Accurate preoperative prediction of nodal metastasis in papillary thyroid microcarcinoma: Towards optimal management of patients.

OBJECTIVE: To enhance the accuracy in predicting lymph node metastasis (LNM) preoperatively in patients with papillary thyroid microcarcinoma (PTMC), refining the "low-risk" classification for tailored treatment strategies. METHODS: This study involves the development and validation of a predictive model using a cohort of 1004 patients with PTMC undergoing thyroidectomy along with central neck dissection. The data was divided into a training cohort (n = 702) and a validation cohort (n = 302). Multivariate logistic regression identified independent LNM predictors in PTMC, leading to the construction of a predictive nomogram model. The model's performance was assessed through ROC analysis, calibration curve analysis, and decision curve analysis. RESULTS: Identified LNM predictors in PTMC included age, tumor maximum diameter, nodule-capsule distance, capsular contact length, bilateral suspicious lesions, absence of the lymphatic hilum, microcalcification, and sex. Especially, tumors larger than 7 mm, nodules closer to the capsule (less than 3 mm), and longer capsular contact lengths (more than 1 mm) showed higher LNM rates. The model exhibited AUCs of 0.733 and 0.771 in the training and validation cohorts respectively, alongside superior calibration and clinical utility. CONCLUSION: This study proposes and substantiates a preoperative predictive model for LNM in patients with PTMC, honing the precision of "low-risk" categorization. This model furnishes clinicians with an invaluable tool for individualized treatment approach, ensuring better management of patients who might be proposed observation or ablative options in the absence of such predictive information.

The effects of oxaliplatin-based adjuvant chemotherapy in high-risk stage II colon cancer with mismatch repair-deficient: a retrospective study.

BACKGROUND: For high-risk stageIImismatch repair deficient (dMMR) colon cancers, the benefit of adjuvant chemotherapy remains debatable. The principal aim of this study was to evaluate the prognostic value of high-risk factors and the effect of oxaliplatin-based adjuvant chemotherapy among dMMR stageIIcolon cancers. METHODS: Patients with stage II dMMR colon cancers diagnosed between June 2011 and May 2018 were enrolled in the study. Clinicopathological characteristics, treatment, and follow-up data were retrospectively collected. The high-risk group was defined as having one of the following factors: pT4 disease, fewer than twelve lymph nodes harvested (< 12 LNs), poorly differentiated histology, perineural invasion (PNI), lymphatic vascular invasion (LVI), or elevated preoperative carcinoembryonic antigen (CEA). The low-risk group did not have any risk factors above. Factors associated with disease-free survival (DFS) were included in univariate and multivariate Cox analyses. RESULTS: We collected a total of 262 consecutive patients with stage II dMMR colon cancer. 179 patients (68.3%) have at least one high-risk factor. With a median follow-up of 50.1 months, the low-risk group was associated with a tended to have a better 3-year DFS than the high-risk group (96.4% vs 89.4%; P = 0.056). Both elevated preoperative CEA (HR 2.93; 95% CI 1.26-6.82; P = 0.013) and pT4 disease (HR 2.58; 95% CI 1.06-6.25; P = 0.037) were independent risk factors of recurrence. Then, the 3-year DFS was 92.6% for the surgery alone group and 88.1% for the adjuvant chemotherapy group (HR 1.64; 95% CI 0.67-4.02; P = 0.280). Furthermore, no survival benefit from oxaliplatin-based adjuvant chemotherapy was observed in the high-risk group and in the subgroups with pT4 disease or < 12 LNs. CONCLUSIONS: These data suggests that not all high-risk factors have a similar impact on stage II dMMR colon cancers. Elevated preoperative CEA and pT4 tumor stage are associated with increased recurrence risk. However, oxaliplatin-based adjuvant chemotherapy shows no survival benefits in stage II dMMR colon cancers, either with or without high-risk factors.

Optimizing robotic thyroid surgery: lessons learned from an retrospective analysis of 104 cases.

Background: Robotic assistance in thyroidectomy is a developing field that promises enhanced surgical precision and improved patient outcomes. This study investigates the impact of the da Vinci Surgical System on operative efficiency, learning curve, and postoperative outcomes in thyroid surgery. Methods: We conducted a retrospective cohort study of 104 patients who underwent robotic thyroidectomy between March 2018 and January 2022. We evaluated the learning curve using the Cumulative Sum (CUSUM) analysis and analyzed operative times, complication rates, and postoperative recovery metrics. Results: The cohort had a mean age of 36 years, predominantly female (68.3%). The average body mass index (BMI) was within the normal range. A significant reduction in operative times was observed as the series progressed, with no permanent hypoparathyroidism or recurrent laryngeal nerve injuries reported. The learning curve plateaued after the 37th case. Postoperative recovery was consistent, with no significant difference in hospital stay duration. Complications were minimal, with a noted decrease in transient vocal cord palsy as experience with the robotic system increased. Conclusion: Robotic thyroidectomy using the da Vinci system has demonstrated a significant improvement in operative efficiency without compromising safety. The learning curve is steep but manageable, and once overcome, it leads to improved surgical outcomes and high patient satisfaction. Further research with larger datasets and longer follow-up is necessary to establish the long-term benefits of robotic thyroidectomy.

Mutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death.

Mutant KRAS (KRASMUT) is often exploited by cancers to shape tumor immunity, but the underlying mechanisms are not fully understood. Here we report that tumor-specific cytotoxic T lymphocytes (CTLs) from KRASMUT cancers are sensitive to activation-induced cell death (AICD). circATXN7, an NF-κB-interacting circular RNA, governs T cell sensitivity to AICD by inactivating NF-κB. Mechanistically, histone lactylation derived from KRASMUT tumor cell-produced lactic acid directly activates transcription of circATXN7, which binds to NF-κB p65 subunit and masks the p65 nuclear localization signal motif, thereby sequestering it in the cytoplasm. Clinically, circATXN7 upregulation in tumor-specific CTLs correlates with adverse clinical outcomes and immunotherapeutic resistance. Genetic ablation of circAtxn7 in CD8+ T cells leads to mutant-selective tumor inhibition, while also increases anti-PD1 efficacy in multiple tumor models in female mice. Furthermore, targeting circATXN7 in adoptively transferred tumor-reactive CTLs improves their antitumor activities. These findings provide insight into how lymphocyte-expressed circRNAs contribute to T-cell fate decisions and anticancer immunotherapies.

The Preserved Thickness Ratio of the Femoral Head Contributes to the Collapse Predictor of Osteonecrosis.

OBJECTIVES: The collapse of femoral head is a serious symptom of osteonecrosis of the femoral head (ONFH), resulting in hip pain and deformity. However, it is hardly possible to reestablish the femoral head nonoperatively once the collapse happens. Predicting femoral head collapse is of great value for the prognosis of ONFH. This study aimed to develop a new method to quantify the preserved thickness of femoral head and to assess its diagnostic contribution in predicting femoral head collapse on plain radiographs. METHODS: This was a single-center retrospective study. A total of 101 hips (85 patients) with ARCO stage II from January 2008 to December 2016 were included in this study. The preserved thickness was measured on standard anteroposterior (AP) and frog-leg (FL) radiographs. The anteroposterior view's preserved thickness ratio (APTR) and the frog-leg view's preserved thickness ratio (FPTR) were calculated to show the preserved thickness ratio of the femoral head anteriorly and laterally. Univariate and multivariate logistic regression was performed to determine the risk factors for collapse. Sensitivity, specificity, and cut-off values for APTR and FPTR were determined by the receiver operating characteristic (ROC) curve analysis. Kaplan-Meier (K-M) analysis was applied to determine femoral head survival in ONFH patients. RESULTS: The mean age of the 27 females and 58 males was 38.93 years old. The mean follow-up time was 74.62 (36-124) months in the non-collapse group and 18.66 (3-82) months in the collapse group. Femoral head collapse was observed in 62 hips during the follow-up period. Logistic regression analysis and ROC results showed that APTR <24.79% and FPTR <10.62% were significantly correlated with femoral head collapse. The Kaplan-Meier survival curve suggested that the overall survival rate of APTR ≥24.79% was 68.2% at 5 and 10 years and FPTR ≥10.62% was 71.63% at 5 and 10 years. At the last follow-up, 26 hips had collapse on the anterior side of the femoral head, 12 hips occurred on the lateral side, and 24 hips happened to collapse on both anterior and lateral sides. CONCLUSION: Femoral head collapse predominantly occurred anteriorly rather than laterally in ONFH patients. The measurements of APTR and FPTR have noticeable implications for the prediction of femoral head collapse, and contribute to the selection of treatment options for ONFH patients with types B and C1 according to the JIC classification.

Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.

Bevacizumab plays an important role in the first and second line treatment for metastatic colorectal cancer (CRC). And induction of hypoxia and the tumors response to it plays an important role in determining the efficacy of antiangiogenic therapy while the connection between them remains unclear. Here, we found that lactate accumulated in the tumor environment of CRC and acted as substrates for histone lactylation, and this process was further induced by cellular enhanced glycolysis in hypoxia. We determined that CRC patients resistant to bevacizumab treatment presented with elevated levels of histone lactylation and inhibition of histone lactylation efficiently suppressed CRC tumorigenesis, progression and survival in hypoxia. Histone lactylation promoted the transcription of RUBCNL/Pacer, facilitating autophagosome maturation through interacting with BECN1 (beclin 1) and mediating the recruitment and function of the class III phosphatidylinositol 3-kinase complex, which had a crucial role in hypoxic cancer cells proliferation and survival. Moreover, combining inhibition of histone lactylation and macroautophagy/autophagy with bevacizumab treatment demonstrated remarkable treatment efficacy in bevacizumab-resistance patients-derived pre-clinical models. These findings delivered a new exploration and important supplement of metabolic reprogramming-epigenetic regulation, and provided a new strategy for improving clinical efficacy of bevacizumab in CRC by inhibition of histone lactylation.Abbreviations: 2-DG: 2-deoxy-D-glucose; BECN1: beclin 1; CQ: chloroquine; CRC: colorectal cancer; DMOG: dimethyloxalylglycine; H3K18la: histone H3 lysine 18 lactylation; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Nala: sodium lactate; PDO: patient-derived orgnoid; PDX: patient-derived xenograft; RUBCNL/Pacer: rubicon like autophagy enhancer; SQSTM1/p62: sequestosome 1.

A positive feedback circuit driven by m6A-modified circular RNA facilitates colorectal cancer liver metastasis.

BACKGROUND: Liver metastasis is the leading cause of death in patients with colorectal cancer (CRC). Emerge evidence suggests that circular RNA (circRNA) is a pivotal player in cancer progression. However, its role in CRC liver metastasis remains largely unknown. METHODS: Circ-YAP expression was detected by qRT-PCR and in situ hybridization. The function of circ-YAP was tested by wound healing, transwell and CCK-8 assays. RNA immunoprecipitation, pull-down, luciferase reporter, chromatin immunoprecipitation assays were used to investigate the mechanism underlying circ-YAP promoting CRC liver metastasis. CRC liver metastasis animal model was established to assess the effect of circ-YAP in vivo. RESULTS: Circ-YAP was notably upregulated in CRC with liver metastasis, which was associated with dismal prognosis. Circ-YAP promoted CRC cell migration and invasion in vitro, and facilitated liver metastasis in patient-derived xenografts (PDX) models in vivo. Mechanistically, circ-YAP encoded a novel truncated protein containing 220 amino acids, termed as YAP-220aa, which competitively bound to LATS1, resulting in YAP dephosphorylation and nuclear translocation, thereby activating a cohort of metastasis-promoting genes. Importantly, N6-methyladenosine (m6A) modification orchestrated efficient initiation of circ-YAP translation, requiring m6A reader YTHDF3 and eIF4G2 translation initiation complex. Intriguingly, circ-YAP was transcriptionally enhanced by YAP/TEAD complex, thus forming a positive regulatory feed-forward loop. CONCLUSIONS: Our findings reveal a previously uncharacterized oncoprotein encoded by circ-YAP, implying a promising biomarker and therapeutic target for CRC patients with liver metastasis.

Update on the outcome of M-protein screening program of multiple myeloma in China: A 7-year cohort study.

BACKGROUND: To improve the early detection rate of multiple myeloma (MM), the M-protein screening system has been performed in the hospital population at Zhongshan Hospital Fudan University since 2014, with electrophoretic-based monoclonal immunoglobulin (M-protein) screening integrated into the blood biochemistry panel. This study updated 7-year follow-up findings of MM patients diagnosed by screening-driven and symptom-driven approaches. METHODS: The retrospective study compared the characteristics and outcomes of patients diagnosed through two patterns by reviewing the plasma cell disease database from January 2014 to October 2021. The screening-driven group included patients diagnosed through the screening system during workups of unrelated medical conditions or routine checkups. In contrast, patients who visited or were referred to the hematological department due to myeloma-related end-organ damage were categorized into the symptom-driven group. RESULTS: There were 3,110,218 serum protein electrophoresis (SPEP) tests performed during 7 years, with 1.95% (60,609) patients yielding positive SPEP results. Of 911 confirmed MM cases (excluding concurrent amyloidosis), 366 were assigned to the screening-driven group, while 545 were to the symptom-driven group. Compared to the symptom-driven group, the screening group had more IgG subtypes, earlier International Stage System stages, fewer disease-related symptoms, lower ECOG scores, less extramedullary disease, a lower percentage of bone marrow plasma cells, and a lower level of lactate dehydrogenase. Frontline response results of two groups were similar. Patients detected through screening had a significantly improved median progression-free survival (PFS) than the symptom-driven group (62.2 vs. 24.9 months, p < 0.001, HR: 2.12, 95% CIs: 1.69-2.65), with median follow-ups of 32.6 and 27.4 months. Furthermore, the median overall survival (OS) was significantly longer in patients of the screening group (not reached vs. 62.3 months, p < 0.001, HR: 2.49, 95% CIs: 1.81-3.41). After being adjusted for well-acknowledged myeloma prognostic factors, the screening-driven diagnostic pattern remained an independent prognostic factor indicating improved PFS and OS in MM patients. CONCLUSION: Routine M-protein screening for MM in the hospital population results in an earlier diagnosis and better patient outcomes.

Clinical profiles in multiple myeloma patients with extreme survivals: a study from a National Medical Center in China.

OBJECTIVES: The clinical outcomes of multiple myeloma (MM) patients are highly variable in the real-world setting. Some MM patients may have clinical endings that do not abide by the book. We aim to describe features of MM patients with extreme survivals in real-world practice. METHODS: This retrospective study enrolled 941 patients consecutively visited a national medical center, China, between July 1995 and December 2021. Among patients, we identified two groups of MM patients with extreme survivals, 56 were in the long-term remission (LR) group with progression-free survival (PFS) ≥ 60 months, and 82 were in the rapid progression (RP) group with PFS ≤ 6 months. RESULTS: CRAB features, of which hypercalcemia, renal insufficiency, and anemia were more common in the RP group, except for bone disease, with a comparable incidence at diagnosis in both groups (88.8 vs 85.7%, P = 0.52). High-risk cytogenetics was detected in 45.7% of patients in the RP group. Of note, 14.3% of MM patients in the LR group harbored del (17p). According to the Revised International Staging System (R-ISS), 9% of patients belonged to stage I in the RP group, and 19% of patients in the LR group were found in stage III. There were 8 (15.7%) patients in the LR group only achieved partial response (PR) as the best response. Median time to best response (TBR) for LR and RP group patients was 4.6 and 1.4 months, respectively. CONCLUSIONS: The disparities in the survivals of MM patients indicated that some unexpected factors have influenced the outcomes in the real-world setting.

The loss of neoantigens is an important reason for immune escape in multiple myeloma patients with high intratumor heterogeneity.

OBJECTIVES: Intratumor heterogeneity (ITH) is an important factor for clinical outcomes in patients with multiple myeloma (MM). High ITH has been proven to be a key reason for tumor immune escape and treatment resistance. Neoantigens are thought to be associated with ITH, but the specific correlation and functional basis for this remains unclear. METHODS: We study this question through the whole-exome sequencing (WES) data from 43 high ITH newly diagnosed MM patients in our center. Mutant allele tumor heterogeneity (MATH) was conducted to quantify ITH. The cutoff value for high intratumor heterogeneity was determined by comparing MATH of different kinds of tumors. NeoPredPipe was performed to predict neoantigens and binding affinity. RESULTS: Compared to other tumors, MM has a relatively low tumor mutation burden but a high ITH. Patients with high MATH had significantly shorter progression-free survival times than those with low MATH (p = 0.001). In high ITH samples, there is a decrease in strong-binding neoantigens (p = 0.019). The loss of strong-binding neoantigens is a key factor for insensitivity to therapy (p = 0.015). Loss of heterozygosity in HLA was not observed. In addition, patients with fewer neoantigens loss had higher rates of disease remission (p = 0.047). CD8 + T cells (p = 0.012) and NK cells (p = 0.011) decreased significantly in patients with high neoantigens loss rate. A prediction model based on neoantigens was built to evaluate the strength of immune escape. CONCLUSION: The loss of strong-binding neoantigens explains why tumors with high ITH have a higher degree of immune escape and may be feasible for deciding the clinical treatment of MM.

Arctiin attenuates iron overload­induced osteoporosis by regulating the PI3K/Akt pathway.

Iron overload is a prevalent pathological factor observed among elderly individuals and those with specific hematological disorders, and is frequently associated with an elevated incidence of osteoporosis. Although arctiin (ARC) has been shown to possess antioxidant properties and the ability to mitigate bone degeneration, its mechanism of action in the treatment of iron overload­induced osteoporosis (IOOP) remains incompletely understood. To explore the potential molecular mechanisms underlying the effects of ARC, the MC3T3­E1 cell osteoblast cell line was used. Cell Counting Kit was used to assess MC3T3­E1 cell viability. Alkaline phosphatase staining and alizarin red staining were assessed for osteogenic differentiation. Calcein AM assay was used to assess intracellular iron concentration. In addition, intracellular levels of reactive oxygen species (ROS), lipid peroxides, mitochondrial ROS, apoptosis rate and mitochondrial membrane potential changes in MC3T3­E1 cells were examined using flow cytometry and corresponding fluorescent dyes. The relationship between ARC and the PI3K/Akt pathway was then explored by western blotting and immunofluorescence. In addition, the effects of ARC on IOOP was verified using an iron overload mouse model. Immunohistochemistry was performed to evaluate expression of osteogenesis­related proteins. Micro-CT and H&E were used to analyze bone microstructural parameters and histomorphometric indices in the bone tissue. Notably, ARC treatment reversed the decreased viability and increased apoptosis in MC3T3­E1 cells originally induced by ferric ammonium citrate, whilst promoting the formation of mineralized bone nodules in MC3T3­E1 cells. Furthermore, iron overload induced a decrease in the mitochondrial membrane potential, augmented lipid peroxidation and increased the accumulation of ROS in MC3T3­E1 cells. ARC not only positively regulated the anti­apoptotic and osteogenic capabilities of these cells via modulation of the PI3K/Akt pathway, but also exhibited antioxidant properties by reducing oxidative stress. In vivo experiments confirmed that ARC improved bone microarchitecture and biochemical parameters in a mouse model of iron overload. In conclusion, ARC exhibits potential as a therapeutic agent for IOOP by modulating the PI3K/Akt pathway, and via its anti­apoptotic, antioxidant and osteogenic properties.

Fibula allograft with cannulated screw fixation versus ordinary cannulated screw fixation for femoral neck fractures: a 10-year retrospective comparative study.

BACKGROUND: For femoral neck fractures in young and middle-aged patients, both fibula allograft with cannulated screw fixation and ordinary cannulated screw fixation are clinically effective treatments. However, for unstable femoral neck fractures, ordinary cannulated screw fixation is characterized by a high risk of postoperative complications and a high rate of mechanical failure after internal fixation. For this study, we systematically compared the long-term efficacy and postoperative complications of these two procedures. METHODS: A total of 156 subjects diagnosed as femoral neck fractures participated in our study. Subjects in the combination group underwent fibula allograft with cannulated screw fixation (n = 76), and those in the control group were treated with ordinary cannulated screw fixation (n = 80). Baseline characteristics, perioperative outcomes, Harris hip score (HHS) and EuroQoL five-dimension questionnaire (EQ-5D); and the incidence of postoperative and bone healing complications in the two groups were recorded and compared. RESULTS: The average follow-up time was more than 10 years. Intra-operative blood loss significantly increased in the combination group compared with the control group (P < 0.05). There were significantly improved performances in healing time, the time course of recovery of full-weight-bearing stepping, HHS and EQ-5D scores in the combination group compared with the control group (P < 0.05). Besides, the incidence rates of femoral head necrosis, nonunion, femoral neck shortening and total hip replacement were significantly lower in the combination group than those in the control group (P < 0.05). CONCLUSION: Fibula allograft with cannulated screw fixation shows a better long-term therapeutic effect than ordinary cannulated screw fixation for femoral neck fractures in young and middle-aged patients. Patients receiving the combination strategy have faster and high-quality functional recovery after femoral neck fractures and a lower incidence rate of postoperative complications.

Effects of miR-143 regulation on cardiomyocytes apoptosis in doxorubicin cardiotoxicity based on integrated bioinformatics analysis.

This study aimed to investigate the effect of miRNAs involving oxidative stress response in doxorubicin (DOX)-induced cardiotoxicity based on the data from Gene Expression Omnibus (GEO) database and experimental results via integrated bioinformatics analysis. MiRNA expression profiles of DOX-induced cardiotoxicity in rat myocardial tissues and adult rat cardiomyocytes (ARC) were extracted from GEO datasets (GSE36239). Differential expression miRNA (DEMs) were separately captured in rat myocardial tissues and in ARC, and intersected between rat myocardial tissues and ARC via Venny 2.1. Subsequently, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) analyzed 46 target genes of miR-143, one of 6 DEMs, and HIF-1 and PI3K-Akt signaling pathway were significantly enriched. Further experimental results showed DOX-induced oxidative stress downregulated the expression of miR-143, and then promoted target gene Bbc3 expression and H9c2 apoptosis, the intervention of phosphocreatine (PCr) or N-acetyl-L-cystine (NAC) alleviated oxidative stress, apoptosis and Bbc3 expression, upregulated miR-143 in DOX-induced cardiotoxicity in vivo and in vitro. Our findings elucidated the regulatory network between miR-143 and oxidative stress in DOX-induced cardiotoxicity, and might unveiled a potential biomarker and molecular mechanisms, which could be helpful to the diagnosis and treatment of DOX-induced cardiotoxicity.

Dihydrotanshinone I attenuates estrogen-deficiency bone loss through RANKL-stimulated NF-κB, ERK and NFATc1 signaling pathways.

Postmenopausal osteoporosis, a chronic condition that predominantly affects postmenopausal women, presents a significant impediment to their overall well-being. The condition arises from estrogen deficiency, leading to enhanced osteoclast activity. Salvia miltiorrhiza, a well-established Chinese herbal medicine with a history of clinical use for osteoporosis treatment, contains diverse active constituents that have shown inhibitory effects on osteoclast formation and bone loss. Dihydrotanshinone I (DTI), a phenanthrenonequinone compound derived from the root of Salvia miltiorrhiza, has been identified as a potential therapeutic agent, although its mechanism of action on osteoclasts remains elusive. In this study, we aimed to elucidate the inhibitory potential of DTI on RANKL-induced osteoclastogenesis. We observed the ability of DTI to effectively impede the expression of key osteoclast-specific genes and proteins, as assessed by Real-time PCR and Western Blotting analyses. Mechanistically, DTI exerted its inhibitory effects on osteoclast formation by modulating critical signaling pathways including NF-κB, ERK, and calcium ion signaling. Notably, DTI intervention disrupted the nuclear translocation and subsequent transcriptional activity of the NFATc1, thus providing mechanistic insights into its inhibitory role in osteoclastogenesis. To further assess the therapeutic potential of DTI, we employed an ovariectomized osteoporosis animal model to examine its impact on bone loss. Encouragingly, DTI demonstrated efficacy in mitigating bone loss induced by estrogen deficiency. In conclusion, our investigation elucidates the ability of DTI to regulate multiple signaling pathways activated by RANKL, leading to the inhibition of osteoclast formation and prevention of estrogen-deficiency osteoporosis. Consequently, DTI emerges as a promising candidate for the treatment of osteoporosis.

MicroRNA-29 differentially mediates preeclampsia-dysregulated cellular responses to cytokines in female and male fetal endothelial cells.

Preeclampsia (PE) differentially impairs female and male fetal endothelial cell function, which is associated with an increased risk of adult-onset cardiovascular disorders in children born to mothers with PE. However, the underlying mechanisms are poorly defined. We hypothesize that dysregulation of microRNA-29a-3p and 29c-3p (miR-29a/c-3p) in PE disturbs gene expression and cellular responses to cytokines in fetal endothelial cells in a fetal sex-dependent manner. RT-qPCR analysis of miR-29a/c-3p was performed on female and male unpassaged (P0) human umbilical vein endothelial cells (HUVECs) from normotensive (NT) pregnancies and PE. Bioinformatic analysis of an RNA-seq dataset was performed to identify PE-dysregulated miR-29a/c-3p target genes in female and male P0-HUVECs. Gain- and loss-of-function assays were conducted to determine the effects of miR-29a/c-3p on endothelial monolayer integrity and proliferation in response to transforming growth factor-ß1 (TGFß1) and tumour necrosis factor-α (TNFα) in NT and PE HUVECs at passage 1. We observed that PE downregulated miR-29a/c-3p in male and female P0-HUVECs. PE dysregulated significantly more miR-29a/c-3p target genes in female vs. male P0-HUVECs. Many of these PE-differentially dysregulated miR-29a/c-3p target genes are associated with critical cardiovascular diseases and endothelial function. We further demonstrated that miR-29a/c-3p knockdown specifically recovered the PE-abolished TGFß1-induced strengthening of endothelial monolayer integrity in female HUVECs, while miR-29a/c-3p overexpression specifically enhanced the TNFα-promoted cell proliferation in male PE HUVECs. In conclusion, PE downregulates miR-29a/c-3p expression and differentially dysregulates miR-29a/c-3p target genes associated with cardiovascular diseases and endothelial function in female and male fetal endothelial cells, possibly contributing to the fetal sex-specific endothelial dysfunction observed in PE. KEY POINTS: Preeclampsia differentially impairs female and male fetal endothelial cell function in responses to cytokines. Pro-inflammatory cytokines are elevated in maternal circulation during pregnancy in preeclampsia. MicroRNAs are critical regulators of endothelial cell function during pregnancy. We have previously reported that preeclampsia downregulated microRNA-29a-3p and 29c-3p (miR-29a/c-3p) in primary fetal endothelial cells. However, it is unknown if PE differentially dysregulates the expression of miR-29a/c-3p in female and male fetal endothelial cells. We show that preeclampsia downregulates miR-29a/c-3p in male and female HUVECs and preeclampsia dysregulates cardiovascular disease- and endothelial function-associated miR-29a/c-3p target genes in HUVECs in a fetal sex-specific manner. MiR-29a/c-3p differentially mediate cell responses to cytokines in female and male fetal endothelial cells from preeclampsia. We have revealed fetal sex-specific dysregulation of miR-29a/c-3p target genes in fetal endothelial cells from preeclampsia. This differential dysregulation may contribute to fetal sex-specific endothelial dysfunction in offspring born to preeclamptic mothers.

Evaluation of total tumor volume reduction ratio in initially unresectable colorectal liver metastases after first-line systemic treatment.

PURPOSE: Total tumor volume (TTV) may play an essential role in the estimation of tumor burden. This study is aimed to investigate the clinical value of the reduction ratio of TTV as a valuable indicator of clinical outcomes in patients with colorectal liver metastases (CRLM). METHODS: A total of 240 initially unresectable CRLM patients who underwent first-line systemic treatment were enrolled in this study. TTV at baseline and at the end of first-line treatment were assessed using a three-dimensional reconstruction system according to CT or MRI images. Survival was evaluated using Kaplan-Meier analysis and compared using Cox proportional hazard ratios (HR). RESULTS: A total of 212 (88.3%) patients achieved tumor regression with a median reduction ratio of TTV of 86.0%. An increasing reduction ratio of TTV was associated with a gradually ascending successful conversion outcome. Patients with a reduction ratio >86.0% had better survival than those with a reduction ratio 0-86.0% or <0 (5-year overall survival (OS) rates, 64.4% vs. 44.9% vs. 23.5%, P < 0.001; 5-year progression-free survival (PFS) rates, 36.3% vs. 28.2% vs. 6.5%, P < 0.001). Multivariate analysis indicated that the reduction ratio of TTV ≤ 86.0% (OR [95%CI]: 4.956 [2.654-9.253], P < 0.001) was an independent factor for conversion failure outcome. Cox analyses revealed that the reduction ratio of TTV ≤ 86.0% was an independent factor for both unfavorable OS (HR [95%CI]: 2.216 [1.332-3.688], P = 0.002) and PFS (HR [95%CI]: 2.023 [1.376-2.974], P < 0.001). CONCLUSIONS: The reduction ratio of TTV was an effective indicator for conversion outcome and long-term prognosis in patients with initially unresectable CRLM after first-line systemic treatment.

Inhibition of CDK1 Overcomes Oxaliplatin Resistance by Regulating ACSL4-mediated Ferroptosis in Colorectal Cancer.

Oxaliplatin is a widely used chemotherapy drug for patients with advanced colorectal cancer (CRC); however, frequent drug resistance limits its therapeutic efficacy in patients. Here, this work identifies cyclin-dependent kinase 1 (CDK1) as a critical contributor to oxaliplatin resistance via in vitro and in vivo CRISPR/Cas9 screening. CDK1 is highly expressed in oxaliplatin-resistant cells and tissues due to the loss of N6-methyladenosine modification. Genetic and pharmacological blockade of CDK1 restore the susceptibility of CRC cells to oxaliplatin in vitro and in cell/patient-derived xenograft models. Mechanistically, CDK1 directly binds to and phosphorylates Acyl-CoA synthetase long-chain family 4 (ACSL4) at S447, followed by recruitment of E3 ubiquitin ligase UBR5 and polyubiquitination of ACSL4 at K388, K498, and K690, which leads to ACSL4 protein degradation. Reduced ACSL4 subsequently blocks the biosynthesis of polyunsaturated fatty acid containing lipids, thereby inhibiting lipid peroxidation and ferroptosis, a unique iron-dependent form of oxidative cell death. Moreover, treatment with a ferroptosis inhibitor nullifies the enhancement of CRC cell sensitivity to oxaliplatin by CDK1 blockade in vitro and in vivo. Collectively, the findings indicate that CDK1 confers oxaliplatin resistance to cells by suppressing ferroptosis. Therefore, administration of a CDK1 inhibitor may be an attractive strategy to treat patients with oxaliplatin-resistant CRC.

Successful rescue of fulminant myocarditis with mechanical circulatory support and immunosuppression therapy: A case report.

Myocarditis is challenging to diagnose because of its various clinical manifestations. Fulminant myocarditis (FM) is a severe type of myocarditis characterized by heart failure, malignant arrhythmia, cardiogenic shock, and cardiac arrest. Its early diagnosis and timely treatment are crucial for a positive long-term prognosis. Here we report a case of 42-year-old woman who presented with fever, chest pain, and cardiogenic shock. An initial examination showed increased myocardial enzyme levels and diffuse ST-segment elevation. Urgent coronary angiography excluded coronary artery stenosis. Echocardiography revealed decreased left ventricular systolic function. Cardiac magnetic resonance imaging revealed cardiomyocyte necrosis and interstitial inflammatory edema. The patient was diagnosed with FM and administered antiviral and anti-infective agents, glucocorticoid, immunoglobulin, and supported with temporary cardiac pacemaker and positive airway therapy, and treated with continuous renal replacement therapy. As her clinical condition deteriorated rapidly, we immediately started an intra-aortic balloon pump and veno-arterial extracorporeal membrane oxygenation. She was discharged on day 15 and recovered normally during follow-up. The early initiation of mechanical circulatory support and immunosuppression are life-saving tools for the treatment of FM.

Case report: Unruptured sinus of Valsalva aneurysms causing postural angina pectoris and false "pulmonary hypertension".

A 37-year-old woman presented with worsening intermittent chest pain and dyspnea in the previous year. Although the dyspnea was exertion-dependent, her chest pain was heavily dependent on her postural position, worsening in the supine position but alleviated by lying prone or by sitting up and leaning forward. She was cyanotic, and a diastolic murmur in the left third intercostal space was auscultated. An electrocardiogram recorded when she laid flat and had angina pectoris attacks showed ST-segment elevation in the aVR and depression in the II, III, aVF, and V3-V6 leads. However, when she sat up for a few minutes, her symptoms and ST-segment abnormalities disappeared. Echocardiography and cardiac computed tomography angiography revealed large unruptured aneurysms of the left and non-coronary sinuses, along with a dilated aortic root, severe aortic regurgitation, and right ventricular high pressure. Coronary angiography showed ∼90% pulsating stenosis of the left main coronary artery and ∼80% pulsating stenosis of the proximal left circumflex artery, presumably caused by pulsation of the dilated sinus of Valsalva aneurysm under blood pressure. Genetic testing revealed c.1781 C > G nonsense mutations in the FLNA gene. The patient underwent surgery, which confirmed dual unruptured left/non-coronary sinus of Valsalva aneurysms. Our case illustrates an unusual postural form of angina pectoris and false "pulmonary hypertension" caused by large dual unruptured left/non-coronary sinus of Valsalva aneurysms.