TEAD Proteins Associate With DNA Repair Proteins to Facilitate Cellular Recovery From DNA Damage.

Transcriptional enhanced associate domain family members 1 to 4 (TEADs) are a family of four transcription factors and the major transcriptional effectors of the Hippo pathway. In order to activate transcription, TEADs rely on interactions with other proteins, such as the transcriptional effectors Yes-associated protein and transcriptional co-activator with PDZ-binding motif. Nuclear protein interactions involving TEADs influence the transcriptional regulation of genes involved in cell growth, tissue homeostasis, and tumorigenesis. Clearly, protein interactions for TEADs are functionally important, but the full repertoire of TEAD interaction partners remains unknown. Here, we employed an affinity purification mass spectrometry approach to identify nuclear interacting partners of TEADs. We performed affinity purification mass spectrometry experiment in parallel in two different cell types and compared a wildtype TEAD bait protein to a nuclear localization sequence mutant that does not localize to the nucleus. We quantified the results using SAINT analysis and found a significant enrichment of proteins linked to DNA damage including X-ray repair cross-complementing protein 5 (XRCC5), X-ray repair cross-complementing protein 6 (XRCC6), poly(ADP-ribose) polymerase 1 (PARP1), and Rap1-interacting factor 1 (RIF1). In cellular assays, we found that TEADs co-localize with DNA damage-induced nuclear foci marked by histone H2AX phosphorylated on S139 (γH2AX) and Rap1-interacting factor 1. We also found that depletion of TEAD proteins makes cells more susceptible to DNA damage by various agents and that depletion of TEADs promotes genomic instability. Additionally, depleting TEADs dampens the efficiency of DNA double-stranded break repair in reporter assays. Our results connect TEADs to DNA damage response processes, positioning DNA damage as an important avenue for further research of TEAD proteins.

Pan-cancer analysis of the tumorigenic role of Fanconi anemia complementation group D2 (FANCD2) in human tumors.

Monoubiquitination of FANCD2 is a central step in the activation of the Fanconi anemia (FA) pathway after DNA damage. Defects in the FA pathway centered around FANCD2 not only lead to genomic instability but also induce tumorigenesis. At present, few studies have investigated FANCD2 in tumors, and no pan-cancer research on FANCD2 has been conducted. We conducted a comprehensive analysis of the role of FANCD2 in cancer using public databases and other published studies. Moreover, we evaluated the role of FANCD2 in the proliferation, migration and invasion of lung adenocarcinoma cells through in vitro and in vivo experiments, and explored the role of FANCD2 in cisplatin chemoresistance. We investigated the regulatory effect of FANCD2 on the cell cycle of lung adenocarcinoma cells by flow cytometry, and verified this effect by western blotting. FANCD2 expression is elevated in most TCGA tumors and shows a strong positive correlation with poor prognosis in tumor patients. In addition, FANCD2 expression shows strong correlations with immune infiltration, immune checkpoints, the tumor mutation burden (TMB), and microsatellite instability (MSI), which are immune-related features, suggesting that it may be a potential target of tumor immunotherapy. We further found that FANCD2 significantly promotes the proliferation, invasion, and migration abilities of lung adenocarcinoma cells and that its ability to promote cancer cell proliferation may be achieved by modulating the cell cycle. The findings indicate that FANCD2 is a potential biomarker and therapeutic target in cancer treatment by analyzing the oncogenic role of FANCD2 in different tumors.

Honokiol ameliorates angiotensin II-induced cardiac hypertrophy by promoting dissociation of the Nur77-LKB1 complex and activating the AMPK pathway.

Pathological cardiac hypertrophy is a key contributor to heart failure, and the molecular mechanisms underlying honokiol (HNK)-mediated cardioprotection against this condition remain worth further exploring. This study aims to investigate the effect of HNK on angiotensin II (Ang II)-induced myocardial hypertrophy and elucidate the underlying mechanisms. Sprague-Dawley rats were exposed to Ang II infusion, followed by HNK or vehicle treatment for 4 weeks. Our results showed that HNK treatment protected against Ang II-induced myocardial hypertrophy, fibrosis and dysfunction in vivo and inhibited Ang II-induced hypertrophy in neonatal rat ventricular myocytes in vitro. Mechanistically, HNK suppressed the Ang II-induced Nur77 expression at the transcriptional level and promoted ubiquitination-mediated degradation of Nur77, leading to dissociation of the Nur77-LKB1 complex. This facilitated the translocation of LKB1 into the cytoplasm and activated the LKB1-AMPK pathway. Our findings suggest that HNK attenuates pathological remodelling and cardiac dysfunction induced by Ang II by promoting dissociation of the Nur77-LKB1 complex and subsequent activation of AMPK signalling. This study uncovers a novel role of HNK on the LKB1-AMPK pathway to protect against cardiac hypertrophy.

The FBXW7-binding sites on FAM83D are potential targets for cancer therapy.

Increasing evidence shows the oncogenic function of FAM83D in human cancer, but how FAM83D exerts its oncogenic function remains largely unclear. Here, we investigated the importance of FAM83D/FBXW7 interaction in breast cancer (BC). We systematically mapped the FBXW7-binding sites on FAM83D through a comprehensive mutational analysis together with co-immunoprecipitation assay. Mutations at the FBXW7-binding sites on FAM83D led to that FAM83D lost its capability to promote the ubiquitination and proteasomal degradation of FBXW7; cell proliferation, migration, and invasion in vitro; and tumor growth and metastasis in vivo, indicating that the FBXW7-binding sites on FAM83D are essential for its oncogenic functions. A meta-evaluation of FAM83D revealed that the prognostic impact of FAM83D was independent on molecular subtypes. The higher expression of FAM83D has poorer prognosis. Moreover, high expression of FAM83D confers resistance to chemotherapy in BCs, which is experimentally validated in vitro. We conclude that identification of FBXW7-binding sites on FAM83D not only reveals the importance for FAM83D oncogenic function, but also provides valuable insights for drug target.

The dual role of FSP1 in programmed cell death: resisting ferroptosis in the cell membrane and promoting necroptosis in the nucleus of THP-1 cells.

BACKGROUND: Acute monocytic leukemia-M5 (AML-M5) remains a challenging disease due to its high morbidity and poor prognosis. In addition to the evidence mentioned earlier, several studies have shown that programmed cell death (PCD) serves a critical function in treatment of AML-M5. However, the role and relationship between ferroptosis and necroptosis in AML-M5 remains unclear. METHODS: THP-1 cells were mainly treated with Erastin and IMP-366. The changes of ferroptosis and necroptosis levels were detected by CCK-8, western blot, quantitative real-time PCR, and electron microscopy. Flow cytometry was applied to detect the ROS and lipid ROS levels. MDA, 4-HNE, GSH and GSSG were assessed by ELISA kits. Intracellular distribution of FSP1 was studied by immunofluorescent staining and western blot. RESULTS: The addition of the myristoylation inhibitor IMP-366 to erastin-treated acute monocytic leukemia cell line THP-1 cell not only resulted in greater susceptibility to ferroptosis characterized by lipid peroxidation, glutathione (GSH) depletion and mitochondrial shrinkage, as the FSP1 position on membrane was inhibited, but also increased p-RIPK1 and p-MLKL protein expression, as well as a decrease in caspase-8 expression, and triggered the characteristic necroptosis phenomena, including cytoplasmic translucency, mitochondrial swelling, membranous fractures by FSP1 migration into the nucleus via binding importin α2. It is interesting to note that ferroptosis inhibitor fer-1 reversed necroptosis. CONCLUSION: We demonstrated that inhibition of myristoylation by IMP-366 is capable of switching ferroptosis and ferroptosis-dependent necroptosis in THP-1 cells. In these findings, FSP1-mediated ferroptosis and necroptosis are described as alternative mechanisms of PCD of THP-1 cells, providing potential therapeutic strategies and targets for AML-M5.

Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study.

BACKGROUND: Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in advanced solid tumours, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. METHODS: This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. Randomisation was done via a centralised interactive response system. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. We report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival. This study is registered with ClinicalTrials.gov (NCT03764293). FINDINGS: Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab-rivoceranib (n=272) or sorafenib (n=271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7·8 months (IQR 4·1-10·6). Median progression-free survival was significantly improved with camrelizumab-rivoceranib versus sorafenib (5·6 months [95% CI 5·5-6·3] vs 3·7 months [2·8-3·7]; hazard ratio [HR] 0·52 [95% CI 0·41-0·65]; one-sided p<0·0001). At the interim analysis for overall survival (Feb 8, 2022), median follow-up was 14·5 months (IQR 9·1-18·7). Median overall survival was significantly extended with camrelizumab-rivoceranib versus sorafenib (22·1 months [95% CI 19·1-27·2] vs 15·2 months [13·0-18·5]; HR 0·62 [95% CI 0·49-0·80]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102 [38%] of 272 patients in the camrelizumab-rivoceranib group vs 40 [15%] of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 [12%] vs 41 [15%]), increased aspartate aminotransferase (45 [17%] vs 14 [5%]), and increased alanine aminotransferase (35 [13%] vs eight [3%]). Treatment-related serious adverse events were reported in 66 (24%) patients in the camrelizumab-rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab-rivoceranib group (ie, multiple organ dysfunction syndrome) and one patient in the sorafenib group (ie, respiratory failure and circulatory collapse). INTERPRETATION: Camrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population. FUNDING: Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.

A "Zn2+ in Salt" Interphase Enabling High-Performance Zn Metal Anodes.

Zinc metal is a promising anode candidate for aqueous zinc ion batteries due to its high theoretical capacity, low cost, and high safety. However, its application is currently restricted by hydrogen evolution reactions (HER), by-product formation, and Zn dendrite growth. Herein, a "Zn2+ in salt" (ZIS) interphase is in situ constructed on the surface of the anode (ZIS@Zn). Unlike the conventional "Zn2+ in water" working environment of Zn anodes, the intrinsic hydrophobicity of the ZIS interphase isolates the anode from direct contact with the aqueous electrolyte, thereby protecting it from HER, and the accompanying side reactions. More importantly, it works as an ordered water-free ion-conducting medium, which guides uniform Zn deposition and facilitates rapid Zn2+ migration at the interface. As a result, the symmetric cells assembled with ZIS@Zn exhibit dendrite-free plating/striping at 4500 h and a high critical current of 14 mA cm-2. When matched with a vanadium-based (NVO) cathode, the full battery exhibits excellent long-term cycling stability, with 88% capacity retention after 1600 cycles. This work provides an effective strategy to promote the stability and reversibility of Zn anodes in aqueous electrolytes.

A real-world study of the effectiveness and safety of apatinib-based regimens in metastatic triple-negative breast cancer.

PURPOSE: This investigation sought to examine the efficacy and safety of low-dose apatinib used alongside chemotherapy in the clinical management of patients with metastatic triple-negative breast cancer (TNBC) within a real-world setting, whilst comparing the outcomes with those treated solely with chemotherapy. METHODS: This case series study analyzed clinical data and treatment outcomes of 163 patients with metastatic TNBC who underwent rescue treatment at the Medical Oncology Department of Clinical Oncology, Fujian Cancer Hospital, School of Fujian Medical University, China, between October 2011 and January 2023. All the patients underwent rescue treatment with either chemotherapy alone or apatinib (250 mg/day) combined with chemotherapy. The study's primary outcome was progression-free survival (PFS), whereas the secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety profiles. RESULTS: The study was designed to compare two groups [1]. Out of the 163 TNBC patients who participated in the study, 107 individuals (65.6%) received treatment based on chemotherapy, whereas 56 patients (34.4%) were given treatment based on a combination of low-dose apatinib (250 mg/day) and other treatments, including chemotherapy. After propensity score matching (PSM), the objective response rate (ORR) and disease control rate (DCR) of patients with advanced triple-negative breast cancer (TNBC) who received apatinib-based treatment were 50.0 and 90.0%, respectively, while they were 6.7 and 20.0%, respectively, for the chemotherapy-based group (P < 0.001). The group that received apatinib-based treatment showed superior results in both PFS and OS compared to the group that received chemotherapy. The median PFS and OS for the apatinib-based group were 7.8 and 20.3 months, respectively, while they were only 2.2 months and 9.0 months, respectively, for the chemotherapy-based group (P < 0.001) [2]. Patients who were administered combo therapies, including PD-1 inhibitors, were excluded. In total, 97 patients received chemotherapy alone, while 34 patients were treated with apatinib in combination with chemotherapy. After propensity score matching (PSM), the ORR and DCR for the total group who received combo therapies were 44.4 and 81.5%, respectively, while they were 11.1 and 22.2%, respectively, for the chemotherapy alone group (P < 0.001). The group receiving both apatinib and chemotherapy displayed notable advantages over the group solely receiving chemotherapy in regards to PFS and OS for the entirety of the population. The PFS was found to be 7.8 months in comparison to 2.1 months (P < 0.001) and the OS was 21.1 months in contrast to 9.0 months (P < 0.001). Apatinib combined with chemotherapy induced grade 3/4 hematological toxicities, including neutropenia (8.8%) and thrombocytopenia (2.9%). Additionally, non-hematological toxicities were commonly observed, such as Hand-foot syndrome (35.3%), proteinuria (26.5%), hypertension (61.8%), higher alanine aminotransferase levels (26.5%), and fatigue (35.3%). The most frequent non-hematological grade 3/4 toxicities were Hand-foot syndrome (2.9%) and hypertension (5.9%). The study did not report any fatal adverse effects. CONCLUSIONS: The combination of low-dose apatinib with chemotherapy has proven to be more effective than chemotherapy alone in treating metastatic triple-negative breast cancer (TNBC). Additionally, the occurrence of grade 3/4 non-hematologic toxicities was significantly lower compared to the recommended dose of apatinib.

Thermally Robust Solvent-Free Liquid Polyplexes for Heat-Shock Protection and Long-Term Room Temperature Storage of Therapeutic Nucleic Acids.

Nucleic acid therapeutics have attracted recent attention as promising preventative solutions for a broad range of diseases. Nonviral delivery vectors, such as cationic polymers, improve the cellular uptake of nucleic acids without suffering the drawbacks of viral delivery vectors. However, these delivery systems are faced with a major challenge for worldwide deployment, as their poor thermal stability elicits the need for cold chain transportation. Here, we demonstrate a biomaterial strategy to drastically improve the thermal stability of DNA polyplexes. Importantly, we demonstrate long-term room temperature storage with a transfection efficiency maintained for at least 9 months. Additionally, extreme heat shock studies show retained luciferase expression after heat treatment at 70 °C. We therefore provide a proof of concept for a platform biotechnology that could provide long-term room temperature storage for temperature-sensitive nucleic acid therapeutics, eliminating the need for the cold chain, which in turn would reduce the cost of distributing life-saving therapeutics worldwide.

PRETREATED LYOPHILIZED HUMAN AMNIOTIC MEMBRANE GRAFT COVERING FOR RETINAL DETACHMENT WITH POSTERIOR RETINAL BREAKS ABOVE CHORIORETINAL ATROPHY IN PATHOLOGIC MYOPIA.

PURPOSE: To compare the surgical results of vitrectomy with untreated or pretreated lyophilized human amniotic membrane grafts covering in treating retinal detachment related to posterior retinal breaks above chorioretinal atrophy in pathologic myopia. METHODS: Nineteen patients with retinal detachment related to macular hole (MH) located above macular atrophy and/or posterior paravascular retinal breaks (PRBs) located above patchy chorioretinal atrophy in pathologic myopia were included. The eyes of these patients underwent vitrectomy with untreated lyophilized human amniotic membrane covering (n = 10) or perfluorocarbon liquid (PFCL)-assisted pretreated lyophilized human amniotic membrane covering (n = 9; grafts were pretreated in 0.125% indocyanine green and 50% hypertonic glucose solution for 15-20 minutes). The closure of the MH or PRBs, reattachment of the retina, and best-corrected visual acuity were measured postoperatively. RESULTS: Postoperatively, graft dislocation or shift was only found in two eyes (20%) in the untreated group. The closure rate of the MH or PRBs was 80% (8/10) and 100% (9/9) in the untreated group and the pretreated group, respectively. The occurrence rate of excessive gliosis was 40% and 11% in the untreated group and the pretreated group, respectively. In both groups, best-corrected visual acuity was improved and the retinal reattachment rate was 100% at the final visit. CONCLUSION: Perfluorocarbon liquid-assisted pretreated lyophilized human amniotic membrane graft covering was effective in treating retinal detachment related to MH and/or PRBs situated above macular atrophy or patchy chorioretinal atrophy in pathologic myopia. This technique appeared to reduce graft dislocation or shift, promote the closures of MHs/PRBs, and reduce the occurrence of gliosis.

Comprehensive Assessment of Lower-Face Volume Reduction Using Laser-Assisted Liposuction as an Additive Procedure in Asian Rhytidectomy.

The most important factor that distinguishes a youthful appearance from an aged one is the shape of the lower face. This study aimed to examine the outcome of volume reduction of the lower face using laser-assisted liposuction (SmartLipo) at the time of rhytidectomy in Asians. There were 20 patients (Group 1) for whom only extended deep-plane rhytidectomy were performed, while extended deep-plane rhytidectomy with laser-assisted liposuction was performed on 42 patients (Group 2). This study was performed retrospectively. The FACE-Q questionnaire was given to evaluate the subjective result of the patient. Efficacy was evaluated by measuring the fat quantity at the midpoint and anterior border of the masseter muscle on each side by using an ultrasound scan in Group 2. Then, the correlation between the change in the quantity of fat and the FACE-Q was investigated. The overall satisfaction, and satisfaction for the lower face, jawline, and the area under the chin were significantly higher for Group 2 for which the procedure was concurrently performed in comparison to Group 1. In Group 2, change in the fat was reduced by 21.2% (Rt.) and 22.5% (Lt.) at the mid-point and 24.5% (Rt.) and 26.4% (Lt.) at the anterior border of the masseter muscle. Changes in the fat quantity and lower face satisfaction displayed a significant correlation. With a greater reduction in fat quantity, the score of lower face satisfaction was higher. In addition, with a higher level of satisfaction for the lower face and jawline, the overall satisfaction score displayed a higher positive correlation. Laser-assisted liposuction was useful for the additive procedure at the time of rhytidectomy and improved patient's satisfaction after surgery.

Existential distress and associated factors in advanced cancer patients: A cross-sectional study.

BACKGROUND: Advanced cancer patients often experience existential distress (ED). However, the factors associated with ED remain unclear. This study investigated the current state of ED and identified the associated factors in Chinese patients with advanced cancer. METHODS: A cross-sectional study was conducted among 352 advanced cancer patients from 3 tertiary hospitals in Fujian, China. Participants were invited to complete the Existential Distress Scale, Number Rating Scale, Self-Perceived Burden Scale, Quality of Life Concerns in the End-of-Life Questionnaire, and Hospital Anxiety and Depression Scale. OBJECTIVES: This study aimed to investigate the level of existential distress among advanced cancer patients in China and identify the associated factors. RESULTS: A total of 352 advanced cancer patients were recruited for this study. The average score for ED was 8.48 ± 7.12 among the advanced cancer patients. Multiple regression showed that the associated factors included depression (ß = 0.32, p = 0.000), self-perceived burden (SPB) (ß = 0.18, p = 0.001), the presence of a spouse (ß = -0.10, p = 0.050), and reception of government subsidies (ß = 0.17, p = 0.001). The factors accounted for 30.1% of the total variance in ED (F = 8.472, p < 0.001). SIGNIFICANCE OF RESULTS: Among the advanced cancer patients queried, ED was found to be positively influenced by depression, SPB, and reception of government subsidies and negatively influenced by the presence of a spouse. Depression was the most important risk factor, and thus future ED interventions should target depression.

Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial.

BACKGROUND: Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours. METHODS: This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450 mg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed. FINDINGS: Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1-17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3-42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0-15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2-40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7-19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7-37·4). INTERPRETATION: Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours. FUNDING: Akeso Biopharma. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

The suppression of hyperlipid diet-induced ferroptosis of vascular smooth muscle cells protests against atherosclerosis independent of p53/SCL7A11/GPX4 axis.

Ferroptosis as a novel programmed cell death that involves metabolic dysfunction due to iron-dependent excessive lipid peroxidation has been implicated in atherosclerosis (AS) development characterized by disrupted lipid metabolism, but the atherogenic role of ferroptosis in vascular smooth muscle cells (VSMCs), which are principal components of atherosclerotic plaque fibrous cap, remains unclear. The aim of this study was to determine the effects of ferroptosis on AS induced by lipid overload, and the effects of that on VSMCs ferroptosis. We found intraperitoneal injection of Fer-1, a ferroptosis inhibitor, ameliorated obviously high-fat diet-induced high plasma levels of triglycerides, total cholesterol, low-density lipoprotein, glucose and atherosclerotic lesions in ApoE-/- mice. Moreover, in vivo and in vitro, Fer-1 reduced the iron accumulation of atherosclerotic lesions through affecting the expression of TFR1, FTH, and FTL in VSMCs. Interestingly, Fer-1 did augment nuclear factor E2-related factor 2/ferroptosis suppressor protein 1 to enhance endogenous resistance to lipid peroxidation, but not classic p53/SCL7A11/GPX4. Those observations indicated inhibition of VSMCs ferroptosis can improve AS lesions independent of p53/SLC7A11/GPX4, which preliminarily revealed the potential mechanism of ferroptosis in aortic VSMCs on AS and provided new therapeutic strategies and targets for AS.

First-line nivolumab plus chemotherapy vs chemotherapy in patients with advanced gastric, gastroesophageal junction and esophageal adenocarcinoma: CheckMate 649 Chinese subgroup analysis.

First-line chemotherapy for advanced/metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric/gastroesophageal junction cancer (GC/GEJC) has poor median overall survival (OS; <1 year). We report efficacy and safety results from Chinese patients in the phase III global CheckMate 649 study of nivolumab plus chemotherapy vs chemotherapy for the first-line treatment of GC/GEJC/esophageal adenocarcinoma (EAC). Chinese patients with previously untreated advanced or metastatic GC/GEJC/EAC were randomized to receive nivolumab (360 mg Q3W or 240 mg Q2W) plus chemotherapy (XELOX [capecitabine and oxaliplatin] Q3W or FOLFOX [oxaliplatin, leucovorin and 5-fluorouracil] Q2W), nivolumab plus ipilimumab (not reported) or chemotherapy alone. OS, blinded independent central review-assessed progression-free survival (PFS), objective response rate (ORR), duration of response (DOR) and safety are reported. Of 1581 patients enrolled and randomized, 208 were Chinese. In these patients, nivolumab plus chemotherapy resulted in clinically meaningful improvement in median OS (14.3 vs 10.2 months; HR 0.61 [95% CI: 0.44-0.85]), median PFS (8.3 vs 5.6 months; HR 0.57 [95% CI: 0.40-0.80]), ORR (66% vs 45%) and median DOR (12.2 vs 5.6 months) vs chemotherapy, respectively. The safety profile was acceptable, with no new safety signals observed. Consistent with results from the global primary analysis of CheckMate 649, nivolumab plus chemotherapy demonstrated a clinically meaningful improvement in OS and PFS and higher response rate vs chemotherapy and an acceptable safety profile in Chinese patients. Nivolumab plus chemotherapy represents a new standard first-line treatment for Chinese patients with non-HER2-positive advanced GC/GEJC/EAC.

Response to Pralsetinib in Multi-Drug-Resistant Breast Cancer With CCDC6-RET Mutation.

Triple-negative breast cancers (TNBC) represent a pathological subtype of breast cancer, which are characterized by strong invasiveness, high metastasis rate, low survival rate, and poor prognosis, especially in patients who have developed resistance to multiline treatments. Here, we present a female patient with advanced TNBC who progressed despite multiple lines of treatments; next-generation sequencing (NGS) was used to find drug mutation targets, which revealed a coiled-coil domain-containing protein 6 (CCDC6)-rearranged during transfection (RET) gene fusion mutation. The patient was then given pralsetinib, and after one treatment cycle, a CT scan revealed partial remission and adequate tolerance to therapy. Pralsetinib (BLU-667) is a RET-selective protein tyrosine kinase inhibitor that can inhibit the phosphorylation of RET and downstream molecules as well as the proliferation of cells expressing RET gene mutations. This is the first case in the literature of metastatic TNBC with CCDC6-RET fusion treated with pralsetinib, an RET-specific antagonist. This case demonstrates the potential efficacy of pralsetinib in cases of TNBC with RET fusion mutations and suggests that NGS may reveal new opportunities and bring new therapeutic interventions to patients with refractory TNBC.

Safety and efficacy of apatinib in patients with advanced gastric or gastroesophageal junction adenocarcinoma after the failure of two or more lines of chemotherapy (AHEAD): a prospective, single-arm, multicenter, phase IV study.

BACKGROUND: Apatinib, a highly selective VEGFR2 inhibitor, significantly improved efficacy versus placebo as a third- and later-line treatment for advanced gastric cancer in phase 2 and 3 trials. This prospective, single-arm, multicenter phase IV AHEAD study was conducted to verify the safety and efficacy of apatinib in patients with advanced or metastatic gastric or gastroesophageal adenocarcinoma after at least two lines of systematic therapy in clinical practice settings. METHODS: Patients with advanced gastric cancer who had previously failed at least two lines of chemotherapy received oral apatinib until disease progression, death or unacceptable toxicity. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Adverse events were summarized by the incidence rate. Median OS and PFS were estimated using the Kaplan-Meier method. ORR, DCR, OS at 3 and 6 months, and PFS at 3 and 6 months were calculated, and their 95% CIs were estimated according to the Clopper-Pearson method. RESULTS: Between May 2015 and November 2019, a total of 2004 patients were enrolled, and 1999 patients who received at least one dose of apatinib were assessed for safety. In the safety population, 87.9% of patients experienced treatment-related adverse events (TRAEs), with the most common hypertension (45.2%), proteinuria (26.5%), and white blood cell count decreased (25.3%). Additionally, 51% of patients experienced grade ≥ 3 TRAEs. Fatal TRAEs occurred in 57 (2.9%) patients. No new safety concerns were reported. Among the 2004 patients included in the intention-to-treat population, the ORR was 4.4% (95% CI, 3.6-5.4%), and DCR was 35.8% (95% CI, 33.7-38.0%). The median PFS was 2.7 months (95% CI 2.2-2.8), and the median OS was 5.8 months (95% CI 5.4-6.1). CONCLUSIONS: The findings in the AHEAD study confirmed the acceptable and manageable safety profile and clinical benefit of apatinib in patients with advanced gastric cancer as a third- or later-line of treatment. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov NCT02426034. Registration date was April 24, 2015.

Baseline C-reactive protein predicts efficacy of the first-line immune checkpoint inhibitors plus chemotherapy in advanced lung squamous cell carcinoma: a retrospective, multicenter study.

AIMS: To investigate the predictive value of baseline C-reactive protein (CRP) levels on the efficacy of chemotherapy plus immune checkpoint inhibitors (ICI) in patients with advanced lung squamous cell carcinoma (LSCC). MATERIALS AND METHODS: In this retrospective multicenter study spanning from January 2016 to December 2020, advanced LSCC patients initially treated with chemotherapy or a combination of chemotherapy and ICI were categorized into normal and elevated CRP subgroups. The relationship between CRP levels and treatment outcomes was analyzed using multivariate Cox proportional hazards models and multivariate logistic regression, focusing primarily on the progression-free survival (PFS) endpoint, and secondarily on overall survival (OS) and objective response rate (ORR) endpoints. Survival curves were generated using the Kaplan-Meier method, with the log-rank test used for comparison between groups. RESULTS: Of the 245 patients evaluated, the 105 who received a combination of chemotherapy and ICI with elevated baseline CRP levels exhibited a significant reduction in PFS (median 6.5 months vs. 11.8 months, HR, 1.78; 95% CI: 1.12-2.81; p = 0.013) compared to those with normal CRP levels. Elevated CRP was identified as an independent risk factor for poor PFS through multivariate-adjusted analysis. However, among the 140 patients receiving chemotherapy alone, baseline CRP levels did not significantly influence PFS. Furthermore, within the combination therapy group, there was a notable decrease in the ORR (51% vs. 71%, p = 0.035), coupled with a significantly shorter OS (median 20.9 months vs. 31.5 months, HR, 2.24; 95% CI: 1.13-4.44; p = 0.033). CONCLUSION: In patients with advanced LSCC, elevated baseline CRP levels were identified as an independent predictive factor for the efficacy of combination therapy with chemotherapy and ICI, but not in chemotherapy alone. This suggests that CRP may be a valuable biomarker for guiding treatment strategies.

Potential mechanism of pyrotinib-induced diarrhea was explored by gut microbiome and ileum metabolomics.

Pyrotinib is a novel epidermal growth factor receptor/human epidermal growth factor receptor-2 (HER2) tyrosine kinase inhibitor that exhibited clinical efficacy in patients with HER2-positive breast cancer and HER2-mutant/amplified lung cancer. However, severe diarrhea adverse responses preclude its practical use. At present, the mechanism of pyrotinib-induced diarrhea is unknown and needs further study. First, to develop a suitable and reproducible animal model, we compared the effects of different doses of pyrotinib (20, 40, 60 and 80 mg/kg) in Wistar rats. Second, we used this model to examine the intestinal toxicity of pyrotinib. Finally, the mechanism underlying pyrotinib-induced diarrhea was fully studied using gut microbiome and host intestinal tissue metabolomics profiling. Reproducible diarrhea occurred in rats when they were given an 80 mg/kg daily dose of pyrotinib. Using the pyrotinib-induced model, we observed that Lachnospiraceae and Acidaminococcaceae decreased in the pyrotinib groups, whereas Enterobacteriaceae, Helicobacteraceae and Clostridiaceae increased at the family level by 16S rRNA gene sequence. Multiple bioinformatics methods revealed that glycocholic acid, ursodeoxycholic acid and cyclic AMP increased in the pyrotinib groups, whereas kynurenic acid decreased, which may be related to the pathogenesis of pyrotinib-induced diarrhea. Additionally, pyrotinib-induced diarrhea may be associated with a number of metabolic changes mediated by the gut microbiome, such as Primary bile acid biosynthesis. We reported the establishment of a reproducible pyrotinib-induced animal model for the first time. Furthermore, we concluded from this experiment that gut microbiome imbalance and changes in related metabolites are significant contributors to pyrotinib-induced diarrhea.

Advances in the Diagnosis and Treatment of Autism Spectrum Disorders in Children.

Objective: This study aims to review recent developments in the diagnosis and treatment of Autism Spectrum Disorder (ASD )and provide insights for its clinical management. Methods: The literatures were researched fro the pubmed, Wanfang and CNKI. We searched for research on the etiology, pathogenesis, diagnosis (screening and evaluation), and treatment of Autism spectrum disorder. When selecting papers to be included, priority should be given to randomized clinical trials, systematic evaluations, meta-analyses, clinical practice guidelines, and articles related to general medical readers. Results: ASD is a widely present neurodevelopmental disorder characterized by social and communication difficulties, narrow interests, and repetitive behavior, accompanied by symptoms such as irritability, self-harm, attention deficit hyperactivity disorder (ADHD), and sleep problems. Irritability, self-harm, ADHD, and sleep problems are common accompanying symptoms that contribute to the challenges faced by individuals with ASD. At present, there is no fully effective treatment method for ASD, and key factors affecting the prognosis of ASD include early diagnosis time, early language communication level, intelligence level, disease severity, comorbidities, family participation, appropriate intervention, and social support. Therefore, early individualized long-term comprehensive training and drug therapy, hyperbaric oxygen therapy, and combined family participation can improve the prognosis of pediatric patients. Before selecting treatment plans for children, collecting as much information as possible about various treatment methods and choosing personalized treatment plans based on the child's developmental assessment level is necessary. In addition, the treatment of ASD is also influenced by factors such as family economic status, parental mentality, and social environment. During the training process, it is important to be family-centered, tolerant, and understand children's behavior. Conclusion: It is significant to take effective treatment measures to improve the quality of life and prognosis of children with autism spectrum disorders.