CDK4/6 Inhibitors Impede Chemoresistance and Inhibit Tumor Growth of Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is characterized by rapid development of chemoresistance and poor outcomes. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are widely used in breast cancer and other cancer types. However, the molecular mechanisms of CDK4/6 in SCLC chemoresistance remain poorly understood. Here, Rb1flox/flox, Trp53flox/flox, Ptenflox/flox (RTP) and Rb1flox/flox, Trp53flox/flox, MycLSL/LSL (RPM) spontaneous SCLC mouse models, SCLC cell line-derived xenograft (CDX) models, and SCLC patient-derived xenograft (PDX) models are established to reveal the potential effects of CDK4/6is on SCLC chemoresistance. In this study, it is found that CDK4/6is palbociclib (PD) or ribociclib (LEE) combined with chemotherapeutic drugs significantly inhibit SCLC tumor growth. Mechanistically, CDK4/6is do not function through the classic Retionblastoma1 (RB) dependent axis in SCLC. CDK4/6is induce impair autophagy through the AMBRA1-lysosome signaling pathway. The upregulated AMBRA1 protein expression leads to CDK6 degradation via autophagy,  and the following TFEB and TFE3 nuclear translocation inhibition leading to the lysosome-related genes levels downregulation. Moreover, it is found that the expression of CDK6 is higher in SCLC tumors than in normal tissue and it is associated with the survival and prognosis of SCLC patients. Finally, these findings demonstrate that combining CDK4/6is with chemotherapy treatment may serve as a potential therapeutic option for SCLC patients.

Diagnostic model for hepatocellular carcinoma using small extracellular vesicle-propagated miRNA signatures.

Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Small extracellular vesicles (sEVs) are bilayer lipid membrane vesicles containing RNA that exhibit promising diagnostic and prognostic potential as cancer biomarkers. Aims: To establish a miRNA panel from peripheral blood for use as a noninvasive biomarker for the diagnosis of HCC. Methods: sEVs obtained from plasma were profiled using high-throughput sequencing. The identified differential miRNA expression patterns were subsequently validated using quantitative real-time polymerase chain reaction analysis. Results: The random forest method identified ten distinct miRNAs distinguishing HCC plasma from non-HCC plasma. During validation, miR-140-3p (p = 0.0001) and miR-3200-3p (p = 0.0017) exhibited significant downregulation. Enrichment analysis uncovered a notable correlation between the target genes of these miRNAs and cancer development. Utilizing logistic regression, we developed a diagnostic model incorporating these validated miRNAs. Receiver operating characteristic (ROC) curve analysis revealed an area under the curve (AUC) of 0.951, with a sensitivity of 90.1% and specificity of 87.8%. Conclusion: These aberrantly expressed miRNAs delivered by sEVs potentially contribute to HCC pathology and may serve as diagnostic biomarkers for HCC.

Vascular clips for preventing lymphocele and symptomatic lymphocele in patients with gynecologic malignancies after laparoscopic pelvic lymphadenectomy.

STUDY OBJECTIVE: To evaluate the effectiveness of using vascular clips to seal targeted lymphatics in gynecological malignancies for the prevention of postoperative pelvic lymphocele and symptomatic lymphocele after laparoscopic pelvic lymphadenectomy. DESIGN: Retrospective analysis. SETTING: Single-center academic hospital. PATIENTS: In total, 217 patients with gynecological malignancies were included. INTERVENTIONS: Patients were classified into two groups: group 1 (vascular clips were used to seal the targeted lymphatics) and group 2 (electrothermal instruments were used to seal the targeted lymphatics). The patients were followed up 4-6 weeks after surgery to evaluate the incidence of lymphoceles by ultrasound or CT. Symptomatic lymphoceles are defined as those that cause infection, deep vein thrombosis with or without swelling of the extremities, edema (swelling) of the extremities or perineum, hydronephrosis and/or moderate to severe pain. MEASUREMENT AND MAIN RESULTS: One hundred and thirteen patients were enrolled in group 1, and 104 patients were enrolled in group 2. Lymphoceles were observed in 46 (21.2%) patients. Fewer lymphoceles occurred in group 1 than in group 2 [8 (7.1%) vs. 38 (36.5%), p < 0.001]. The percentage of significantly sized lymphoceles was lower in group 1 than that in group 2 [4 (3.5%) vs. 30 (28.8%), p < 0.001]. Symptomatic lymphoceles occurred in 18 patients (8.3%), and only one (1.0%) occurred in group 1, while 17 (16.3%) occurred in group 2 (p < 0.001). A multivariate analysis revealed that vascular clips were the only independent factor for preventing lymphocele (OR = 7.65, 95% CI = [3.30, 17.13], p < 0.001) and symptomatic lymphocele (OR = 22.03, 95% CI = [2.84, 170.63], p = 0.003). CONCLUSIONS: The results indicate that the use of vascular clips may be useful for the prevention of the development of lymphocele and symptomatic lymphocele secondary to pelvic lymphadenectomy performed via laparoscopy.

Preoperative chemoradiotherapy in older patients with rectal cancer guided by comprehensive geriatric assessment within a multidisciplinary team-a multicenter phase II trial.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as "fit" by comprehensive geriatric assessment (CGA). METHODS: A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of "fit" (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22). RESULTS: One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47). CONCLUSION: This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA. TRIAL REGISTRATION: The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).

Minimal residual disease profiling predicts pathological complete response in esophageal squamous cell carcinoma.

Accurate presurgical prediction of pathological complete response (pCR) can guide treatment decisions, potentially avoiding unnecessary surgeries and improving the quality of life for cancer patients. We developed a minimal residual disease (MRD) profiling approach with enhanced sensitivity and specificity for detecting minimal tumor DNA from cell-free DNA (cfDNA). The approach was validated in two independent esophageal squamous cell carcinoma (ESCC) cohorts. In a cohort undergoing neoadjuvant, surgical, and adjuvant therapy (NAT cohort), presurgical MRD status precisely predicted pCR. All MRD-negative cases (10/10) were confirmed as pCR by pathological evaluation on the resected tissues. In contrast, MRD-positive cases included all the 27 non-pCR cases and only one pCR case (10/10 vs 1/28, P < 0.0001, Fisher's exact test). In a definitive radiotherapy cohort (dRT cohort), post-dRT MRD status was closely correlated with patient prognosis. All MRD-negative patients (25/25) remained progression-free during the follow-up period, while 23 of the 26 MRD-positive patients experienced disease progression (25/25 vs 3/26, P < 0.0001, Fisher's exact test; progression-free survival, P < 0.0001, log-rank test). The MRD profiling approach effectively predicted the ESCC patients who would achieve pCR with surgery and those likely to remain progression-free without surgery. This suggests that the cancer cells in these MRD-negative patients have been effectively eliminated and they could be suitable candidates for a watch-and-wait strategy, potentially avoiding unnecessary surgery.

Biomechanical and clinical outcomes of 3D-printed versus modular hemipelvic prostheses for limb-salvage reconstruction following periacetabular tumor resection: a mid-term retrospective cohort study.

BACKGROUND: Debates persist over optimal pelvic girdle reconstruction after acetabular tumor resection, with surgeons grappling between modular and 3D-printed hemipelvic endoprostheses. We hypothesize superior outcomes with 3D-printed versions, yet scarce comparative research exists. This study fills the gap, examining biomechanics and clinical results retrospectively. METHODS: From February 2017 to June 2021, we retrospectively assessed 32 patients undergoing en bloc resection for malignant periacetabular tumors at a single institution. PRIMARY OUTCOME: limb function. SECONDARY OUTCOMES: implant precision, hip joint rotation center restoration, prosthesis-bone osteointegration, and complications. Biomechanical characteristics were evaluated through finite element analysis on pelvic defect models. RESULTS: In the 3D-printed group, stress distribution mirrored a normal pelvis, contrasting the modular group with elevated overall stress, unstable transitions, and higher stress peaks. The 3D-printed group exhibited superior functional scores (MSTS: 24.3 ± 1.8 vs. 21.8 ± 2.0, p < 0.05; HHS: 79.8 ± 5.2 vs. 75.3 ± 3.5, p < 0.05). Prosthetic-bone interface osteointegration, measured by T-SMART, favored 3D-printed prostheses, but surgery time (426.2 ± 67.0 vs. 301.7 ± 48.6 min, p < 0.05) and blood loss (2121.1 ± 686.8 vs. 1600.0 ± 505.0 ml, p < 0.05) were higher. CONCLUSIONS: The 3D-printed hemipelvic endoprosthesis offers precise pelvic ring defect matching, superior stress transmission, and function compared to modular endoprostheses. However, complexity, fabrication expertise, and challenging surgical implantation result in prolonged operation times and increased blood loss. A nuanced consideration of functional outcomes, complexity, and patient conditions is crucial for informed treatment decisions. LEVEL OF EVIDENCE: Level III, therapeutic study (Retrospective comparative study).

Nicorandil-Pretreated Mesenchymal Stem Cell-Derived Exosomes Facilitate Cardiac Repair After Myocardial Infarction via Promoting Macrophage M2 Polarization by Targeting miR-125a-5p/TRAF6/IRF5 Signaling Pathway.

Background: Exosomes derived from bone marrow mesenchymal stem cells (MSC-exo) have been considered as a promising cell-free therapeutic strategy for ischemic heart disease. Cardioprotective drug pretreatment could be an effective approach to improve the efficacy of MSC-exo. Nicorandil has long been used in clinical practice for cardioprotection. This study aimed to investigate whether the effects of exosomes derived from nicorandil pretreated MSC (MSCNIC-exo) could be enhanced in facilitating cardiac repair after acute myocardial infarction (AMI). Methods: MSCNIC-exo and MSC-exo were collected and injected into the border zone of infarcted hearts 30 minutes after coronary ligation in rats. Macrophage polarization was detected 3 days post-infarction, cardiac function as well as histological pathology were measured on the 28th day after AMI. Macrophages were separated from the bone marrow of rats for in vitro model. Exosomal miRNA sequencing was conducted to identify differentially expressed miRNAs between MSCNIC-exo and MSC-exo. MiRNA mimics and inhibitors were transfected to MSCs or macrophages to explore the specific mechanism. Results: Compared to MSC-exo, MSCNIC-exo showed superior therapeutic effects on cardiac functional and structural recovery after AMI and markedly elevated the ratio of CD68+ CD206+/ CD68+cells in infarcted hearts 3 days post-infarction. The notable ability of MSCNIC-exo to promote macrophage M2 polarization was also confirmed in vitro. Exosomal miRNA sequencing and both in vivo and in vitro experiments identified and verified that miR-125a-5p was an effector of the roles of MSCNIC-exo in vivo and in vitro. Furthermore, we found miR-125a-5p promoted macrophage M2 polarization by inhibiting TRAF6/IRF5 signaling pathway. Conclusion: This study suggested that MSCNIC-exo could markedly facilitate cardiac repair post-infarction by promoting macrophage M2 polarization by upregulating miR-125a-5p targeting TRAF6/IRF5 signaling pathway, which has great potential for clinical translation.

Distinctive Craniofacial and Oral Anomalies in MN1 C-terminal Truncation Syndrome.

MN1 C-terminal truncation (MCTT) syndrome was first reported in 2020 and only 28 patients have been recorded to date. Since MCTT syndrome is a newly defined and rare syndrome with many clinical features, the present study reviewed the manifestations and management of oral and dental anomalies. Gene variants of MCTT syndrome and their positive phenotypes were summarised. The phenotypes of variants in two exons differed from each other mainly in the craniomaxillofacial region, including brain MRI abnormalities and palatal morphology. Pathogenic mechanisms, especially in craniofacial and oral anomalies, were discussed. Appropriate treatments in the stomatology and respiratory departments could improve the symptoms of MCTT syndrome. The different sites of MN1 gene variants may influence the clinical symptoms and there may be racial differences in MCTT syndrome. We recommend oral and pulmonary evaluations for the multidisciplinary treatment of MCTT syndrome.

Investigating the causal impact of polycystic ovary syndrome on gestational diabetes mellitus: a two-sample Mendelian randomization study.

Introduction: Determining the causal relationship between polycystic ovary syndrome (PCOS) and gestational diabetes mellitus (GDM) holds significant implications for GDM prevention and treatment. Despite numerous observational studies suggesting an association between PCOS and GDM, it remains unclear whether a definitive causal relationship exists between these two conditions and which specific features of PCOS contribute to increased incidence of GDM. Methods: The causal relationship between polycystic ovary syndrome (PCOS), its characteristic indices, and gestational diabetes mellitus (GDM) was investigated using a two-sample Mendelian randomization study based on publicly available statistics from genome-wide association studies (GWAS). The inverse-variance weighted method was employed as the primary analytical approach to examine the association between PCOS, its characteristic indices, and GDM. MR Egger intercept was used to assess pleiotropy, while Q values and their corresponding P values were utilized to evaluate heterogeneity. It is important to note that this study adopts a two-sample MR design where PCOS and its characteristic indices are considered as exposures, while GDM is treated as an outcome. Results: The study results indicate that there is no causal relationship between PCOS and GDM (all methods P > 0.05, 95% CI of OR values passed 1). The IVW OR value was 1.007 with a 95% CI of 0.906 to 1.119 and a P value of 0.904. Moreover, the MR Egger Q value was 8.141 with a P value of 0.701, while the IVW Q value was also 8.141 with a P value of 0.774, indicating no significant heterogeneity. Additionally, the MR Egger intercept was 0.0004, which was close to zero with a P value of 0.988, suggesting no pleiotropy. However, the study did find a causal relationship between several other factors such as testosterone, high-density lipoprotein, sex hormone-binding globulin, body mass index, waist-hip ratio, apolipoprotein A-I, number of children, diabetes illnesses of mother, father and siblings, hemoglobin A1c, fasting insulin, fasting blood glucose, years of schooling, and GDM based on the IVW method. Conclusion: We observed no association between genetically predicted PCOS and the risk of GDM, implying that PCOS itself does not confer an increased susceptibility to GDM. The presence of other PCOS-related factors such as testosterone, high-density lipoprotein, and sex hormone-binding globulin may elucidate the link between PCOS and GDM. Based on these findings, efforts aimed at preventing GDM in individuals with PCOS should prioritize those exhibiting high-risk features rather than encompassing all women with PCOS.

Therapeutic Window of Intravenous Immunoglobulin (IVIG) and its correlation with IVIG-resistant in Kawasaki Disease: a retrospective study

Abstract Objective: To investigate the optimal timing of initial intravenous immunoglobulin (IVIG) treatment in Kawasaki disease (KD) patients. Methods: KD patients were classified as the early group (day 1-4), conventional group (day 5-7), conventional group (day 8-10), and late group (after day 10). Differences among the groups were analyzed by ANOVA and Chi-square analysis. Predictors of IVIG resistance and the optimal cut-off value were determined by multiple logistic regression analyses and receiver operating characteristic (ROC) curve analysis. Results: There were no significant differences in IVIG resistance among the 4 groups (p = 0.335). The sensitivity analysis also confirmed no difference in the IVIG resistance between those who started the initial IVIG ≤ day 7 of illness and those who received IVIG >day 7 of illness (p = 0.761). In addition, patients who received IVIG administration more than 7 days from the onset had a higher proportion of coronary artery abnormalities (p = 0.034) and longer length of hospitalization (p = 0.033) than those who started IVIG administration less than 7 days. The optimal cut-off value of initial IVIG administration time for predicting IVIG resistance was >7 days, with a sensitivity of 75.25% and specificity of 82.41%. Conclusions: IVIG therapy within 7 days of illness is found to be more effective for reducing the risk of coronary artery abnormalities than those who received IVIG >day 7 of illness. IVIG treatment within the 7 days of illness seems to be the optimal therapeutic window of IVIG. However, further prospective studies with long-term follow-up are required.

Double-Breasted Anterior Rectus Sheath Turnover Flap.

The management of the open abdomen follows wound management with temporary abdominal closure prior to definitive closure while concurrently managing patient nutrient and fluid losses. This case report describes the successful use of double-breasted anterior rectus sheath turnover (DART) flap for early open abdomen closure to facilitate oncological management. The patient is a 47-year-old female with uterine smooth muscle neoplasm whose laparotomy wound was complicated with abdominal wound dehiscence and intra-abdominal infection. The abdomen could be closed with no fistula formation, iatrogenic bowel perforations, or overlying skin necrosis, and a follow-up showed no hernia occurrence. In conclusion, the DART flap provides a simple and autologous option for early tension-free midline closure of the open abdomen with acceptable intra- and postoperative complications.

Compressed variance component mixed model reveals epistasis associated with flowering in Arabidopsis.

Introduction: Epistasis is currently a topic of great interest in molecular and quantitative genetics. Arabidopsis thaliana, as a model organism, plays a crucial role in studying the fundamental biology of diverse plant species. However, there have been limited reports about identification of epistasis related to flowering in genome-wide association studies (GWAS). Therefore, it is of utmost importance to conduct epistasis in Arabidopsis. Method: In this study, we employed Levene's test and compressed variance component mixed model in GWAS to detect quantitative trait nucleotides (QTNs) and QTN-by-QTN interactions (QQIs) for 11 flowering-related traits of 199 Arabidopsis accessions with 216,130 markers. Results: Our analysis detected 89 QTNs and 130 pairs of QQIs. Around these loci, 34 known genes previously reported in Arabidopsis were confirmed to be associated with flowering-related traits, such as SPA4, which is involved in regulating photoperiodic flowering, and interacts with PAP1 and PAP2, affecting growth of Arabidopsis under light conditions. Then, we observed significant and differential expression of 35 genes in response to variations in temperature, photoperiod, and vernalization treatments out of unreported genes. Functional enrichment analysis revealed that 26 of these genes were associated with various biological processes. Finally, the haplotype and phenotypic difference analysis revealed 20 candidate genes exhibiting significant phenotypic variations across gene haplotypes, of which the candidate genes AT1G12990 and AT1G09950 around QQIs might have interaction effect to flowering time regulation in Arabidopsis. Discussion: These findings may offer valuable insights for the identification and exploration of genes and gene-by-gene interactions associated with flowering-related traits in Arabidopsis, that may even provide valuable reference and guidance for the research of epistasis in other species.

[RETRACTED ARTICLE] Therapeutic effect and potential mechanism of pioglitazone in rats with severe acute pancreatitis

Caspase recruitment domain-containing protein 9 (Card9) is located upstream of the nuclear factor kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) inflammatory pathways. This study investigated the therapeutic effect and potential mechanism of pioglitazone in rats with severe acute pancreatitis (SAP). SAP was induced by a retrograde infusion of 5.0% sodium taurocholate into the biliopancreatic duct of Sprague Dawley rats (n=54), which were then treated with pioglitazone. Blood and pancreatic tissues were harvested at 3, 6, and 12 h after SAP induction. Pancreatic pathological damage was evaluated by hematoxylin and eosin staining. Serum amylase, serum pro-inflammatory cytokines, and pancreatic myeloperoxidase (MPO) activities were determined by enzyme-linked immunosorbent assay. The expression of Card9 mRNA and protein in pancreatic tissues was detected by real-time polymerase chain reaction and western blotting. Pioglitazone had a therapeutic effect in treating rats with SAP by decreasing the level of amylase activity, ameliorating pancreatic histological damage, decreasing serum pro-inflammatory cytokine levels and tissue MPO activity, and downregulating the expression of NF-κB, p38MAPK, and Card9 mRNAs and proteins (P<0.05). The present study demonstrated that the inhibition of Card9 expression could reduce the severity of SAP. Card9 has a role in the pathogenic mechanism of SAP.