Chinese medicine (CM) treatment in 296 patients with NSCLC in Tianjin Medical University Cancer Institute and Hospital from January 2011 to December 2015. The compounds of LK were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and the corresponding targets were performed from Swiss Target Prediction. NSCLC-related targets were obtained from Therapeutic Target Database and Comparative Toxicogenomics Database. Key compounds and targets were identified from the compound-target-disease network and protein-protein interaction (PPI) network analysis, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis were used to predict the potential signaling pathways involved in the treatment of advanced NSCLC with LK. The binding affinities between key ingredients and targets were further verified using molecular docking. Finally, A549 cell proliferation and migration assay were used to evaluate the antitumor activity of LK. Western blot was used to further verify the expression of key target proteins related to the predicted pathways. RESULTS: Kaplan-Meier survival analysis showed that the overall survival of the CM group was longer than that of the non-CM group (36 months vs. 26 months), and COX regression analysis showed that LK treatment was an independent favorable prognostic factor (P=0.027). Next, 97 components and 86 potential targets were included in the network pharmacology, KEGG and GO analyses, and the results indicated that LK was associated with proliferation and apoptosis. Moreover, molecular docking revealed a good binding affinity between the key ingredients and targets. In vitro, A549 cell proliferation and migration assay showed that the biological inhibition effect was more obvious with the increase of LK concentration (P<0.05). And decreased expressions of nuclear factor κB1 (NF-κB1), epidermal growth factor receptor (EGFR) and AKT serine/threonine kinase 1 (AKT1) and increased expression of p53 (P<0.05) indicated the inhibitory effect of LK on NSCLC by Western blot. CONCLUSION: LK inhibits NSCLC by inhibiting EGFR/phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, NFκB signaling pathway and inducing apoptosis, which provides evidence for the therapeutic mechanism of LK to increase overall survival in NSCLC patients.

Syringic Acid Attenuates the IL-1ß-Induced Akt Pathway in Chondrocyte ATDC5 Cells.

BACKGROUND: Osteoarthritis (OA) is a chronic progressive joint ailment that is largely predominant worldwide. However, it typically gets worse over time, occurs more frequently, and becomes more crippling. OBJECTIVES: Syringic acid (SA) is a well-known phenolic compound reported to suppress inflammation, cell proliferation, and apoptosis of various cancer cells. Since the role of SA in OA remains unknown, there is a need to hypothesize the anti-inflammatory activities of SA on IL- 1ß-induced ATDC5 chondrocyte­like cells and to elucidate its protective action against OA. METHODS: The cytotoxicity, inflammatory mediators, mRNA expression of MMPs, ADAMTS, COX-2, and Akt/NF-κB protein expression of SA activity on ATDC5 cells were examined through CCK-8 assay, ELISA, RT-qPCR, and western blot. It was found that SA (10, 20, and 30 µM) did not show any inhibitory effects on the viability of the ATDC5 cells in a concentrationdependent manner. RESULTS: SA markedly reduced the inflammatory mediators, cytokines, PGE2, MMPs, COX-2, and ADAMTS in a concentration-dependent manner. Likewise, SA expressively attenuated IL- 1ß-stimulated Akt phosphorylation and NF-κB activation as well as IL-1ß- induced ATDC5 chondrocytes. CONCLUSION: This study revealed that SA is a novel candidate applicable for the treatment of OA.

Thoracic spinal cord injury and paraplegia caused by intradural cement leakage after percutaneous kyphoplasty: A case report.

BACKGROUND: Percutaneous kyphoplasty (PKP) is a pivotal intervention for osteoporotic fractures, pathological vertebral compression fractures, and vertebral bone tumors. Despite its efficacy, the procedure presents challenges, notably complications arising from intradural cement leakage. Timely and accurate diagnosis, coupled with emergent intervention is imperative to improve patient prognosis. This case report illuminates the intricacies and potential complications associated with PKP, emphasizing the critical need for vigilant monitoring, prompt diagnosis, and immediate intervention to mitigate adverse outcomes. CASE SUMMARY: A 58-year-old male patient, experiencing a T7 osteoporosis-related pathological compression fracture, underwent PKP at a local hospital. Two weeks post-procedure, the patient developed paraplegic and dysuric symptoms, necessitating emergency decompression surgery. Gradual improvement was achieved, marked by the restoration of muscle strength, sensation, and mobility. CONCLUSION: PKP Intradural cement leakage following PKP is unusual and potentially fatal. Prompt imaging examinations, urgent evaluation, and the decompression surgery are essential, which help alleviate symptoms associated with spinal damage, markedly improving the overall prognosis.

Cancer-associated fibroblasts promote enzalutamide resistance and PD-L1 expression in prostate cancer through CCL5-CCR5 paracrine axis.

Cancer-associated fibroblasts (CAFs) have been shown to play a key role in prostate cancer treatment resistance, but the role of CAFs in the initial course of enzalutamide therapy for prostate cancer remains unclear. Our research revealed that CAFs secrete CCL5, which promotes the upregulation of androgen receptor (AR) expression in prostate cancer cells, leading to resistance to enzalutamide therapy. Furthermore, CCL5 also enhances the expression of tumor programmed death-ligand 1 (PD-L1), resulting in immune escape. Mechanistically, CCL5 binds to the receptor CCR5 on prostate cancer cells and activates the AKT signaling pathway, leading to the upregulation of AR and PD-L1. The CCR5 antagonist maraviroc to inhibit the CAFs mediated CCL5 signaling pathway can effectively reduce the expression of AR and PD-L1, and improve the efficacy of enzalutamide. This study highlights a promising therapeutic approach targeting the CCL5-CCR5 signaling pathway to improve the effectiveness of enzalutamide.

Platinum-Loaded Cerium Oxide Capable of Repairing Neuronal Homeostasis for Cerebral Ischemia-Reperfusion Injury Therapy.

Effective neuroprotective agents are required to prevent neurological damage caused by reactive oxygen species (ROS) generated by cerebral ischemia-reperfusion injury (CIRI) following an acute ischemic stroke. Herein, it is aimed to develop the neuroprotective agents of cerium oxide loaded with platinum clusters engineered modifications (Ptn-CeO2). The density functional theory calculations show that Ptn-CeO2 could effectively scavenge ROS, including hydroxyl radicals (·OH) and superoxide anions (·O2 -). In addition, Ptn-CeO2 exhibits the superoxide dismutase- and catalase-like enzyme activities, which is capable of scavenging hydrogen peroxide (H2O2). The in vitro studies show that Ptn-CeO2 could adjust the restoration of the mitochondrial metabolism to ROS homeostasis, rebalance cytokines, and feature high biocompatibility. The studies in mice CIRI demonstrate that Ptn-CeO2 could also restore cytokine levels, reduce cysteine aspartate-specific protease (cleaved Caspase 3) levels, and induce the polarization of microglia to M2-type macrophages, thus inhibiting the inflammatory responses. As a result, Ptn-CeO2 inhibits the reperfusion-induced neuronal apoptosis, relieves the infarct volume, reduces the neurological severity score, and improves cognitive function. Overall, these findings suggest that the prominent neuroprotective effect of the engineered Ptn-CeO2 has a significant neuroprotective effect and provides a potential therapeutic alternative for CIRI.

Nickel-Catalyzed Reductive Cross-Coupling of Propargylic Acetates with Chloro(vinyl)silanes: Access to Silylallenes.

Because of their various reactivities, propargyl acetates are refined chemical intermediates that are extensively applied in pharmaceutical synthesis. Currently, reactions between propargyl acetates and chlorosilanes may be the most effective method for synthesizing silylallenes. Nevertheless, owing to the adaptability and selectivity of substrates, transition metal catalysis is difficult to achieve. Herein, nickel-catalyzed reductive cross-coupling reactions between propargyl acetates and substituted vinyl chlorosilanes for the synthesis of tetrasubstituted silylallenes are described. Therein, metallic zinc is a crucial reductant that effectively enables two electrophilic reagents to selectively construct C(sp2)-Si bonds. Additionally, a Ni-catalyzed reductive mechanism involving a radical process is proposed on the basis of deuteration-labeled experiments.

Ultralong Nanowires of Cadmium Phosphate Hydroxide Synthesized Using a Cadmium Oleate Precursor Hydrothermal Method and Sulfidation Conversion to Ultralong CdS Nanowires.

Ultralong nanowires with ultrahigh aspect ratios exhibit high flexibility, and they are promising for applications in various fields. Herein, a cadmium oleate precursor hydrothermal method is developed for the synthesis of ultralong nanowires of cadmium phosphate hydroxide. In this method, water-soluble cadmium salt is used as the cadmium source, water-soluble phosphate is used as the phosphorus source, and sodium oleate is adopted as a reactant to form cadmium oleate precursor and as a structure-directing agent. By using this method, ultralong nanowires of cadmium phosphate hydroxide are successfully synthesized using CdCl2, sodium oleate, and NaH2PO4 as reactants in an aqueous solution by hydrothermal treatment at 180 °C for 24 h. In addition, a new type of flexible fire-resistant inorganic paper with good electrical insulation performance is fabricated using ultralong nanowires of cadmium phosphate hydroxide. As an example of the extended application of this synthetic method, ultralong nanowires of cadmium phosphate hydroxide can be converted to ultralong CdS nanowires through a convenient sulfidation reaction. In this way, ultralong CdS nanowires are successfully synthesized by simple sulfidation of ultralong nanowires of cadmium phosphate hydroxide under mild conditions. The as-prepared ultralong nanowires of cadmium phosphate hydroxide are promising for applications as the precursors and templates for synthesizing other inorganic ultralong nanowires and have wide applications in various fields.

Delivery of gefitinib loaded nanoparticles for effectively inhibiting prostate cancer progression.

Androgen deprivation therapy is administered to suppress the growth of prostate cancer (PCa). However, some cells continue to proliferate independent of hormones, leading to the development of castration-resistant prostate cancer (CRPC). Overexpression of the epidermal growth factor receptor (EGFR) has been observed in CRPC and is associated with an unfavorable prognosis. Gefitinib (GEF) is an EGFR inhibitor used to treat patients with CRPC. Nevertheless, some clinical studies have reported that gefitinib does not result in prostate-specific antigen (PSA) or objectively measurable CRPC reactions. This lack of response may be attributed to the limited solubility in water, high side effects, low tumor aggregation, and insufficient tumor-specific reactions of GEF. In order to tackle these obstacles, we present a practical and efficient approach to administer GEF, encompassing the utilization of biocompatible nanostructures as a vehicle for drug delivery to augment its bioaccessibility and curative potency. Despite their small particle size, poly(D,L-lactide-co-glycolide) acid nanoparticles (PLGA NPs) exhibit a high drug-loading capacity, low toxicity, biocompatibility, biodegradability, and minimal immunogenicity. The drug delivery efficiency can be improved by employing GEF@PLGA NPs, which could also enhance drug cytotoxicity and impede the advancement of prostate cancer. Moreover, through experiments in vivo, it has been verified that GEF@PLGA NPs exhibit selective accumulation in the tumor and effectively restrain tumor growth. Therefore, the GEF@PLGA NPs hold great promise for the treatment of PCa.

Sparganosis of a thoracic vertebra misdiagnosed as bone metastasis from lung cancer.

Sparganosis is a rare parasitic infection caused by plerocercoid tapeworm larvae. We described a case of a 27-year-old man presenting with numbness in both legs and masses in the right lung and spine, initially thought to have spinal metastasis from lung cancer. However, after pathological and parasitological examinations, the patient was found to have spinal sparganosis, likely due to a history of consuming raw frogs. The patient was successfully treated with praziquantel, resulting in the recovery of muscle strength in his legs. This case highlights the importance of considering spinal sparganosis as a differential diagnosis in patients with spinal masses, especially those with a history of consuming raw or undercooked frogs. Accurate diagnosis and early treatment are crucial for managing this infection.

Clinical evaluation of a multitarget fecal immunochemical test-sDNA test for colorectal cancer screening in a high-risk population: a prospective, multicenter clinical study.

Colorectal cancer (CRC) is a major malignancy threatening the health of people in China and screening could be effective for preventing the occurrence and reducing the mortality of CRC. We conducted a multicenter, prospective clinical study which recruited 4,245 high-risk CRC individuals defined as having positive risk-adapted scores or fecal immunochemical test (FIT) results, to evaluate the clinical performance of the multitarget fecal immunochemical and stool DNA (FIT-sDNA) test for CRC screening. Each participant was asked to provide a stool sample prior to bowel preparation, and FIT-sDNA test and FIT were performed independently of colonoscopy. We found that 186 (4.4%) were confirmed to have CRC, and 375 (8.8%) had advanced precancerous neoplasia among the high CRC risk individuals. The sensitivity of detecting CRC for FIT-sDNA test was 91.9% (95% CI, 86.8-95.3), compared with 62.4% (95% CI, 54.9-69.3) for FIT (P < 0.001). The sensitivity for detecting advanced precancerous neoplasia was 63.5% (95% CI, 58.3-68.3) for FIT-sDNA test, compared with 30.9% (95% CI, 26.3-35.6) for FIT (P < 0.001). Multitarget FIT-sDNA test detected more colorectal advanced neoplasia than FIT. Overall, these findings indicated that in areas with limited colonoscopy resources, FIT-sDNA test could be a promising further risk triaging modality to select patients for colonoscopy in CRC screening.

Upregulated LncRNA H19 Sponges MiR-106a-5p and Contributes to Aldosterone-Induced Vascular Calcification via Activating the Runx2-Dependent Pathway.

BACKGROUND: Excess aldosterone is implicated in vascular calcification (VC), but the mechanism by which aldosterone-MR (mineralocorticoid receptor) complex promotes VC is unclear. Emerging evidence indicates that long-noncoding RNA H19 (H19) plays a critical role in VC. We examined whether aldosterone-induced osteogenic differentiation of vascular smooth muscle cells (VSMCs) through H19 epigenetic modification of Runx2 (runt-related transcription factor-2) in a MR-dependent manner. METHODS: We induced in vivo rat model of chronic kidney disease using a high adenine and phosphate diet to explore the relationship among aldosterone, MR, H19, and VC. We also cultured human aortic VSMCs to explore the roles of H19 in aldosterone-MR complex-induced osteogenic differentiation and calcification of VSMCs. RESULTS: H19 and Runx2 were significantly increased in aldosterone-induced VSMC osteogenic differentiation and VC, both in vitro and in vivo, which were significantly blocked by the MR antagonist spironolactone. Mechanistically, our findings reveal that the aldosterone-activated MR bound to H19 promoter and increased its transcriptional activity, as determined by chromatin immunoprecipitation, electrophoretic mobility shift assay, and luciferase reporter assay. Silencing H19 increased microRNA-106a-5p (miR-106a-5p) expression, which subsequently inhibited aldosterone-induced Runx2 expression at the posttranscriptional level. Importantly, we observed a direct interaction between H19 and miR-106a-5p, and downregulation of miR-106a-5p efficiently reversed the suppression of Runx2 induced by H19 silencing. CONCLUSIONS: Our study clarifies a novel mechanism by which upregulation of H19 contributes to aldosterone-MR complex-promoted Runx2-dependent VSMC osteogenic differentiation and VC through sponging miR-106a-5p. These findings highlight a potential therapeutic target for aldosterone-induced VC.

Risk factors for postoperative recurrence in patients with stage II colorectal cancer.

BACKGROUND: Recurrences are the main reasons for unfavorable outcomes for patients with stage II colorectal cancer (CRC). To obtain a clear understanding of the high-risk factors, further investigation is warranted. The present study aimed to analyze the risk factors associated with postoperative recurrence in patients with stage II CRC. METHODS: Eligible patients with pathologically confirmed stage II CRC were enrolled in the study retrospectively based on a prospectively maintained database from April 2008 to March 2019. The Kaplan-Meier method were used to calculate the overall survival (OS) rate and the cumulative recurrence rate. Univariate and multivariable Cox regression analyses were performed to identify risk factors for recurrence. RESULTS: There were 2515 patients included, of whom 233 (9.3%) developed local or distant recurrence. Recurrence was associated with a significantly worse 5-year OS (45.4% vs. 95.5%, p < 0.0001). The 5-year cumulative recurrence rate was 13.0% in patients with stage II CRC. On multivariable Cox analysis, tumor size (Hazard Ratio (HR) [95% confidence interval (CI)] = 1.79[1.38, 2.33]), preoperative carbohydrate antigen (CA) 125 level (HR [95% CI] = 1.78[1.17, 2.70]), preoperative CA 199 level (HR [95% CI] = 1.56[1.09, 2.22]), and ulcerating tumor (HR [95% CI] = 1.61[1.19, 2.17]) were found to be associated with postoperative recurrence. Adjuvant chemotherapy was associated with a lower cumulative recurrence rate in patients with these risk factors (p = 0.00096). CONCLUSION: The tumor diameter, preoperative CA125 level, preoperative CA199 level, and an ulcerative tumor can predict postoperative recurrence in patients with stage II CRC, and postoperative chemotherapy could reduce the cumulative recurrence rate in patients with these high-risk factors.

Photochemically controlled activation of STING by CAIX-targeting photocaged agonists to suppress tumor cell growth.

Controllable activation of the innate immune adapter protein - stimulator of interferon genes (STING) pathway is a critical challenge for the clinical development of STING agonists due to the potential "on-target off-tumor" toxicity caused by systematic activation of STING. Herein, we designed and synthesized a photo-caged STING agonist 2 with a tumor cell-targeting carbonic anhydrase inhibitor warhead, which could be readily uncaged by blue light to release the active STING agonist leading to remarkable activation of STING signaling. Furthermore, compound 2 was found to preferentially target tumor cells, stimulate the STING signaling in zebrafish embryo upon photo-uncaging and to induce proliferation of macrophages and upregulation of the mRNA expression of STING as well as its downstream NF-kB and cytokines, thus leading to significant suppression of tumor cell growth in a photo-dependent manner with reduced systemic toxicity. This photo-caged agonist not only provides a powerful tool to precisely trigger STING signalling, but also represents a novel controllable STING activation strategy for safer cancer immunotherapy.

A high-fidelity RNA-targeting Cas13 restores paternal Ube3a expression and improves motor functions in Angelman syndrome mice.

Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by loss of function mutations in maternally expressed UBE3A. No gene-specific treatment is available for patients so far. Although intact and transcriptionally active, paternally inherited UBE3A is silenced by elongation of antisense long noncoding RNA UBE3A-ATS in neurons. Here, we demonstrated that RNA targeting of paternal Ube3a-ATS with a high-fidelity CRISPR-Cas13 (hfCas13x.1) system could restore Ube3a expression to similar levels as that of maternal Ube3a in the cultured mouse neurons. Furthermore, injection into lateral ventricles with neuron-specific hSyn1 promoter-driven hfCas13x.1 packaged in adeno-associated virus (AAV-PHP.eb) could restore paternal Ube3a expression in cortex and hippocampus of neonatal AS mice for up to 4 months after treatment. Behavioral tests showed that expression of paternal Ube3a significantly alleviated AS-related symptoms, including obesity and motor function. Our results suggested that hfCas13x.1-mediated suppression of the Ube3a-ATS lncRNA potentially serves as a promising targeted intervention for AS.

The Pathology of Primary Familial Brain Calcification: Implications for Treatment.

Primary familial brain calcification (PFBC) is an inherited neurodegenerative disorder mainly characterized by progressive calcium deposition bilaterally in the brain, accompanied by various symptoms, such as dystonia, ataxia, parkinsonism, dementia, depression, headaches, and epilepsy. Currently, the etiology of PFBC is largely unknown, and no specific prevention or treatment is available. During the past 10 years, six causative genes (SLC20A2, PDGFRB, PDGFB, XPR1, MYORG, and JAM2) have been identified in PFBC. In this review, considering mechanistic studies of these genes at the cellular level and in animals, we summarize the pathogenesis and potential preventive and therapeutic strategies for PFBC patients. Our systematic analysis suggests a classification for PFBC genetic etiology based on several characteristics, provides a summary of the known composition of brain calcification, and identifies some potential therapeutic targets for PFBC.

Prognostic and clinicopathological values of LINC00665 in cancers: a systematic review and China population-based meta-analysis.

BACKGROUND: Recent studies have uncovered that the aberrant expression of LINC00665 contributes to the malignant pathological process of various cancers and is closely related to the unfavorable prognosis of patients with cancer. However, a systematic analysis of the prognostic and clinicopathologic values of LINC00665 in cancers has not been conducted. OBJECTIVE: We aim to clarify the association of LINC00665 expression with patient survival and clinicopathologic phenotypes in cancers. METHODS: An electronic search of PubMed, Embase and Web of Science was performed to select eligible literature. Pooled hazard ratio (HR) and odds ratio (OR) were calculated to assess the clinical importance of LINC00665. The fixed-effects model was used to analyze the combined HR values and 95% CI when the studies had no significant heterogeneity (P > 0.1 for the Chi-square test or I2 < 50%). Begg's test and sensitivity analysis were also conducted. This study was registered in The International Prospective Register of Systematic Reviews (PROSPERO registration number: CRD42021290123). RESULTS: A total of 710 patients from 10 eligible studies were enrolled in this meta-analysis, which was based on China population. The pooled results of this analysis revealed that high-level expression of LINC00665 was notably correlated with poor overall survival (HR = 2.08, 95% CI = 1.57-2.75) and recurrence-free survival (HR = 2.49, 95% CI = 1.63-3.80) in human cancers. Elevated LINC00665 expression was also correlated with more advanced clinical stage, earlier lymph node metastasis, lower tumor differentiation, earlier distant metastasis and larger tumor size. CONCLUSION: LINC00665 expression was critically related to the cancer prognosis, which has important prognostic implications for clinical prediction.

Glutathione-sensitive nanoparticles enhance the combined therapeutic effect of checkpoint kinase 1 inhibitor and cisplatin in prostate cancer.

Prostate cancer (PCa) is the second most common malignant tumor among males. Traditional treatments for PCa, which include surgery and endocrine therapy, have shown limited success, and more effective therapies are needed. Cisplatin (DDP) is an approved chemotherapeutic drug that causes DNA damage in cancer, whereas AZD7762, an inhibitor of CHK1, can significantly inhibit DNA repair. The effective therapeutic combination of cisplatin and the DNA damage response inhibitor AZD7762 has been considered to be a potential solution to the resistance to cisplatin and the adverse reactions that occur in many cancers. However, the co-transmission of cisplatin and AZD7762 and the unsatisfactory tumor-targeting efficacy of this therapy remain problems to be solved. Here, we confirmed the combined therapeutic efficacy of cisplatin and AZD7762 in PCa. Furthermore, we show that the glutathione-targeted Cys8E nanoparticles we synthesized, which have high drug-loading capacity, remarkable stability, and satisfactory release efficiency, enhanced the therapeutic efficacy of this treatment and reduced the required dosages of these drugs both in vitro and in vivo. Overall, we propose combination therapy of cisplatin and AZD7762 for PCa and facilitate it using Cys8E nanoparticles, which allow for better drug loading release, higher release efficiency, and more accurate tumor-targeting efficacy.

Design, synthesis and antitumor activity evaluation of novel indole acrylamide derivatives as IMPDH inhibitors.

Inosine 5'-monophosphate dehydrogenase (IMPDH; EC1.1.1.205) is the rate-limiting enzyme of GMP biosynthesis. The inhibition of IMPDH limits the growth and survival of tumors. Based on the systematic summary of clinical IMPDH inhibitors, 38 acrylamide derivatives with differently substituted indoles at the 3-position as the core scaffold were designed and synthesized. In addition, the actions of these compounds at the enzyme and cellular levels were evaluated. An MTT assay with different kinds of cells was used to assess the cytotoxic activities of compounds 14e and 14n, which displayed potent hIMPDH2 inhibitory activities (IC50 = 4.207 and 2.948 µM, respectively). Biological evaluation indicated that target compounds 14e and 14n displayed the most significant effects on SW480 human colon cancer cells (IC50 = 15.34 ± 0.06 and 15.31 ± 0.09 µM, respectively), and it was determined that these compounds are effective and valuable IMPDH inhibitors for cancer intervention.

Short-term Outcomes of Laparoscopy-Assisted vs Open Surgery for Patients With Low Rectal Cancer: The LASRE Randomized Clinical Trial.

Importance: The efficacy of laparoscopic vs open surgery for patients with low rectal cancer has not been established. Objective: To compare the short-term efficacy of laparoscopic surgery vs open surgery for treatment of low rectal cancer. Design, Setting, and Participants: This multicenter, noninferiority randomized clinical trial was conducted in 22 tertiary hospitals across China. Patients scheduled for curative-intent resection of low rectal cancer were randomized at a 2:1 ratio to undergo laparoscopic or open surgery. Between November 2013 and June 2018, 1070 patients were randomized to laparoscopic (n = 712) or open (n = 358) surgery. The planned follow-up was 5 years. Data analysis was performed from April 2021 to March 2022. Interventions: Eligible patients were randomized to receive either laparoscopic or open surgery. Main Outcomes and Measures: The short-term outcomes included pathologic outcomes, surgical outcomes, postoperative recovery, and 30-day postoperative complications and mortality. Results: A total of 1039 patients (685 in laparoscopic and 354 in open surgery) were included in the modified intention-to-treat analysis (median [range] age, 57 [20-75] years; 620 men [59.7%]; clinical TNM stage II/III disease in 659 patients). The rate of complete mesorectal excision was 85.3% (521 of 685) in the laparoscopic group vs 85.8% (266 of 354) in the open group (difference, -0.5%; 95% CI, -5.1% to 4.5%; P = .78). The rate of negative circumferential and distal resection margins was 98.2% (673 of 685) vs 99.7% (353 of 354) (difference, -1.5%; 95% CI, -2.8% to 0.0%; P = .09) and 99.4% (681 of 685) vs 100% (354 of 354) (difference, -0.6%; 95% CI, -1.5% to 0.5%; P = .36), respectively. The median number of retrieved lymph nodes was 13.0 vs 12.0 (difference, 1.0; 95% CI, 0.1-1.9; P = .39). The laparoscopic group had a higher rate of sphincter preservation (491 of 685 [71.7%] vs 230 of 354 [65.0%]; difference, 6.7%; 95% CI, 0.8%-12.8%; P = .03) and shorter duration of hospitalization (8.0 vs 9.0 days; difference, -1.0; 95% CI, -1.7 to -0.3; P = .008). There was no significant difference in postoperative complications rate between the 2 groups (89 of 685 [13.0%] vs 61 of 354 [17.2%]; difference, -4.2%; 95% CI, -9.1% to -0.3%; P = .07). No patient died within 30 days. Conclusions and Relevance: In this randomized clinical trial of patients with low rectal cancer, laparoscopic surgery performed by experienced surgeons was shown to provide pathologic outcomes comparable to open surgery, with a higher sphincter preservation rate and favorable postoperative recovery. Trial Registration: ClinicalTrials.gov Identifier: NCT01899547.