Atorvastatin reduces calcification in valve interstitial cells via the NF-κB signalling pathway by promoting Atg5-mediated autophagy.

Aortic valve calcification (AVC) is a common cardiovascular disease and a risk factor for sudden death. However, the potential mechanisms and effective therapeutic drugs need to be explored. Atorvastatin is a statin that can effectively prevent cardiovascular events by lowering cholesterol levels. However, whether atorvastatin can inhibit AVC by reducing low-density lipoprotein (LDL) and its possible mechanism of action require further exploration. In the current study, we constructed an in vitro AVC model by inducing calcification of the valve interstitial cells. We found that atorvastatin significantly inhibited osteogenic differentiation, reduced the deposition of calcium nodules in valve interstitial cells, and enhanced autophagy in calcified valve interstitial cells, manifested by increased expression levels of the autophagy proteins Atg5 and LC3B-II/I and the formation of smooth autophagic flow. Atorvastatin inhibited the NF-κB signalling pathway and the expression of inflammatory factors mediated by NF-κB in calcified valve interstitial cells. The activation of the NF-κB signalling pathway led to the reversal of atorvastatin's effect on enhancing autophagy and alleviating valve interstitial cell calcification. In conclusion, atorvastatin inhibited the NF-κB signalling pathway by upregulating autophagy, thereby alleviating valve interstitial cell calcification, which was conducive to improving AVC.

CRISPR applications in cancer diagnosis and treatment.

Cancer remains a significant global health challenge, necessitating the exploration of novel and more precise therapeutic options beyond conventional treatments. In this regard, clustered regularly interspaced short palindromic repeats (CRISPR) systems have emerged as highly promising tools for clinical gene editing applications. The CRISPR family encompasses diverse CRISPR-associated (Cas) proteins that possess the ability to recognize specific target sequences. The initial CRISPR system consisted of the Cas9 protein and a single-guide RNA, which guide Cas9 to the desired target sequence, facilitating precise double-stranded cleavage. In addition to the traditional cis-cleavage activity, the more recently discovered Cas12 and Cas13 proteins exhibit trans-cleavage activity, which expands their potential applications in cancer diagnosis. In this review, we provide an overview of the functional characteristics of Cas9, Cas12, and Cas13. Furthermore, we highlight the latest advancements and applications of these CRISPR systems in cancer gene therapy and molecular diagnosis. We also emphasize the importance of understanding the strengths and limitations of each CRISPR system to maximize their clinical utility. By providing a comprehensive overview of the current state of CRISPR technology in cancer research, we aim to inspire further exploration and innovation in this rapidly evolving field.

TRIM11 promotes cell proliferation of non-small cell lung cancer through the inhibition of ferroptosis by AMPK.

Lung cancer is one of the leading causes of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent type. This study investigates the role of TRIM11 gene in NSCLC and its underlying mechanism. NSCLC patients were recruited from our hospital and showed upregulated TRIM11 mRNA and protein expressions. Patients with high TRIM11 expression had lower survival rates. TRIM11 gene was found to promote cell proliferation and reduce ROS-induced ferroptosis in NSCLC. Additionally, TRIM11 gene induced AMPK expression and its regulation affected TRIM11's effects on cell proliferation and ferroptosis in NSCLC. IP analysis revealed that TRIM11 protein interacted with AMPK protein in NSCLC. These data confirmed that TRIM11 promotes cell proliferation and reduces ROS-induced ferroptosis in NSCLC through AMPK. Hence, TRIM11 is a potential target for the treatment of NSCLC and other cancers.

Application of preoperative 3D printing in the internal fixation of posterior rib fractures with embracing device: a cohort study.

BACKGROUND: To explore the impact of preoperative 3D printing on the fixation of posterior rib fractures utilizing a memory alloy embracing device of rib under thoracoscopy. METHODS: The enrolled patients were divided into the 3D printing (11 patients) and the non-3D printing (18 patients) groups, based on whether a 3D model of ribs was prepared prior to surgery. Analysis was conducted comparing the average fixation time per fracture, postoperative fixation loss, and poor reduction of fractured end between the two groups. RESULTS: The average fixation time of each fracture was 27.2 ± 7.7 min in the 3D printing group and 29.3 ± 8.2 min in the non-3D printing group, with no statistically significant difference observed between the two groups (P > 0.05). The incidence of poor fracture fixation in the 3D printing group was statistically lower than that in the non-3D printing group (12.9% vs. 44.7%, P < 0.05). Further stratified analysis revealed that the off-plate rate in the 3D printing group and the non-3D group was (3.2% vs. 12.8%, P > 0.05), and the dislocation rate of the fractured end was (9.7% vs. 31.9%, P < 0.05). CONCLUSIONS: The application of 3D printing technology to prepare the rib model before surgery is proves beneficial in reducing the occurrence of poor fixation of fractures and achieving precise and individualized treatment.

Epcoritamab, a Novel, Subcutaneous CD3xCD20 Bispecific T-Cell-Engaging Antibody, in Relapsed or Refractory Large B-Cell Lymphoma: Dose Expansion in a Phase I/II Trial.

PURPOSE: Epcoritamab is a subcutaneously administered CD3xCD20 T-cell-engaging, bispecific antibody that activates T cells, directing them to kill malignant CD20+ B cells. Single-agent epcoritamab previously demonstrated potent antitumor activity in dose escalation across B-cell non-Hodgkin lymphoma subtypes. PATIENTS AND METHODS: In the dose-expansion cohort of a phase I/II study (ClinicalTrials.gov identifier: NCT03625037), adults with relapsed or refractory CD20+ large B-cell lymphoma and at least two prior therapy lines (including anti-CD20 therapies) received subcutaneous epcoritamab in 28-day cycles (once weekly step-up doses in weeks 1-3 of cycle 1, then full doses once weekly through cycle 3, once every 2 weeks in cycles 4-9, and once every 4 weeks in cycle 10 and thereafter) until disease progression or unacceptable toxicity. The primary end point was overall response rate by the independent review committee. RESULTS: As of January 31, 2022, 157 patients were treated (median age, 64 years [range, 20-83]; median of three [range, 2-11] prior therapy lines; primary refractory disease: 61.1%; prior chimeric antigen receptor (CAR) T-cell exposure: 38.9%). At a median follow-up of 10.7 months, the overall response rate was 63.1% (95% CI, 55.0 to 70.6) and the complete response rate was 38.9% (95% CI, 31.2 to 46.9). The median duration of response was 12.0 months (among complete responders: not reached). Overall and complete response rates were similar across key prespecified subgroups. The most common treatment-emergent adverse events were cytokine release syndrome (49.7%; grade 1 or 2: 47.1%; grade 3: 2.5%), pyrexia (23.6%), and fatigue (22.9%). Immune effector cell-associated neurotoxicity syndrome occurred in 6.4% of patients with one fatal event. CONCLUSION: Subcutaneous epcoritamab resulted in deep and durable responses and manageable safety in highly refractory patients with large B-cell lymphoma, including those with prior CAR T-cell exposure.

Minimally invasive surgery rib fracture fixation based on location and anatomical landmarks.

BACKGROUND: Rib fracture is closely related to thoracic injury with high morbidity and mortality. This study aimed to investigate the clinical effect of Zhang ZhiFei (ZZF) zoning method on the selection of incision and approach in minimally invasive surgery for rib fracture. METHODS: A total of 110 patients with rib fractures from July 2017 to July 2019 were enrolled in the study. Preoperative computed tomography and three-dimensional reconstruction of ribs was performed. Then, the rib fractures to be surgically fixed were divided into costal cartilage zone, chest zone, lateral costal zone, high posterior costal zone, low posterior costal subscapular zone, and low posterior costal paraspinal zone, which was called ZZF zoning method. Rib fractures in each zone had unique minimally invasive incision approach, and the open reduction and internal fixation of rib fracture was performed under minimally invasive surgery of corresponding small incision. RESULTS: The average incision length and number of incisions of the 110 patients were 6.2 cm and 1.3, respectively. The average number of internal fixation was 5.3 and the average operation time was 82 min. The postoperative fracture end was well aligned. After 3 months of follow-up, no internal fixation was displaced or detached. CONCLUSION: Based on the anatomical characteristics of different zones of the chest wall, ZZF zoning method provides a new idea and reference for the selection of incision and approach in minimally invasive internal fixation for rib fracture.

Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: Few effective second-line treatments exist for women with recurrent or metastatic cervical cancer. Accordingly, we aimed to evaluate the efficacy and safety of tisotumab vedotin, a tissue factor-directed antibody-drug conjugate, in this patient population. METHODS: This multicentre, open-label, single-arm, phase 2 study was done across 35 academic centres, hospitals, and community practices in Europe and the USA. The study included patients aged 18 years or older who had recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer; disease progression on or after doublet chemotherapy with bevacizumab (if eligible by local standards); who had received two or fewer previous systemic regimens for recurrent or metastatic disease; had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 2·0 mg/kg (up to a maximum of 200 mg) tisotumab vedotin intravenously once every 3 weeks until disease progression (determined by the independent review committee) or unacceptable toxicity. The primary endpoint was confirmed objective response rate based on RECIST (version 1.1), as assessed by the independent review committee. Activity and safety analyses were done in patients who received at least one dose of the drug. This study is ongoing with recruitment completed and is registered with ClinicalTrials.gov, NCT03438396. FINDINGS: 102 patients were enrolled between June 12, 2018, and April 11, 2019; 101 patients received at least one dose of tisotumab vedotin. Median follow-up at the time of analysis was 10·0 months (IQR 6·1-13·0). The confirmed objective response rate was 24% (95% CI 16-33), with seven (7%) complete responses and 17 (17%) partial responses. The most common treatment-related adverse events included alopecia (38 [38%] of 101 patients), epistaxis (30 [30%]), nausea (27 [27%]), conjunctivitis (26 [26%]), fatigue (26 [26%]), and dry eye (23 [23%]). Grade 3 or worse treatment-related adverse events were reported in 28 (28%) patients and included neutropenia (three [3%] patients), fatigue (two [2%]), ulcerative keratitis (two [2%]), and peripheral neuropathies (two [2%] each with sensory, motor, sensorimotor, and neuropathy peripheral). Serious treatment-related adverse events occurred in 13 (13%) patients, the most common of which included peripheral sensorimotor neuropathy (two [2%] patients) and pyrexia (two [2%]). One death due to septic shock was considered by the investigator to be related to therapy. Three deaths unrelated to treatment were reported, including one case of ileus and two unknown causes. INTERPRETATION: Tisotumab vedotin showed clinically meaningful and durable antitumour activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer. Given the poor prognosis for this patient population and the low activity of current therapies in this setting, tisotumab vedotin, if approved, would represent a new treatment for women with recurrent or metastatic cervical cancer. FUNDING: Genmab, Seagen, Gynaecologic Oncology Group, and European Network of Gynaecological Oncological Trial Groups.

Application of 3D printing and framework internal fixation technology for high complex rib fractures.

OBJECTIVE: To explore the clinical effect of 3D printing combined with framework internal fixation technology on the minimally invasive internal fixation of high complex rib fractures. METHODS: Total 16 patients with high complex rib fractures were included in the study. Before the procedure, the 3D rib model was reconstructed based on the thin-layer chest CT scan. According to the 3D model, the rib locking plate was pre-shaped, and the preoperative planning were made including the direction of the locking plate, the location of each nail hole and the length of the screw. During the operation, the locking plate was inserted from the sternum to the outermost fracture lines of ribs with screws at both ends. In addition, the locking plate was used as the frame to sequentially reduce the middle fracture segment and fix with screws or steel wires. Chest x-rays or chest CT scans after surgery were used to assess the ribs recovery. All patients were routinely given non-steroidal anti-inflammatory drugs (NSAIDS) for analgesia, and the pain level was evaluated using numerical rating scale (NRS). RESULTS: The preoperative planning according to the 3D printed rib model was accurate. The reduction and fixation of each fracture segment were successfully completed through the framework internal fixation technology. No cases of surgical death, and postoperative chest pain was significantly alleviated. Five to 10 months follow up demonstrated neither loosening of screws, nor displacement of fixtures among patients. The lungs of each patients were clear and in good shape. CONCLUSION: The application of 3D printing combined with framework internal fixation technology to the high complex rib fractures is beneficial for restoring the inherent shape of the thoracic cage, which can realize the accurate and individualized treatment as well as reduces the operation difficulty.

Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Neuroendocrine Tumors: Results From the Phase II KEYNOTE-158 Study.

PURPOSE: KEYNOTE-158 (ClinicalTrials.gov identifier: NCT02628067) investigated the efficacy and safety of pembrolizumab across multiple cancers. We present results from patients with previously treated advanced well-differentiated neuroendocrine tumors (NET). PATIENTS AND METHODS: Pembrolizumab 200 mg was administered every 3 weeks for 2 years or until progression, intolerable toxicity, or physician/patient decision. Tumor imaging was performed every 9 weeks for the first year and then every 12 weeks. Endpoints included objective response rate (ORR) per RECIST v1.1 by independent central radiologic review (primary) and duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety (secondary). RESULTS: A total of 107 patients with NETs of the lung, appendix, small intestine, colon, rectum, or pancreas were treated. Median age was 59.0 years (range, 29-80), 44.9% had ECOG performance status 1, 40.2% had received ≥3 prior therapies for advanced disease, and 15.9% had PD-L1-positive tumors (combined positive score ≥1). Median follow-up was 24.2 months (range, 0.6-33.4). ORR was 3.7% (95% CI, 1.0-9.3), with zero complete responses and four partial responses (three pancreatic and one rectal) all in patients with PD-L1-negative tumors. Median DOR was not reached, with one of four responses ongoing after ≥21 months follow-up. Median PFS was 4.1 months (95% CI, 3.5-5.4); the 6-month PFS rate was 39.3%. Median OS was 24.2 months (95% CI, 15.8-32.5). Treatment-related adverse events (AE) occurred in 75.7% of patients, 21.5% of whom had grade 3-5 AEs. CONCLUSIONS: Pembrolizumab monotherapy showed limited antitumor activity and manageable safety in patients with previously treated advanced well-differentiated NETs.

Analysis of the advantages of 3D printing in the surgical treatment of multiple rib fractures: 5 cases report.

BACKGROUND: Rib fractures account for a fairly high proportion of chest injuries, ranging from 55 to 80%. The most common mechanisms of injury include: traffic accident, extrusion and falls from significant heights. Besides, the surgical treatment of multiple rib fractures has been accepted by more and more medical professionals. We reported 5 clinical cases of patients with multiple rib fractures undergoing open reduction and internal fixation using 3D printing technology. CASE PRESENTATION: Retrospective analysis of 5 clinical cases of multiple rib fractures from January 2017 to August 2018 in our hospital. A preoperative CT thin slice scan was used to reconstruct the 3D model according to the scanning results, and 3D printing technology was adopted to prepare the rib model. Preoperative reconstruction of the rib's normal shape and lock plate for the shaped ribs was created according to reconstructed model. For multiple fractures especially patients with severely deformed rib shape, it is suggested to intraoperative shape directly to the metal bone plate fixed on the ribs on both ends of the fracture line, in order to establish a basic support frame. The other various fracture section can be fixed on the lock plate respectively. Postoperative chest radiographs of the 5 patients showed that the internal fixations were in good and natural shape. The thoracic contour was well formed and symmetrically with the contralateral side. CONCLUSION: Making the rib model and the pre-shaped titanium alloy rib locking plate using 3D printing technology, provided a more minimally invasive and precisely individualized treatment for some rib fracture operations.

3D printing and thoracoscopy assisted MIPO in treatment of long-range comminuted rib fractures, a case report.

BACKGROUND: To investigate the application of 3D printing technology combined with percutaneous Minimally Invasive Plate Oseoynthesis (MIPO) and thoracoscopic techniques in the treatment of long comminuted rib fractures. CASE PRESENTATION: One case of multiple rib fractures with abnormal respiratory disease (including rib 3 and 4 of long comminuted fractures) due to a fall injury was selected. The 3D model of comminuted rib fracture was reconstructed and printed according to the thin-layer CT scan results. After the fracture model was restored to the normal rib anatomy, the metal plate was accurately shaped according to the 3D rib shape. CONCLUSIONS: 3D printing technology combined with MIPO technology under thoracoscopy in the minimally invasive treatment of long-range comminuted rib fractures, greatly reduced the time and improved the accuracy of intraoperative fixation, reduced the difficulty of surgery, patient injury, and perfectly reconstructed the chest wall. Application of the 3D printing technique to make the rib model and pre-mold the metal plate combined the thoracoscopic MIPO technology provides less invasive and accurate individualized treatment for complex rib fractures.

Bioinformatics Analysis Reveals the Altered Gene Expression of Patients with Postmenopausal Osteoporosis Using Liuweidihuang Pills Treatment.

Postmenopausal osteoporosis (PMOP), as well as its associated increased risk for fragility fracture, is one of the most disabling consequences of aging in women. This present study aimed to identify candidate genes that involve pathogenesis of PMOP and the therapeutic mechanism of Liuweidihuang (LWDH) pills on PMOP. We integrated microarray datasets of PMOP derived from the Gene Expression Omnibus (GEO) to screen differentially expressed genes (DEGs) between PMOP and normal controls as well as patients with PMOP and patients after treatment of LWDH pills. GO and KEGG enrichment analysis for DEGs were performed. The shared DEGs, associated with both the pathogenesis of PMOP and the therapeutic mechanism of LWDH, were further analyzed by protein-protein interaction (PPI) network. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to verify the DEGs obtained by our integrated analysis. Compared with normal controls, 1732 DEGs in PMOP were obtained with p<0.05. According to the qRT-PCR results, expression of ATF2, FBXW7, RDX, and RBBP4 was consistent with that in our integrated analysis, generally. GO and KEGG enrichment analysis showed that those DEGs were significantly enriched in regulation of transcription, DNA-dependent, cytoplasm, protein binding, and MAPK signaling pathway. A total of 58 shared DEGs in PMOP versus normal control and in patients with PMOP versus patients after LWDH treatment were identified, which had opposite expression trend in these two comparisons. In the PPI network, CSNK2A1, ATF2, and FBXW7 were three hub proteins. Three genes including ATF2, FBXW7, and RDX were speculated to be therapeutic targets of LWDH for PMOP based on BATMAN-TCM database. We speculated that three genes of ATF2, FBXW7, and RDX may play crucial roles in both pathogenesis of PMOP and therapeutic mechanism of LWDH on PMOP. Our results may provide clues for the molecular pathogenesis of PMOP and offer new possibilities for treatment of PMOP.