MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions.

OBJECTIVES: Cancer cells undergo metabolic reprogramming to adapt to high oxidative stress, but little is known about how metabolic remodeling enables gastric cancer cells to survive stress associated with aberrant reactive oxygen species (ROS) production. Here, we aimed to identify the key metabolic enzymes that protect gastric cancer (GC) cells from oxidative stress. METHODS: ROS level was detected by DCFH-DA probes. Multiple cell biological studies were performed to identify the underlying mechanisms. Furthermore, cell-based xenograft and patient-derived xenograft (PDX) model were performed to evaluate the role of MTHFD2 in vivo. RESULTS: We found that overexpression of MTHFD2, but not MTHFD1, is associated with reduced overall and disease-free survival in gastric cancer. In addition, MTHFD2 knockdown reduces the cellular NADPH/NADP+ ratio, colony formation and mitochondrial function, increases cellular ROS and cleaved PARP levels and induces in cell death under hypoxia, a hallmark of solid cancers and a common inducer of oxidative stress. Moreover, genetic or pharmacological inhibition of MTHFD2 reduces tumor burden in both tumor cell lines and patient-derived xenograft-based models. DISCUSSION: our study highlights the crucial role of MTHFD2 in redox regulation and tumor progression, demonstrating the therapeutic potential of targeting MTHFD2.

Association between vitamin B2 intake and prostate-specific antigen in American men: 2003-2010 National Health and Nutrition Examination Survey.

BACKGROUND: Accumulating evidence suggests a pivotal role of vitamin B2 in the pathogenesis and progression of prostate cancer (PCa). Vitamin B2 intake has been postulated to modulate the screening rate for PCa by altering the concentration of prostate-specific antigen(PSA). However, the relationship between vitamin B2 and PSA remains indeterminate. Hence, we conducted a comprehensive evaluation of the association between vitamin B2 intake and PSA levels, utilizing data from the National Health and Nutrition Examination Survey (NHANES) database. METHODS: From a pool of 20,371 participants in the NHANES survey conducted between 2003 and 2010, a cohort of 2,323 participants was selected for the present study. The male participants were classified into four distinct groups based on their levels of vitamin B2 intake. We employed a multiple linear regression model and a non-parametric regression method to investigate the relationship between vitamin B2 and PSA levels. RESULTS: The study cohort comprised of 2,323 participants with a mean age of 54.95 years (± 11.73). Our findings revealed a statistically significant inverse correlation between vitamin B2 intake (mg) and PSA levels, with a reduction of 0.13 ng/ml PSA concentration for every unit increase in vitamin B2 intake. Furthermore, we employed a fully adjusted model to construct a smooth curve to explore the possible linear relationship between vitamin B2 intake and PSA concentration. CONCLUSIONS: Our study in American men has unveiled a notable inverse association between vitamin B2 intake and PSA levels, potentially posing a challenge for the identification of asymptomatic prostate cancer. Specifically, our findings suggest that individuals with higher vitamin B2 intake may be at a greater risk of being diagnosed with advanced prostate cancer in the future, possibly indicating a detection bias. These results may offer a novel explanation for the observed positive correlation between vitamin B2 intake and prostate cancer.

Neuropilin-1-Targeted Nanomedicine for Spatiotemporal Tumor Suppression through Photodynamic Vascular Damage and Antiangiogenesis.

Antiangiogenic therapy is an effective way to disrupt nutrient supply and starve tumors, but it is restricted by poor efficacy and negative feedback-induced tumor relapse. In this study, a neuropilin-1 (NRP-1)-targeted nanomedicine (designated as FPPT@Axi) is reported for spatiotemporal tumor suppression by combining photodynamic therapy (PDT) with antiangiogenesis. In brief, FPPT@Axi is prepared by utilizing an NRP-1-targeting chimeric peptide (Fmoc-K(PpIX)-PEG8-TKPRR) to encapsulate the antiangiogenic drug Axitinib (Axi). Importantly, the NRP-1-mediated targeting property enables FPPT@Axi to selectively concentrate at vascular endothelial and breast cancer cells, facilitating the production of reactive oxygen species (ROS) in situ for specific vascular disruption and enhanced cell apoptosis under light stimulation. Moreover, the codelivered Axi can further inhibit vascular endothelial growth factor receptor (VEGFR) to impair the negative feedback of PDT-induced tumor neovascularization. Consequently, FPPT@Axi spatiotemporally restrains the tumor growth through blocking angiogenesis, destroying tumor vessels, and inducing tumor apoptosis. Such an NRP-1-mediated targeting codelivery system sheds light on constructing an appealing candidate with translational potential by using clinically approved PDT and chemotherapy.

A radical 1,4-aryl migration enables nickel-catalysed remote cross-electrophile coupling of ß-bromo amino acid esters with vinyl triflates.

A radical 1,4-aryl migration enabling a cross-electrophile coupling reaction toward remote transalkylation of N-benzyl alanine has been developed. In this strategy, with the occurrence of a radical-mediated Turce-Smiles rearrangement, key α-aminoalkyl radicals are generated. The as-formed α-aminoalkyl radical serves as a robust coupling partner for cross-electrophilic coupling with vinyl triflates, affording a series of olefin-tethered amino acid motifs.

Pollution Status and Associated Risk Assessment of Heavy Metals in Sewage Sludge in the Yangtze River Delta, China.

The risk assessment of heavy metals (HMs) in sewage sludge (SS) is essential before land application. Six HMs in nineteen SS collected in the Yangtze River Delta were analyzed to assess risks to environment, ecosystem, and human health. HMs concentrations were ranked in the order of Zn > Cu > Cr > Ni > Pb > Cd, with Cu, Zn, and Ni in a total of 16% of samples exceeding the legal standard. Zn showed greatest extractability according to EDTA-extractable concentrations. HMs in 16% of SS samples posed heavy contamination to the environment with Zn as the major pollutant. HMs in 26% of samples posed ecological risk to the ecosystem and Cd was the highest risky HM. The probabilistic health risk assessment revealed that HMs posed carcinogenic risks to all populations, but non-carcinogenic risks only to children. This work will provide fundamental information for land application of SS in this area.

Andrographolide causes p53-independent HCC cell death through p62 accumulation and impaired DNA damage repair.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly lethal cancer characterized by dominant driver mutations, including p53. Consequently, there is an urgent need to search for novel therapeutic agents to treat HCC. Andrographolide (Andro), a clinically available anti-inflammatory phytochemical agent, has shown inhibitory effects against various types of cancer, including HCC. However, the underlying molecular mechanisms of its action remain poorly understood. PURPOSE: This study aims to investigate the molecular mechanisms by which p53 and p62 collectively affect Andro-induced HCC cell death, using both in vitro and in vivo models. METHODS: In vitro cellular experiments were conducted to examine the effects of Andro on cell viability and elucidate its mechanisms of action. In vivo xenograft experiments further validated the anti-cancer effects of Andro. RESULTS: Andro induced dose- and time-dependent HCC cell death while sparing normal HL-7702 hepatocytes. Furthermore, Andro caused DNA damage through the generation of reactive oxygen species (ROS), a critical event leading to cell death. Notably, HCC cells expressing p53 exhibited greater resistance to Andro-induced cell death compared to p53-deficient cells, likely due to the ability of p53 to induce G2/M cell cycle arrest. Additionally, Andro-induced p62 aggregation led to the proteasomal degradation of RAD51 and 53BP1, two key proteins involved in DNA damage repair. Consequently, silencing or knocking out p62 facilitated DNA damage repair and protected HCC cells. Importantly, disruption of either p53 or p62 did not affect the expression of the other protein. These findings were further supported by the observation that xenograft tumors formed by p62-knockout HCC cells displayed increased resistance to Andro treatment. CONCLUSION: This study elucidates the mechanistic basis of Andro-induced HCC cell death. It provides valuable insights for repurposing Andro for the treatment of HCC, regardless of the presence of functional p53.

Where is the optimal plane to mobilize the anterior rectal wall in female patients undergoing total mesorectal excision?

BACKGROUND: Since Heald proposed the total mesorectal excision (TME) procedure, the prognosis of patients with rectal cancer has been significantly improved. But Heald did not specifically describe the anterior surgical plane in female patients. And the surgical plane for mobilizing the anterior rectal wall during TME surgery in female patients remains controversial. AIM: To investigate the anatomy of the female pelvis and identify the optimal plane for mobilizing the anterior rectal wall. METHODS: We retrospectively collected surgical procedure videos and clinical data of female patients diagnosed with middle or low rectal cancer who underwent the TME procedure between January 2020 and October 2022 across six hospitals. The patients were divided into two groups based on the surgical approach used to mobilize the anterior rectal wall: The experimental group was to open the peritoneum at the lowest point of the peritonea reflection and enter the plane for mobilizing, while the control group was cut at 0.5-1 cm above the peritoneal reflection and enter another plan. Then, we compared the preoperative and postoperative information between the two groups. We also dissected and observed ten adult female pelvises to analyze the anatomic structure and compare the entry plane between the two approaches. Finally, we researched the pathological structure between the rectum and the vagina. RESULTS: Finally, 77 cases that met the criteria were included in our study. Our observations revealed that the experimental group underwent a smooth procedure, entering the plane amidst the mesorectal fascia and adventitia of the vagina, whereas the control group entered the plane between the vaginal adventitia and muscle layers. Compared to the control group, the experimental group showed a significant decrease in intraoperative bleeding [22.5 (19.5-50) mL vs 17 (5-20) mL, P = 0.01], as well as a shorter duration of hospitalization [9 (7-11.25) d vs 7 (6-10) d, P = 0.03]. Through the examination of surgical videos and cadaveric studies, we discovered that Denonvilliers' fascia is absent in females. Additionally, pathological sections further revealed the absence of Denonvilliers' fascia in females, with only loose connective tissue present between the mesorectal fascia and adventitia of the vagina. CONCLUSION: The plane amidst the mesorectal fascia and vaginal adventitia is the optimal surgical plane to mobilize the anterior rectal wall for female patients undergoing the TME procedure.

[Determination of 15 halogenated polycyclic aromatic hydrocarbons in aquatic products by stable isotope dilution coupled with gas chromatography-triple quadrupole mass spectrometry].

Halogenated polycyclic aromatic hydrocarbons (H-PAHs), including chlorinated polycyclic aromatic hydrocarbons (Cl-PAHs) and brominated polycyclic aromatic hydrocarbons (Br-PAHs), are compounds in which one or more hydrogen atoms replaced by chlorine or bromine atoms. These compounds are not only difficult to degrade but also highly fat soluble and toxic. They are a new type of high-risk organic pollutants with structures similar to those of dioxins, and their toxicity is even higher than that of the parent polycyclic aromatic hydrocarbons (PAHs). The bioaccumulation of H-PAHs can be predicted by their octanol-water partition coefficient (Kow); in general, higher bioaccumulation capacity and Kow values indicate greater fat solubility. Therefore, animal-derived foods with higher fat contents, such as animal meat, milk, aquatic products, and their processed forms, are more likely to be contaminated with higher contents of H-PAHs than those with lower fat contents. In this work, a gas chromatography-triple quadrupole mass spectrometry (GC-MS/MS) method coupled with stable isotope dilution was established to determine 15 H-PAHs in aquatic products. The instrument and pretreatment methods were systematically optimized. The GC-MS/MS used in this method can effectively eliminate matrix interferences and features high sensitivity and low analytical cost; thus, it has good application prospects. The samples were added with an isotope internal standard before extraction to calibrate the loss of the tested substance during the pretreatment process, extracted by accelerated solvent extraction, purified using gel permeation chromatography and PRiME HLB columns, and then analyzed by GC-MS/MS. The use of two DB-5MS chromatographic columns (30 m×0.25 mm×0.25 µm) and microplate fluidics technology to connect chromatographic columns 1 and 2 in series led to better separation effects, good peak shapes, and high target compound responses. The 15 H-PAHs demonstrated good linearities in the range of 1-50 µg/L, with correlation coefficients (r) greater than or equal to 0.993. The relative standard deviation (RSD) values of the relative response factor (RRF) of the H-PAHs were less than 9%, the method detection limit (MDL) was 0.009-0.072 µg/kg, and the method quantification limit (MQL) was 0.031-0.240 µg/kg. Three spiked levels of 0.25, 1.0, 2.5 µg/kg were added to the blank samples to determine the recovery and precision. The recoveries for these spiked levels were 74.6%-116.8%, 77.8%-123.2%, and 71.9%-124.8%, respectively, and the corresponding RSDs were 0.6%-8.2%, 0.6%-9.0%, and 0.4%-10.6%, respectively. The total actual content of H-PAHs in aquatic product samples was 0.60-3.54 µg/kg. Among the H-PAHs investigated, 9-chlorophenanthrene (9-ClPhe) showed the greatest detection rate (100%) and highest content (1.15 µg/kg), indicating that H-PAHs widely exist in aquatic products. Thus, further assessment of the dietary exposure risk of these compounds is necessary. The developed method simplifies the pretreatment step, and has the advantages of simplicity, rapid analysis, high recoveries, and good stability. It is suitable for the qualitative and quantitative analysis of H-PAHs in actual aquatic product samples and provides reliable technical support for the residue status and risk assessment of H-PAHs in aquatic products.

Feedback-Elevated Antitumor Amplifier of Self-Delivery Nanomedicine by Suppressing Photodynamic Therapy-Caused Inflammation.

Inflammation activation is accompanied by tumor growth, migration, and differentiation. Photodynamic therapy (PDT) can trigger an inflammatory response to cause negative feedback of tumor inhibition. In this paper, a feedback-elevated antitumor amplifier is developed by constructing self-delivery nanomedicine for PDT and cascade anti-inflammation therapy. Based on the photosensitizer chlorin e6 (Ce6) and COX-2 inhibitor indomethacin (Indo), the nanomedicine is prepared via molecular self-assembly technology without additional drug carriers. It is exciting that the optimized nanomedicine (designated as CeIndo) possesses favorable stability and dispersibility in the aqueous phase. Moreover, the drug delivery efficiency of CeIndo is significantly improved, which could be effectively accumulated at the tumor site and internalized by tumor cells. Importantly, CeIndo not only exhibits a robust PDT efficacy on tumor cells but also drastically decreases the PDT-induced inflammatory response in vivo, resulting in feedback-elevated tumor inhibition. By virtue of the synergistic effect of PDT and cascade inflammation suppression, CeIndo tremendously reduces tumor growth and leads to a low side effect. This study presents a paradigm for the development of codelivery nanomedicine for enhanced tumor therapy through inflammation suppression.

Diet quality and survival after ovarian cancer: results from an ovarian cancer follow-up study (OOPS).

Background and aims: Owing to the limited studies and controversial evidence, the connection between diet quality and survival of patients with ovarian cancer (OC) has been indistinct. Our study intends to first investigate this topic based on Chinese diet quality scores. Methods: Our data come from an ovarian cancer follow-up study, which includes 796 patients with OC between 2015 and 2020. Three diet quality scores, including the Chinese Healthy Eating Index (CHEI), Dietary Balance Index (DBI), and Chinese Food Pagoda Score (CFPS), were calculated using a validated 111-item food frequency questionnaire. We used the Cox proportional hazards regression model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Potential multiplicative and additive interactions were also assessed. Results: With a median follow-up time of 37.17 months (interquartile: 24.73-50.17 months), we recorded 130 deaths. According to comparisons of the highest to lowest tertile of scores, the pre-diagnosis CHEI was linked to better overall survival (OS) in patients (HR = 0.56, 95% CI: 0.36, 0.88). A dose-response relationship between CHEI and OS was also observed (HR = 0.85, 95% CI: 0.71, 1.00, per 1 standard deviation increment). However, no evidence of significant associations between DBI and CFPS with OS was observed. Additionally, significant multiplicative and additive interactions were seen in the diet quality scores (CHEI and DBI) with the body mass index and the menopausal status. Conclusions: A high CHEI was associated with an improved OS for patients with OC, while DBI and CFPS were unrelated to OC survival.

Non-Genetic Factors and Risk of Cervical Cancer: An Umbrella Review of Systematic Reviews and Meta-Analyses of Observational Studies.

Objectives: The association between non-genetic risk factors and cervical cancer (CC) remains controversial and unclear. This umbrella review was conducted to evaluate and synthesize previously published systematic reviews and meta-analyses related to non-genetic factors and CC risk. Methods: We searched PubMed, Web of Science, and EMBASE to identify studies investigating the association between extragenetic factors and CC risk. For each article, we calculated the summary effect size and the 95% confidence interval. Specific criteria were used to classify the association into four levels: strong, highly suggestive, suggestive, or weak. Results: A total of 18 meta-analyses of different risk factors for CC were examined; these studies covered risk factors related to diet, lifestyle, reproduction, disease, viral infection, microorganisms, and parasites. Oral contraceptive use and Chlamydia trachomatis infection were shown to increase CC risk, and this was supported by strong evidence. Additionally, there were four risk factors supported by highly suggestive evidence and six risk factors supported by suggestive evidence. Conclusion: In conclusion, there is a strong association between oral contraceptive use, Chlamydia trachomatis infection, and increased CC risk.

Targeting BRCA-mutant biliary tract cancer: Current evidence and future perspectives.

Biliary tract cancers (BTCs) are aggressive tumors of the biliary system, which are often diagnosed at the advanced stage with a dismal prognosis. Among BTC patients, germline or somatic breast cancer-related gene 1/2 (BRCA1/2) mutation has been reported and the use of poly(ADP-ribose) polymerase inhibitor (PARPi) has achieved a certain effect, with no obvious severe side effects. The frequencies and mutated types of BRCA1/2 in advanced BTCs vary among studies. BRCA1 and BRCA2 play distinct roles in the development of BTC regardless of age or gender difference. Surprisingly, some BTC patients with germline BRCA mutation can achieve better therapeutic effects than those with a somatic mutation, and patients who carry BRCA mutation are more likely to benefit from immunotherapy alone or in combination. Herein, we provide an overview of the targeted therapies in BRCA-mutant BTCs, with a particular focus on the differences between germline and somatic BRCA1/2 mutations, as well as review the current status and perspectives.

Chidamide as maintenance after chemotherapy or hematopoietic stem cell transplantation in 27 children with T-cell lymphoblastic leukemia: A real-world prospective study.

Background: The long-term overall survival of children with T-cell acute lymphoblastic leukemia (T-ALL) is limited to approximately 80-85% because of a high incidence of relapse after achieving remission with intensive chemotherapy and hematopoietic stem cell transplantation (HSCT). Novel treatment strategies inducing long-term remission are needed to improve the outcome. Histone deacetylase inhibitors (HDACis) have been reported to be effective in a series of T-ALL cases. Preclinical studies suggested that T-ALL cells are sensitive to Chidamide, which is a selective HDACi. Methods: This preliminary clinical study evaluated the efficacy and safety of Chidamide in combination with chemotherapy or post-HSCT for children with T-ALL at a dose of 0.5 mg/kg weight of patient twice per week for at least 6 months. Results: In total, 27 children with a mean age of 7.88 years were included. The high-risk proportion was 66.7%. After a median follow-up period of 37.8 months (9.5-67.9 months), the overall survival and event-free survival in the patients treated with Chidamide were 94.1 and 95.2%, respectively. All patients except two maintained persistent remission with <0.01% blast cells in minimal residual disease. Conclusion: The combination therapy with Chidamide in a case series of T-ALL shows the promising clinical efficacy and good safety in children. Clinical trial registration: https://www.chictr.org.cn/, identifier ChiCTR2000030357.

Bioengineered Bacterial Membrane Vesicles with Multifunctional Nanoparticles as a Versatile Platform for Cancer Immunotherapy.

Inducing immunogenic cell death (ICD) is a critical strategy for enhancing cancer immunotherapy. However, inefficient and risky ICD inducers along with a tumor hypoxia microenvironment seriously limit the immunotherapy efficacy. Non-specific delivery is also responsible for this inefficiency. In this work, we report a drug-free bacteria-derived outer membrane vesicle (OMV)-functionalized Fe3O4-MnO2 (FMO) nanoplatform that realized neutrophil-mediated targeted delivery and photothermally enhanced cancer immunotherapy. In this system, modification of OMVs derived from Escherichia coli enhanced the accumulation of FMO NPs at the tumor tissue through neutrophil-mediated targeted delivery. The FMO NPs underwent reactive decomposition in the tumor site, generating manganese and iron ions that induced ICD and O2 that regulated the tumor hypoxia environment. Moreover, OMVs are rich in pathogen-associated pattern molecules that can overcome the tumor immunosuppressive microenvironment and effectively activate immune cells, thereby enhancing specific immune responses. Photothermal therapy (PTT) caused by MnO2 and Fe3O4 can not only indirectly stimulate systemic immunity by directly destroying tumor cells but also promote the enrichment of neutrophil-equipped nanoparticles by enhancing the inflammatory response at the tumor site. Finally, the proposed multi-modal treatment system with targeted delivery capability realized effective tumor immunotherapy to prevent tumor growth and recurrence.

Ethanol Embolization of Chest Wall Arteriovenous Malformations: Four-Year Findings.

OBJECTIVES: To summarize the clinical characteristics and investigate the efficacy of ethanol embolotherapy in the treatment of chest well arteriovenous malformation (AVM). Treatment-associated complications were also explored. MATERIALS AND METHODS: Between March 2017 and August 2021, 32 consecutive patients (mean age, 23.7 years; age range, 5-54 years) who underwent ethanol embolotherapy for chest well AVMs under general anesthesia were included in this study. Embolization was performed through a direct puncture, transarterial catheterization, or a combination of the 2 procedures. The mean follow-up duration after the last treatment was 18.0 months (range, 3-42 months). The degree of devascularization on follow-up (assessed using angiography or computed tomography), and the clinical signs and symptoms of AVMs were evaluated as the therapeutic outcomes. The major and minor complications associated with the procedures were recorded. RESULTS: A total of 103 embolization procedures (mean, 3.2; range, 2-7) comprising 101 ethanol embolization and 2 coil embolizations were performed on 32 patients with chest wall AVMs. The AVM nidus was accessed through the transarterial approach alone in 4 patients, by direct puncture in 11, and a combined procedure in 17 patients. Overall, more than 80% of the procedures were performed using the combined approach. Complete AVM devascularization was achieved in 12 (37.5%) patients. Moreover, 76% to 99% AVM was achieved in 18 patients (56.3%), and 50% to 75% in 2 patients (6.3%). Bleeding, pain, heart failure, and cosmetic deformities were the indications for treatment. For 3 patients (3/32, 9.4%) who had bleeding, the treatment stopped the hemorrhage. Complete pain relief was reported in 8 patients (8/32, 25.0%), whereas complete relief from congestive heart failure post-embolization was observed in 5 of the 6 patients with congestive heart failure (5/6, 83.3%). Complete correction of cosmesis deformities after embolization was achieved in 10 patients (10/32, 31.3%). Two patients who underwent surgery to correct persistent deformity after embolization only showed insignificant improvement. In addition, 6 (18.8%) patients developed 13 complications including blister, necrosis, hemothorax, transient hemoglobinuria, and transient pulmonary artery hypertension. CONCLUSIONS: Ethanol embolotherapy is a safe and effective procedure for chest well AVMs. Surgery is required for some patients with residual cosmesis deformity. CLINICAL IMPACT: Currently, there is no standard treatment for chest well AVMs due to their rarity and high heterogeneity. The present study shows that thanol embolotherapy is a safe and clinically effective treatment procedure for the chest well AVMs. Transarterial embolization in combination with direct puncture embolization can reach the AVM nidus. Ethanol embolotherapy can achieve complete obliteration of the AVM nidus in the majority of patients. Surgery may still be needed to correct cosmetic deformity after embolization. The present study provides valuable evidence to inform clinical decision-making.

Response of occurrence in microplastics and its adsorped cadmium capacity to simulated agricultural environmental scenarios in sludge-amended soil.

Large amounts of microplastics (MPs) enter the soil along with the amendment of sludge to soil. However, it is still unclear about the response of MPs occurrence and the adsorption behaviors of cadmium (Cd)on MPs to typical agricultural environmental scenarios. In present work, three kinds of MPs (polyethylene, polypropylene, and polystyrene) were chosen to investigate that response in three agricultural environmental scenarios with sludge-amended soil, including dry-wet alteration (7 d, five cycles), microbial addition (Bacillus subtilis, 0.05 g/g soil), and Ultraviolet (UV) irradiation (340 nm, 4 × 15 W, 4 d). The results showed that there was the highest adsorption capacity of Cd on MPs (36.21, 45.15, 12.43 µg/g for PE, PP, PS, respectively) after UV irradiation exceeding those from MPs triggered by other two scenarios). UV irradiation caused an increase in the abundance of Streptomyces, an expansion in specific surface area, a significant change in surface morphologies, an improvement in crystallinity or the formation of new crystals, and an enhancement in C-O and CO content, and then resulted in the incremental adsorption capacity of Cd on MPs. The findings are important of significance for controlling the environmental risks from sludge MPs via carrying heavy metals in the soil-plant systems.

Discovery of novel hydroxyamidine based indoleamine 2,3-dioxygenase 1 (IDO1) and thioredoxin reductase 1 (TrxR1) dual inhibitors.

In order to take advantage of both immunotherapeutic and metabolic antitumor agents, novel dual indoleamine 2,3- dioxygenase 1 (IDO1) and thioredoxin reductase 1 (TrxR1) inhibitors were designed. Thioredoxin reductase 1 (TrxR1) is a main ROS modulator within CRC cells. Indoleamine 2,3-dioxygenase (IDO1) is crucial controller for tryptophan (Trp) metabolism that is also important for CRC immunotherapy. Herein, ten compounds 12a-j containing hydroxyamidine scaffold were designed, synthesized and evaluated for inhibitory activities against IDO1/TrxR1 enzyme and CRC cells. Among these compounds, the most active compound 12d (ZC0109) showed excellent and balanced activity against both IDO1 (IC50 = 0.05 µM) and TrxR1 (IC50 = 3.00 ± 0.25 µM) were selected for further evaluation. Compound ZC0109 exhibited good dual inhibition against IDO1 and TrxR1 both in vitro and in vivo. Further mechanistic studies reveal that, through IDO1 and TrxR1 inhibition by ZC0109 treatment, accumulated ROS effectively induced apoptosis and G1/S cell cycle arrest in cancer cells. In vivo evaluation demonstrated excellent anti-tumor effect of ZC0109 with the notable ability of promoting ROS-induced apoptosis, reducing kynurenine level in plasma and restoring anti-tumor immune response. Thus, ZC0109 represents a potential CRC therapy agent for further development.

[The first metatarsophalangeal joint fusion combined with lateral toe rotation Weil osteotomy for hallux valgus with severe metatarsal adduction].

OBJECTIVE: To explore clinical effect of the first metatarsophalangeal joint fusion combined with lateral toe rotation Weil osteotomy in treating hallux valgus with severe metatarsal adduction. METHODS: From March 2017 to August 2021, 37 patients ( 69 feet ) with severe plantar adductor hallux valgus were treated with the first metatarsophalangeal joint fusion combined with rotational Weil osteotomy were retrospectively analyzed, including 8 males(11 feet) and 29 females (58 feet), aged from 67 to 83 years old with an average of (70.03±2.87) years old;3 cases on the left side, 2 cases on the right side and 32 cases on both sides. Visual analogue scale(VAS) was used to evaluate degree of pain relief before operation, 6 weeks after operation and at the final follow-up. American Orthopaedic Foot and Ankle Surgery (AOFAS) forefoot score was used to evaluate function of the affected foot before operation and final follow-up. Hallux valgus angle(HVA) and intermetatarsal angle(IMA) were measured before operation and at the final follow-up. RESULTS: Thirty-seven patients(69 feet) were followed up from 12 to 48 months with an average of(22.8±0.6) months. Bone healing was achieved at the first metatarsophalangeal joint from 7 to 10 weeks with an average of (8.00±1.21) weeks after operation, without delay and nonunion. HVA was increased from (44.30±2.84)° before operation to (15.20±2.13) °at the final follow-up, and had statistical difference(t=65.781, P<0.05);while no difference in IMA before and after operation(P>0.05). VAS was decreased from (6.73±1.48) points to (2.78±0.71) points at 6 months after operation(t=3.279, P<0.05), and had difference compared with the latest follow-up(1.16±1.12)(t=4.859, P<0.05). AOFAS forefoot score increased from (52.14±5.78) preoperatively to (86.70±4.86) at the fonal follow-up, and 25 feet got excellent results, 40 feet good and 4 feet fair. CONCLUSION: The first metatarsophalangeal joint fusion combined with lateral toe rotation Weil osteotomy in treating severe plantar adduction hallux valgus could significantly relieve pain and appearance of forefoot, stabilize the first sequence, and significantly improve walking function.