A new perspective on prostate cancer treatment: the interplay between cellular senescence and treatment resistance.

The emergence of resistance to prostate cancer (PCa) treatment, particularly to androgen deprivation therapy (ADT), has posed a significant challenge in the field of PCa management. Among the therapeutic options for PCa, radiotherapy, chemotherapy, and hormone therapy are commonly used modalities. However, these therapeutic approaches, while inducing apoptosis in tumor cells, may also trigger stress-induced premature senescence (SIPS). Cellular senescence, an entropy-driven transition from an ordered to a disordered state, ultimately leading to cell growth arrest, exhibits a dual role in PCa treatment. On one hand, senescent tumor cells may withdraw from the cell cycle, thereby reducing tumor growth rate and exerting a positive effect on treatment. On the other hand, senescent tumor cells may secrete a plethora of cytokines, growth factors and proteases that can affect neighboring tumor cells, thereby exerting a negative impact on treatment. This review explores how radiotherapy, chemotherapy, and hormone therapy trigger SIPS and the nuanced impact of senescent tumor cells on PCa treatment. Additionally, we aim to identify novel therapeutic strategies to overcome resistance in PCa treatment, thereby enhancing patient outcomes.

Enhanced cellular therapy: revolutionizing adoptive cellular therapy.

Enhanced cellular therapy has emerged as a novel concept following the basis of cellular therapy. This treatment modality applied drugs or biotechnology to directly enhance or genetically modify cells to enhance the efficacy of adoptive cellular therapy (ACT). Drugs or biotechnology that enhance the killing ability of immune cells include immune checkpoint inhibitors (ICIs) / antibody drugs, small molecule inhibitors, immunomodulatory factors, proteolysis targeting chimera (PROTAC), oncolytic virus (OV), etc. Firstly, overcoming the inhibitory tumor microenvironment (TME) can enhance the efficacy of ACT, which can be achieved by blocking the immune checkpoint. Secondly, cytokines or cytokine receptors can be expressed by genetic engineering or added directly to adoptive cells to enhance the migration and infiltration of adoptive cells to tumor cells. Moreover, multi-antigen chimeric antigen receptors (CARs) can be designed to enhance the specific recognition of tumor cell-related antigens, and OVs can also stimulate antigen release. In addition to inserting suicide genes into adoptive cells, PROTAC technology can be used as a safety switch or degradation agent of immunosuppressive factors to enhance the safety and efficacy of adoptive cells. This article comprehensively summarizes the mechanism, current situation, and clinical application of enhanced cellular therapy, describing potential improvements to adoptive cellular therapy.

Mitofilin in cardiovascular diseases: Insights into the pathogenesis and potential pharmacological interventions.

The impact of mitochondrial dysfunction on the pathogenesis of cardiovascular disease is increasing. However, the precise underlying mechanism remains unclear. Mitochondria produce cellular energy through oxidative phosphorylation while regulating calcium homeostasis, cellular respiration, and the production of biosynthetic chemicals. Nevertheless, problems related to cardiac energy metabolism, defective mitochondrial proteins, mitophagy, and structural changes in mitochondrial membranes can cause cardiovascular diseases via mitochondrial dysfunction. Mitofilin is a critical inner mitochondrial membrane protein that maintains cristae structure and facilitates protein transport while linking the inner mitochondrial membrane, outer mitochondrial membrane, and mitochondrial DNA transcription. Researchers believe that mitofilin may be a therapeutic target for treating cardiovascular diseases, particularly cardiac mitochondrial dysfunctions. In this review, we highlight current findings regarding the role of mitofilin in the pathogenesis of cardiovascular diseases and potential therapeutic compounds targeting mitofilin.

Pan-cancer analysis of NUP155 and validation of its role in breast cancer cell proliferation, migration, and apoptosis.

NUP155 is reported to be correlated with tumor development. However, the role of NUP155 in tumor physiology and the tumor immune microenvironment (TIME) has not been previously examined. This study comprehensively investigated the expression, immunological function, and prognostic significance of NUP155 in different cancer types. Bioinformatics analysis revealed that NUP155 was upregulated in 26 types of cancer. Additionally, NUP155 upregulation was strongly correlated with advanced pathological or clinical stages and poor prognosis in several cancers. Furthermore, NUP155 was significantly and positively correlated with DNA methylation, tumor mutational burden, microsatellite instability, and stemness score in most cancers. Additionally, NUP155 was also found to be involved in TIME and closely associated with tumor infiltrating immune cells and immunoregulation-related genes. Functional enrichment analysis revealed a strong correlation between NUP155 and immunomodulatory pathways, especially antigen processing and presentation. The role of NUP155 in breast cancer has not been examined. This study, for the first time, demonstrated that NUP155 was upregulated in breast invasive carcinoma (BRCA) cells and revealed its oncogenic role in BRCA using molecular biology experiments. Thus, our study highlights the potential value of NUP155 as a biomarker in the assessment of prognostic prediction, tumor microenvironment and immunotherapeutic response in pan-cancer.

Knowledge mapping of application of image-guided surgery in prostate cancer: a bibliometric analysis (2013-2023).

BACKGROUND: Image-guided surgery (IGS) refers to surgery navigated by medical imaging technology, helping doctors better clarify tumor boundaries, identify metastatic lymph nodes and preserve surrounding healthy tissue function. Recent studies have provided expectable momentum of the application of IGS in prostate cancer (PCa). The authors aim to comprehensively construct a bibliometric analysis of the application of IGS in PCa. METHOD: The authors searched publications related to application of IGS in PCa from 2013 to 2023 on the web of science core collection (WoSCC) databases. VOSviewer, CiteSpace, and R package 'bibliometrix' were used for bibliometric analysis. RESULTS: Two thousand three eighty-nine articles from 75 countries and 2883 institutions led by the United States were included. The number of publications related to the application of IGS in PCa kept high in the last decade. Johns Hopkins University is the top research institutions. Journal of Nuclear Medicine has the highest popularity as the selection of journal and co-cited journal. Pomper Martin G. had published the most paper. Ali Afshar-Oromieh was co-cited most frequently. The clinical efficacy of PSMA-PET/CT in PCa diagnosis and treatment are main topics in this research field, with emerging focuses on the use of fluorescence imaging guidance technology in PCa. 'PSMA' and 'PET/CT' are the main keywords as long-term research hotspots. CONCLUSION: This study is the first bibliometric analysis of researches on application of IGS in PCa with three recognized bibliometric software, providing an objective description and comprehensive guidance for the future relevant investigations.

Sivelestat in Patients at a High Risk of Postoperative Acute Lung Injury After Scheduled Cardiac Surgery: A Prospective Cohort Study.

Background: Sivelestat, a neutrophil elastase inhibitor, is specifically developed to mitigate the occurrence of acute lung injury (ALI) in individuals who are undergoing cardiovascular surgery. However, its impact on patients who are at a heightened risk of developing ALI after scheduled cardiac surgery has yet to be determined. In order to address this knowledge gap, we undertook a study to assess the efficacy of sivelestat in protecting the lungs of these patients. Methods: We conducted a prospective cohort study involving 718 patients who were at high risk of developing postoperative acute lung injury (ALI) and underwent scheduled cardiac surgery between April 25th, 2022, and September 7th, 2023. Among them, 52 patients received sivelestat (administered at a dosage of 0.2mg/kg/h for 3 days), while 666 patients served as controls, not receiving sivelestat. The control conditions were the same for all patients, including ventilation strategy, extubating time, and fluid management. Subsequently, a propensity-score matched cohort was established, consisting of 40 patients in both the sivelestat and control groups. The primary outcome measure encompassed a composite of adverse outcomes, including 30-day mortality, ALI, acute respiratory distress syndrome (ARDS), and others. Secondary outcomes assessed included pneumonia, ventricular arrhythmias, mechanical ventilation (MV) time, and more. Results: After conducting propensity matching in our study, we observed that there were no significant differences in 30-day mortality between the sivelestat and control groups (0% vs 2.5%, P=0.32). However, the use of sivelestat exhibited a significant reduction in the incidence of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) compared to the control group (0% vs 55%, P<0.01), pneumonia (0 vs 37.5%, P<0.01), MV time (median:8 hours, IQR:4-14.8 hours vs median: 15.2 hours, IQR:14-16.3 hours, P<0.01). Compared to the control group, the sivelestat could significantly decrease white cell count (P<0.01), neutrophile percentage (P<0.01) and C-reactive protein (P<0.01) in the period of postoperative 5 days. Conclusion: The prophylactic administration of sivelestat has shown promising results in reducing the occurrence of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) in patients with a heightened risk of developing these conditions after elective cardiac surgery. Our study findings indicate that sivelestat may provide protective effects by suppressing inflammation triggered by neutrophil activation, thereby safeguarding pulmonary function. Registration: ChiCTR2200059102, https://www.chictr.org.cn/showproj.html?proj=166643.

Transcriptome data-based status of PI3K/AKT/mTOR pathway indicates heterogeneity and immune modulation in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited treatment options. The PI3K/AKT/mTOR pathway is commonly activated in PDAC and plays a critical role in its progression. METHODS AND RESULTS: In this study, the effect of taselisib (a selective PI3K inhibitor) on PDAC cell proliferation was investigated, and a significant decrease in viability was observed with increasing concentrations of taselisib. Differential analysis on samples from the Genotype-Tissue Expression and The Cancer Genome Atlas databases revealed 24 dysregulated PI3K/AKT/mTOR pathway-related genes (PRGs). Unsupervised clustering-based analysis of transcriptome cohorts revealed two clusters with high consistency between RNA-seq and microarray cohorts. Cluster B had higher enrichment of immune cells, particularly CD8+ T cells, and lower levels of immunosuppressive Treg cells. Moreover, we investigated the relationship between drug sensitivity and different clusters and found that cluster A had a better response to PI3K/AKT/mTOR pathway-related inhibitors and chemotherapy. Finally, cluster A exhibited significant activation of PI3K/AKT/mTOR and related oncogenic pathways, contributing to poor prognosis. The study also developed a risk score based on the expression profiles of PRGs and machine learning, which showed a significant increase in overall survival time among patients in the low-risk group. Importantly, the PI3K/AKT/mTOR pathway could be used to better predict individual risk scores, as evidenced by stratified survival analysis. CONCLUSIONS: These findings suggest that targeting the PI3K/AKT/mTOR pathway may have therapeutic potential in PDAC, and distinct pathway states, immune modulation and tumor microenvironments have prognostic value.

Transcriptomic landscape of endothelial cells: Key tumor microenvironment components indicating variable clinical outcomes in pancreatic ductal adenocarcinoma.

Endothelial cells (ECs) present in the tumor microenvironment (TME) exhibit significant diversity that may impact the efficacy of anti-tumor treatments. Thus, our study sought to elucidate the various clusters of ECs present in pancreatic ductal adenocarcinoma (PDAC) and explore their possible interactions and influence on clinical outcomes. We obtained single-cell transcriptome data from 24 PDAC tumors and 11 normal pancreases, minimizing any batch effects between samples. Next, we compared the relative abundance of various ECs clusters across distinct sample types. Pseudo-time analysis was employed to investigate the differentiation origin of ECs. A variety of bioinformatics methods were used to investigate potential communication between ECs and malignant cells, as well as assess metabolic changes, pathway alterations, and immune-related markers expression within distinct EC clusters. Lastly, we investigated the impact of particular ECs clusters on patient prognosis in bulk transcriptome data. Our study identified seven distinct clusters of ECs, denoted as CA4+ ECs, MMP2+ ECs, SPP1+ ECs, MT1F+ ECs, CCL5+ ECs, RGS5+ ECs, and TYROBP+ ECs. Pseudo-time analysis suggested that the loss of CA4+ ECs and MT1F+ ECs may promote malignant progression. Cell communication elucidated that MT1F+ ECs exhibited the strongest outgoing interaction strength, whereas RGS5+ ECs displayed the strongest incoming interaction strength. Furthermore, TYROBP+ ECs exhibited greater metabolic activity, and notably, CCL5+ ECs displayed increased expression of immune-related molecules. Lastly, across cohorts of bulk transcriptome levels, CA4+ ECs, MT1F+ ECs, and RGS5+ ECs consistently demonstrated prognostic indicative effects. PDAC patients exhibit the presence of seven distinct EC clusters, each demonstrating significant metabolic and immunological heterogeneity. Targeted therapeutic approaches directed toward CA4+ ECs and MT1F+ ECs may prove advantageous in addressing challenges associated with PDAC treatment. Additionally, variations in the relative abundance of CA4+ ECs, MT1F+ ECs, and RGS5+ ECs were indicated as predictive of patient prognosis.

Tape Eyelid Closure: An Effective Solution for Nocturnal Lagophthalmos in Patients with Ptosis and Poor Bell's Phenomenon.

BACKGROUND: Poor Bell's phenomenon is often considered a relative contraindication for ptosis surgery, as it increases the risk of corneal exposure and dry eye symptoms after surgery. However, the Bell's phenomenon may vary in different individuals and sleep stages, making it inaccurate to predict the position of the eye during sleep based on awake examination. This study aimed to investigate the role of Bell's phenomenon in ptosis surgery and the management of nocturnal lagophthalmos. METHODS: We conducted a retrospective case series of 23 patients with ptosis and poor Bell's phenomenon who underwent different surgical techniques at Xijing Hospital from April 2020 to June 2021. We assessed Bell's phenomenon at different stages of sleep and collected data on ptosis degree, surgical approach, lagophthalmos, complications, and outcomes. RESULTS: Of the total 23 patients originally considered for study, 9 with frontalis muscle advancement technique, 8 with conjoint fascial sheath suspension, 4 with levator resection technique, and 2 with levator aponeurosis plication technique. All patients achieved satisfactory correction of ptosis. One patient had prolonged lagophthalmos and underwent reoperation to lower the eyelid height. Other complications were minor and resolved with conservative treatment. CONCLUSION: We conclude that poor Bell's phenomenon is not a relative contraindication for ptosis surgery. Nocturnal lagophthalmos should be monitored after ptosis surgery regardless of the Bell's phenomenon results. Tape eyelid closure can be an effective solution to protect the corneal surface during nocturnal lagophthalmos. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Key Roles of Conjunctiva Fornix-Bulbar Conjunctiva-Tenon Capsule in Conjoint Fascial Sheath Suspension.

BACKGROUND: Bulbar conjunctival prolapse is one of the complications of conjoint fascial sheath (CFS) suspension and has a negative impact on surgical results. To explore the prevention methods of this complication, the authors compared the incidence of it between the below-conjunctiva fornix-bulbar conjunctiva-Tenon capsule (CBT) approach and the above-CBT approach to dissecting CFS in CFS suspension and shared their experience in the treatment of bulbar conjunctival prolapse. METHODS: From January of 2020 to August of 2021, 81 patients with severe congenital ptosis who underwent CFS suspension were enrolled and divided into two groups. Forty-five patients' (group A) CFS was dissected by means of the below-CBT approach and 36 patients' (group B) CFS was dissected by means of the above-CBT approach. Data regarding the incidence and outcomes of bulbar conjunctival prolapse and the postoperative condition were collected and analyzed. RESULTS: The incidence of bulbar conjunctival prolapse was 24.44% in group A and 2.78% in group B. Of the 12 bulbar conjunctival prolapse patients, seven patients' conditions improved after conservative treatment, and five did not. All of them underwent bulbar conjunctiva resection within 1 year and were cured. No recurrent prolapse was observed within 3 months postoperatively. At the last follow-up, the mean marginal reflex distance 1 and palpebral fissure height were 4.09 ± 0.19 mm and 9.85 ± 0.62 mm, respectively. There were no complications except lagophthalmos (16 eyelids), asymmetric eyelid contour (one patient), and trichiasis (two eyelids). CONCLUSIONS: The incidence of bulbar conjunctival prolapse decreased significantly by dissecting CFS by means of the above-CBT approach. For patients with bulbar conjunctival prolapse after CFS suspension, bulbar conjunctiva resection could provide satisfactory results. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Network pharmacology-integrated molecular docking analysis of phytocompounds of Caesalpinia pulcherrima (peacock flower) as potential anti-metastatic agents.

Caesalpinia pulcherrima, or peacock flower, has been a subject of cancer therapeutics research, showing promising anti-cancer and anti-metastatic properties. The present research aims to investigate the anti-metastatic potential of the flower, through bioinformatics approaches. Metastasis targets numbering 471 were identified through overlap analysis following NCBI gene, Gene Card and OMIM query. Phytocompounds of the flower were retrieved from PubChem and their protein interactions predicted using Super-PRED and TargetNet. The 28 targets that overlapped with the predicted proteins were used to generate STRING >0.7. Enrichment analysis revealed that C. pulcherrima may inhibit metastasis through angiogenesis-related and leukocyte migration-related pathways. HSP90AA1, ESR1, PIK3CA, ERBB2, KDR and MMP9 were identified as potential core targets while and 6 compounds (3-[(4-Hydroxyphenyl)methylidene]-7,8-dimethoxychromen-4-one (163076213), clotrimazole (2812), Isovouacapenol A (636673), [(4aR,5R,6aS,7R,11aS,11bR)-4a-hydroxy-4,4,7,11b-tetramethyl-9-oxo-1,2,3,5,6,6a,7,11a-octahydronaphtho[2,1-f][1]benzofuran-5-yl] benzoate (163104827), Stigmast-5-en-3beta-ol (86821) and 4,2'-dihydroxy-4'-methoxychalcone (592216)) were identified as potential core compounds. Molecular docking analysis and molecular dynamics simulations investigations revealed that ERBB2, HSP90AA1 and KDR, along with the newly discovered 163076213 compound to be the most significant metastasis targets and bioactive compound, respectively. These three core targets demonstrated interactions consistent with angiogenesis and leukocyte migration pathways. Furthermore, potentially novel interactions, such as KDR-MMP9, KDR-PIK3CA, ERBB2-HSP90AA1, ERBB2-ESR1, ERBB2-PIK3CA and ERBB2-MMP9 interactions were identified and may play a role in crosslinking the aforementioned metastatic pathways. Therefore, the present study revealed the main mechanisms behind the anti-metastatic effects of C. pulcherrima, paving the path for further research on these compounds and proteins to accelerate the research of cancer therapeutics and application of C. pulcherrima.Communicated by Ramaswamy H. Sarma.

Tape Tarsorrhaphy in the Management of Lagophthalmos Caused by Severe Congenital Blepharoptosis Procedures.

BACKGROUND: Lagophthalmos, a common complication after blepharoptosis correction, has plagued oculoplastic surgeons. The goal of this study was to investigate the effect of tape eyelid closure on reducing the occurrence of lagophthalmos after blepharoptosis correction. METHODS: From April 2020 to June 2021, a total of 112 patients with severe congenital ptosis received corrective surgery at the Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University. Of these, 48 underwent frontalis muscle advancement technique and 64 underwent conjoint fascial sheath suspension. Preoperative data collected included demographics, levator function, Bell's phenomenon, and marginal reflex distance 1 (MRD1). Postoperative data included surgery type, MRD1, eyelid closure function, aesthetic outcomes (including eyelid contour, eyelid symmetry, and eyelid crease), keratitis, and other complications. RESULTS: Frontalis muscle advancement technique group: the median of safe eye closure time was 7.3 months (positive Bell's phenomenon; interquartile range [IQR], 3.8-10.8 months) and 13.9 months (poor Bell's phenomenon; IQR, 11.6-16.1 months). There was a significant improvement between the preoperative and postoperative MRD1 (-1.52 ± 0.82 vs 3.85 ± 0.58 mm, P < 0.05). Conjoint fascial sheath suspension group: the median of safe eye closure time was 5.7 months (positive Bell's phenomenon; IQR, 2.9-8.5 months) and 12.4 months (poor Bell's phenomenon; IQR, 8.1-16.7 months). There was a significant improvement between the preoperative and postoperative MRD1 (-1.02 ± 0.91 vs 4.15 ± 1.03 mm, P < 0.05). All patients/guardians were satisfied with the aesthetic outcomes. CONCLUSIONS: Tape tarsorrhaphy is a safe, easy-to-learn method for treating lagophthalmos with a good aesthetic outcome.

The Aesthetic Evaluation of the Brow-Eye Continuum After Correction of Severe Congenital Ptosis in Children With Extended Frontalis Muscle Advancement Technique.

BACKGROUND: Severe congenital ptosis is a common ocular deformity in pediatric patients that can significantly impact visual development and aesthetic appearance, leading to negative psychosocial outcomes. The frontalis muscle advancement technique is a well-established surgical treatment for severe congenital ptosis. Aesthetic changes of the brow-eye continuum often plays an important role in ptosis surgery. METHODS: We conducted a single-center retrospective case series study of patients with severe congenital ptosis who underwent the frontalis muscle advancement technique at the Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University between April 2020 and June 2021. The study aimed to evaluate the aesthetic changes of the eyebrow-eyelid continuum after surgery. The main outcome measurements included marginal reflex distance 1, palpebral fissure height, eyebrow position, upper eyelid to lower eyebrow distance, lower eyelid to upper eyebrow distance, and nasal base to lower eyelid distance. RESULTS: The study included 48 patients (66 eyelids), with 30 unilateral and 18 bilateral patients. Our analysis found that eyebrow height decreased by an average of 4.8% postoperatively relative to preoperatively in all patients. CONCLUSIONS: The frontalis muscle advancement technique has demonstrated effectiveness in achieving aesthetically pleasing outcomes in children with severe ptosis. It is crucial to pay careful attention to the brow-eye continuum during the correction process, as its harmony can greatly impact the final result.

From basic to clinical: Anatomy of Denonvilliers' fascia and its application in laparoscopic radical resection of rectal cancer.

The total mesorectal excision (TME) approach has been established as the gold standard for the surgical treatment of middle and lower rectal cancer. This approach is widely accepted to minimize the risk of local recurrence and increase the long-term survival rate of patients undergoing surgery. However, standardized TME causes urogenital dysfunction in more than half of patients, thus lowering the quality of life of patients. Of note, pelvic autonomic nerve damage during TME is the most pivotal cause of postoperative urogenital dysfunction. The anatomy of the Denonvilliers' fascia (DVF) and its application in surgery have been investigated both nationally and internationally. Nevertheless, controversy exists regarding the basic to clinical anatomy of DVF and its application in surgery. Currently, it is a hotspot of concern and research to improve the postoperative quality of life of patients with rectal cancer through the protection of their urinary and reproductive functions after radical resection. Herein, this study systematically describes the anatomy of DVF and its application in surgery, thus providing a reference for the selection of surgical treatment modalities and the enhancement of postoperative quality of life in patients with middle and low rectal cancer.

The effect of different timing of blood transfusion on oncological outcomes of patients undergoing radical cystectomy for bladder cancer: a systematic review and meta-analysis.

Highlights: This meta-analysis and systematic review aim to analyze the association between BT and oncological outcomes of patients undergoing RC for bladder cancer, and tries to find out whether the timing of blood transfusion could also have an effect on this relationship. A total of 20 retrospective studies from online databases and other sources are identified and enrolled in this study. The results show that BT administration during RC operation or perioperative period is significantly associated with worse oncological outcomes including ACM, CSM and DR. Background: Bladder cancer is one of the most common urological malignancies. Radical cystectomy (RC) remains the main treatment for localized muscle-invasive bladder cancer (MIBC) or high-grade non-muscle-invasive bladder cancer (NMIBC). In the process of RC, the administration of blood transfusion (BT) is sometimes needed, however, it may cause transfusion-related complications or lead to worse oncological outcomes. This meta-analysis and systematic review aims to give a comprehensive insight into the association between BT and oncological outcomes of patients undergoing RC, and tries to find out whether the timing of blood transfusion could also have an impact on this association. Methods: This systematic review and meta-analysis were carried out according to the PRISMA 2020 reporting guideline. We have searched four bibliographic databases including PubMed (Medline), EMBASE, Cochrane Library, and Web of Science with no language limitation. Studies investigating the association between BT and oncological outcomes of patients undergoing RC are identified and included in this research from inception through March 20, 2023. This research calculates the pooled hazard ratios (pHR) and 95% confidence intervals (95% CI) of all-cause mortality (ACM), cancer-specific mortality (CSM) and disease recurrence (DR) using Random Effects models or Fixed Effects models. Subgroup analyses stratified by parameters such as timing of transfusion are also conducted. This meta-analysis was registered with PROSPERO, CRD42022381656. Results: A total of 20 retrospective studies from online databases and other sources are identified and enrolled in this study. Results show that blood transfusion significantly increased the risks for ACM (HR = 1.33, 95% CI: 1.23-1.44), CSM (HR = 1.25, 95% CI: 1.15 - 1.35) and DR (HR = 1.26, 95% CI: 1.15 - 1.38). However, when stratified by the timing of BT, we find that only intraoperative and perioperative transfusion significantly increased in risks for worse prognosis, while postoperative transfusion raised none of the risks of ACM (HR = 1.26, 95% CI: 0.92-1.73), CSM (HR = 1.08, 95% CI: 0.93-1.26) nor DR (HR = 1.08, 95% CI: 0.90-1.29) significantly. Conclusion: BT administration during RC operation or perioperative period is significantly associated with worse oncological outcomes including ACM, CSM and DR. Clinicians should consider carefully when deciding to administrate BT to patients undergoing RC and carry out according to current guidelines.

Diagnosis of Early Bacterial Pneumonia and Sepsis After Cardiovascular Surgery: A Diagnostic Prediction Model Based on LASSO Logistic Regression.

Background: Early postoperative bacterial pneumonia and sepsis (ePOPS), which occurs within the first 48 hours after cardiovascular surgery, is a serious life-threatening complication. Diagnosis of ePOPS is extremely challenging, and the existing diagnostic tools are insufficient. The purpose of this study was to construct a novel diagnostic prediction model for ePOPS. Methods: Least Absolute Shrinkage and Selection Operator (LASSO) with logistic regression was used to construct a model to diagnose ePOPS based on patients' comorbidities, medical history, and laboratory findings. The area under the receiver operating characteristic curve (AUC) was used to evaluate the model discrimination. Results: A total of 1203 patients were recruited and randomly split into a training and validation set in a 7:3 ratio. By early morning on the 3rd postoperative day (POD3), 103 patients had experienced 133 episodes of bacterial pneumonia or sepsis (15 patients had both). LASSO logistic regression model showed that duration of mechanical ventilation (P=0.015), NYHA class ≥ III (P=0.001), diabetes (P<0.001), exudation on chest radiograph (P=0.011) and IL-6 on POD3 (P<0.001) were independent risk factors. Based on these factors, we created a nomogram named DICS-I with an AUC of 0.787 in the training set and 0.739 in the validation set. Conclusion: The DICS-I model may be used to predict the risk of ePOPS after cardiovascular surgery, and is also especially suitable for predicting the risk of IRAO. The DICS-I model could help clinicians to adjust antibiotics on the POD3.

A case report of Erdheim-Chester disease-clinically characterized by recurrent fever, multiple bone destruction, and antinuclear antibodies.

Background: Erdheim-Chester disease is a form of histiocytosis. It is an extremely rare illness. Since its discovery, hundreds of cases of this disease have been identified across the globe. Pathologically, the condition is characterized by proliferation of lipid-rich foam-like tissue cells, which is especially prevalent in bones. Approximately 50% of patients develop infiltration into organs other than the bones. Case description: A patient with fever and bone pain is described in this case report. After visiting multiple hospitals and departments, undergoning battery of investigations, and ruling out other diseases, the patient was pathologically diagnosed with Erdheim-Chester disease after a biopsy of the associated bone destruction. The condition improved with symptomatic therapy. Conclusion: Numerous clinical symptoms make non-Langerhans cell histiocytosis challenging to diagnose and requires pathological diagnosis. Patients with unexplained multiple bone destruction must be alert against this disease from a clinical standpoint.

[Effect of proprotein convertase subtilisin/kexin type 9 on platelet activation associated with sepsis].

OBJECTIVE: To investigate the effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) on platelet activation in sepsis. METHODS: (1) Clinical trial: a prospective study was conducted. Patients with sepsis and septic shock aged ≥ 18 years old who met the diagnostic criteria of Sepsis-3 admitted to the department of intensive care medicine of the Affiliated Hospital of Binzhou Medical College from January to October in 2021 were selected as subjects. Healthy subjects in the same period were taken as healthy control group. Platelet count (PLT) in the first routine blood test after admission was recorded. Venous blood was taken 1 day after diagnosis, and serum PCSK9 level was determined by enzyme-linked immunosorbent assay (ELISA). The differences of PCSK9 level and PLT between the two groups were compared, and subgroup analysis was conducted based on PLT for patients with sepsis. The correlation between PCSK9 level and PLT in septic patients was analyzed by Pearson correlation method. (2) Animal experiment: 80 male C57BL/6 mice were randomly divided into control group, sepsis model group [lipopolysaccharide (LPS) group], PCSK9 inhibitor pretreatment group (PCSK9 inhibitor+LPS group) and PCSK9 inhibitor control group (PCSK9 inhibitor group), with 20 mice in each group. The mouse model of sepsis was reproduced by intraperitoneal injection of LPS 12 mg/kg, and the control group and PCSK9 inhibitor group were intraperitoneally injected with the same amount of sterile normal saline. PCSK9 inhibitor+LPS group and PCSK9 inhibitor group were pretreated with PCSK9 inhibitor 5 mg/kg intraperitoneal injection for 7 days before injection of LPS or normal saline, respectively, and the control group and LPS group were injected with an equal amount of sterile normal saline. The lung tissues were taken for pathological and immunohistochemical observation 24 hours after modeling. Blood was taken from the heart for determining PLT. Platelet activation was detected by flow cytometry. The expression level of platelet-activation marker CD40L was detected by Western blotting. RESULTS: (1) Clinical trial: there were 57 cases in the sepsis group and 27 cases in the healthy control group. Serum PCSK9 level in the sepsis group was significantly higher than that in the healthy control group (µg/L: 232.25±72.21 vs. 191.72±54.92, P < 0.05), and PLT was significantly lower than that in the healthy control group [×109/L: 146.00 (75.50, 204.50) vs. 224.00 (194.00, 247.00), P < 0.01]. Subgroup analysis showed that the serum PCSK9 level in the thrombocytopenia patients (n = 20) was significantly higher than that in the non-thrombocytopenia patients (n = 37; µg/L: 264.04±60.40 vs. 215.06±72.95, P < 0.01). Correlation analysis showed a significant negative correlation between serum PCSK9 levels and PLT in septic patients (r = -0.340, P = 0.010). (2) Animal experiment: there were no significant pathological changes in lung tissue in the control group and PCSK9 inhibitor group under light microscope, and no significant differences in PLT, platelet activation and plasma CD40L protein expression was found between the two groups. In the LPS group, a large number of inflammatory cells were infiltrated in the pulmonary interstitium, the alveolar structure was damaged obviously, the alveolar septum was widened, the alveolar cavity was extensively bleeding, the capillary dilatation with bleeding and platelet aggregation were found, the PLT was significantly decreased, the platelet activation and the expression level of CD40L protein in plasma were significantly increased. The infiltration of inflammatory cells in lung tissue of mice in the PCSK9 inhibitor+LPS group was reduced to a certain extent, the thickening of alveolar septa was reduced, the platelet aggregation in lung tissue was decreased as compared with the LPS group, the PLT was significantly increased (×109/L: 515.83±46.60 vs. 324.83±46.31, P < 0.05), the platelet activation and the expression level of CD40L protein in plasma were significantly decreased [positive expression rate of platelet activation dependent granule surface facial mask protein CD62P: (12.15±1.39)% vs. (18.33±2.74)%, CD40L protein (CD40L/ß-actin): 0.77±0.08 vs. 1.18±0.10, both P < 0.05]. CONCLUSIONS: PCSK9 level has a certain effect on promoting platelet activation in sepsis, and inhibition of PCSK9 level may have potential research value in improving adverse outcomes caused by sepsis thrombocytopenia.

Predicting diabetic kidney disease for type 2 diabetes mellitus by machine learning in the real world: a multicenter retrospective study.

Objective: Diabetic kidney disease (DKD) has been reported as a main microvascular complication of diabetes mellitus. Although renal biopsy is capable of distinguishing DKD from Non Diabetic kidney disease(NDKD), no gold standard has been validated to assess the development of DKD.This study aimed to build an auxiliary diagnosis model for type 2 Diabetic kidney disease (T2DKD) based on machine learning algorithms. Methods: Clinical data on 3624 individuals with type 2 diabetes (T2DM) was gathered from January 1, 2019 to December 31, 2019 using a multi-center retrospective database. The data fell into a training set and a validation set at random at a ratio of 8:2. To identify critical clinical variables, the absolute shrinkage and selection operator with the lowest number was employed. Fifteen machine learning models were built to support the diagnosis of T2DKD, and the optimal model was selected in accordance with the area under the receiver operating characteristic curve (AUC) and accuracy. The model was improved with the use of Bayesian Optimization methods. The Shapley Additive explanations (SHAP) approach was used to illustrate prediction findings. Results: DKD was diagnosed in 1856 (51.2 percent) of the 3624 individuals within the final cohort. As revealed by the SHAP findings, the Categorical Boosting (CatBoost) model achieved the optimal performance 1in the prediction of the risk of T2DKD, with an AUC of 0.86 based on the top 38 characteristics. The SHAP findings suggested that a simplified CatBoost model with an AUC of 0.84 was built in accordance with the top 12 characteristics. The more basic model features consisted of systolic blood pressure (SBP), creatinine (CREA), length of stay (LOS), thrombin time (TT), Age, prothrombin time (PT), platelet large cell ratio (P-LCR), albumin (ALB), glucose (GLU), fibrinogen (FIB-C), red blood cell distribution width-standard deviation (RDW-SD), as well as hemoglobin A1C(HbA1C). Conclusion: A machine learning-based model for the prediction of the risk of developing T2DKD was built, and its effectiveness was verified. The CatBoost model can contribute to the diagnosis of T2DKD. Clinicians could gain more insights into the outcomes if the ML model is made interpretable.

Pan-cancer analysis reveals the prognostic and immunologic roles of cereblon and its significance for PROTAC design.

Background: Cereblon (CRBN) has emerged as a vital E3 ubiquitin ligase for Proteolysis-targeting chimera (PROTAC) design. However, few studies focus on the physiological mechanism of CRBN, and more studies are needed to explore the influence of CRBN on tumorigenesis. This pan-cancer analysis aims to explore the prognostic and immunologic roles of CRBN, and provide new insight for CRBN into cancer treatment and PROTAC design. Methods: The TCGA database, TIMER 2.0 database, and TISIDB database were used to analyze the role of CRBN in pan-cancer. Multiple bioinformatic methods (ssGSEA, Kaplan-Meier, univariate cox regression, ESTIMATE, CIBERSORT) were applied to investigate the CRBN expression status, gene activity, prognostic values, and its correlation with immune scores, immune infiltration, immune-related functions, HALLMARKs functions, and response to immunotherapy in pan-cancer. Results: In most cancer types, the expression and activity of CRBN in tumor groups were lower compared with normal groups. Upregulated CRBN expression may indicate a better prognosis for cancer patients. The Immune score, stromal score, and tumor purity varied greatly among different cancer types. GSEA analysis showed that high CRBN expression was correlated with the downregulation of tumor-promoting signaling pathways. The level of CRBN was associated with Tumor mutation burden (TMB), Microsatellite instability (MSI), objective response rate (ORR), and immune cell infiltration in a few cancer types. Conclusion: Pan-cancer analysis reveals the potential role of CRBN as a prognostic biomarker and versatile immunologic roles in different cancer types. Upregulated expression of CRBN may be beneficial to CRBN-related immunotherapy and PROTAC design.