TGF-ß1 mediates hypoxia-preconditioned olfactory mucosa mesenchymal stem cells improved neural functional recovery in Parkinson's disease models and patients.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN). Activation of the neuroinflammatory response has a pivotal role in PD. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for various nerve injuries, but there are limited reports on their use in PD and the underlying mechanisms remain unclear. METHODS: We investigated the effects of clinical-grade hypoxia-preconditioned olfactory mucosa (hOM)-MSCs on neural functional recovery in both PD models and patients, as well as the preventive effects on mouse models of PD. To assess improvement in neuroinflammatory response and neural functional recovery induced by hOM-MSCs exposure, we employed single-cell RNA sequencing (scRNA-seq), assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) combined with full-length transcriptome isoform-sequencing (ISO-seq), and functional assay. Furthermore, we present the findings from an initial cohort of patients enrolled in a phase I first-in-human clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients. RESULTS: A functional assay identified that transforming growth factor-ß1 (TGF-ß1), secreted from hOM-MSCs, played a critical role in modulating mitochondrial function recovery in dopaminergic neurons. This effect was achieved through improving microglia immune regulation and autophagy homeostasis in the SN, which are closely associated with neuroinflammatory responses. Mechanistically, exposure to hOM-MSCs led to an improvement in neuroinflammation and neural function recovery partially mediated by TGF-ß1 via activation of the anaplastic lymphoma kinase/phosphatidylinositol-3-kinase/protein kinase B (ALK/PI3K/Akt) signaling pathway in microglia located in the SN of PD patients. Furthermore, intraspinal transplantation of hOM-MSCs improved the recovery of neurologic function and regulated the neuroinflammatory response without any adverse reactions observed in patients with PD. CONCLUSIONS: These findings provide compelling evidence for the involvement of TGF-ß1 in mediating the beneficial effects of hOM-MSCs on neural functional recovery in PD. Treatment and prevention of hOM-MSCs could be a promising and effective neuroprotective strategy for PD. Additionally, TGF-ß1 may be used alone or combined with hOM-MSCs therapy for treating PD.

[Establishment of a predictive scoring model and preventive measures for bladder neck contracture after laparoscopic enucleation of the prostate with urethra preservation].

OBJECTIVE: To establish a predictive scoring model for bladder neck contracture (BNC) after laparoscopic enucleation of the prostate with preservation of the urethra (Madigan surgery) and explore the preventive measures against this postoperative complication. METHODS: We included 362 cases of BPH treated by laparoscopic Madigan surgery from January 2019 to March 2022 (45 with and 317 without postoperative BNC) in the training group and another 120 cases treated the same way in the verification group, collected the clinical data on the patients and evaluated the results of surgery. Using the least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression, we analyzed the risk factors for postoperative BNC and constructed a predictive scoring model for evaluation of the factors. RESULTS: Compared with the baseline, the IPSS, quality of life (QOL) score and postvoid residual urine volume (PVR) were significantly decreased (P < 0.05) while the maximum urinary flow rate (Qmax) remarkably increased (P < 0.05) in the BPH patients at 3 months after surgery. Eight non-zero characteristic predictors were identified by LASSO regression analysis. Multivariate logistic regression analysis showed that short clinical experience of the surgeon, concurrent prostatitis, bladder rinse solution temperature <34℃, catheter blockage, urethral balloon injection volume >40 ml and postoperative constipation were independent risk factors for postoperative BNC (P < 0.05). The best cut-off value was 2.36 points in both the training and the verification groups. The results of evaluation exhibited a high discriminability of the predictive scoring model. CONCLUSION: Laparoscopic Madigan surgery is a safe and effective method for the treatment of BPH. Short clinical experience of the surgeon, concurrent prostatitis, bladder rinse solution temperature <34℃, catheter blockage, water injected into the urethral balloon >40 ml and postoperative constipation were independent risk factors for postoperative BNC. The predictive scoring model constructed in this study has a good discriminability and is simple and feasible, contributive to the prediction of postoperative BNC in BPH patients undergoing laparoscopic Madigan surgery.

Polyethyleneimine-mediated assembly of DNA nanotubes for KRAS siRNA delivery in lung adenocarcinoma therapy.

Self-assembled DNA nanostructures hold great promise in biosensing, drug delivery and nanomedicine. Nevertheless, challenges like instability and inefficiency in cellular uptake of DNA nanostructures under physiological conditions limit their practical use. To tackle these obstacles, this study proposes a novel approach that integrates the cationic polymer polyethyleneimine (PEI) with DNA self-assembly. The hypothesis is that the positively charged linear PEI can facilitate the self-assembly of DNA nanostructures, safeguard them against harsh conditions and impart them with the cellular penetration characteristic of PEI. As a demonstration, a DNA nanotube (PNT) was successfully synthesized through PEI mediation, and it exhibited significantly enhanced stability and cellular uptake efficiency compared to conventional Mg2+-assembled DNA nanotubes. The internalization mechanism was further found to be both clathrin-mediated and caveolin-mediated endocytosis, influenced by both PEI and DNA. To showcase the applicability of this hybrid nanostructure for biomedical settings, the KRAS siRNA-loaded PNT was efficiently delivered into lung adenocarcinoma cells, leading to excellent anticancer effects in vitro. These findings suggest that the PEI-mediated DNA assembly could become a valuable tool for future biomedical applications.

Ghrelin alleviates intestinal ischemia-reperfusion injury by activating the GHSR-1α/Sirt1/FOXO1 pathway.

Ischemia-reperfusion (IR) injury is primarily characterized by the restoration of blood flow perfusion and oxygen supply to ischemic tissue and organs, but it paradoxically leads to tissue injury aggravation. IR injury is a challenging pathophysiological process that is difficult to avoid clinically and frequently occurs during organ transplantation, surgery, shock resuscitation, and other processes. The major causes of IR injury include increased levels of free radicals, calcium overload, oxidative stress, and excessive inflammatory response. Ghrelin is a newly discovered brain-intestinal peptide with anti-inflammatory and antiapoptotic effects that improve blood supply. The role and mechanism of ghrelin in intestinal ischemia-reperfusion (IIR) injury remain unclear. We hypothesized that ghrelin could attenuate IIR-induced oxidative stress and apoptosis. To investigate this, we established IIR by using a non-invasive arterial clip to clamp the root of the superior mesenteric artery (SMA) in mice. Ghrelin was injected intraperitoneally at a dose of 50 µg/kg 20 min before IIR surgery, and [D-Lys3]-GHRP-6 was injected intraperitoneally at a dose of 12 nmol/kg 20 min before ghrelin injection. We mimicked the IIR process with hypoxia-reoxygenation (HR) in Caco-2 cells, which are similar to intestinal epithelial cells in structure and biochemistry. Our results showed that ghrelin inhibited IIR/HR-induced oxidative stress and apoptosis by activating GHSR-1α. Moreover, it was found that ghrelin activated the GHSR-1α/Sirt1/FOXO1 signaling pathway. We further inhibited Sirt1 and found that Sirt1 was critical for ghrelin-mediated mitigation of IIR/HR injury. Overall, our data suggest that pretreatment with ghrelin reduces oxidative stress and apoptosis to attenuate IIR/HR injury by binding with GHSR-1α to further activate Sirt1.

MCU inhibition protects against intestinal ischemia‒reperfusion by inhibiting Drp1-dependent mitochondrial fission.

Intestinal ischemia‒reperfusion (IIR) injury is a common complication of surgery, but clear molecular insights and valuable therapeutic targets are lacking. Mitochondrial calcium overload is an early sign of various diseases and is considered a vital factor in ischemia‒reperfusion injury. The mitochondrial calcium uniporter (MCU), which is located on the inner mitochondrial membrane, is the primary mediator of calcium ion entry into the mitochondria. However, the specific mechanism of MCU in IIR injury remains to be clarified. In this study, we generated an IIR model using C57BL/6 mice and Caco-2 cells and found increases in the calcium levels and MCU expression following IIR injury. The specific inhibition of MCU markedly attenuated IIR injury. Moreover, MCU knockdown alleviates mitochondrial dysfunction by reducing oxidative stress and apoptosis. Mechanistically, MCU knockdown substantially reduced the translocation of Drp1 and thus its binding to Fis1 receptors, resulting in decreased mitochondrial fission. Taken together, our findings demonstrated that MCU is a novel upstream regulator of Drp1 in ischemia‒reperfusion and represents a predictive and therapeutic target for IIR.

Activation of Piezo1 increases the sensitivity of breast cancer to hyperthermia therapy.

Photothermal therapy (PTT) of nanomaterials is an emerging novel therapeutic strategy for breast cancer. However, there exists an urgent need for appropriate strategies to enhance the antitumor efficacy of PTT and minimize damage to surrounding normal tissues. Piezo1 might be a promising novel photothermal therapeutic target for breast cancer. This study aims to explore the potential role of Piezo1 activation in the hyperthermia therapy of breast cancer cells and investigate the underlying mechanisms. Results showed that the specific agonist of Piezo1 ion channel (Yoda1) aggravated the cell death of breast cancer cells triggered by heat stress in vitro. Reactive oxygen species (ROS) production was significantly increased following heat stress, and Yoda1 exacerbated the rise in ROS release. GSK2795039, an inhibitor of NADPH oxidase 2 (NOX2), reversed the Yoda1-mediated aggravation of cellular injury and ROS generation after heat stress. The in vivo experiments demonstrate the well photothermal conversion efficiency of TiCN under the 1,064 nm laser irradiation, and Yoda1 increases the sensitivity of breast tumors to PTT in the presence of TiCN. Our study reveals that Piezo1 activation might serve as a photothermal sensitizer for PTT, which may develop as a promising therapeutic strategy for breast cancer.

Duodenal-jejunal bypass improves hypothalamic oxidative stress and inflammation in diabetic rats via glucagon-like peptide 1-mediated Nrf2/HO-1 signaling.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is often accompanied by impaired glucose utilization in the brain, leading to oxidative stress, neuronal cell injury and infla-mmation. Previous studies have shown that duodenal jejunal bypass (DJB) surgery significantly improves brain glucose metabolism in T2DM rats, the role and the metabolism of DJB in improving brain oxidative stress and inflammation condition in T2DM rats remain unclear. AIM: To investigate the role and metabolism of DJB in improving hypothalamic oxidative stress and inflammation condition in T2DM rats. METHODS: A T2DM rat model was induced via a high-glucose and high-fat diet, combined with a low-dose streptozotocin injection. T2DM rats were divided into DJB operation and Sham operation groups. DJB surgical intervention was carried out on T2DM rats. The differential expression of hypothalamic proteins was analyzed using quantitative proteomics analysis. Proteins related to oxidative stress, inflammation, and neuronal injury in the hypothalamus of T2DM rats were analyzed by flow cytometry, quantitative real-time PCR, Western blotting, and immunofluorescence. RESULTS: Quantitative proteomics analysis showed significant differences in proteins related to oxidative stress, inflammation, and neuronal injury in the hypothalamus of rats with T2DM-DJB after DJB surgery, compared to the T2DM-Sham groups of rats. Oxidative stress-related proteins (glucagon-like peptide 1 receptor, Nrf2, and HO-1) were significantly increased (P < 0.05) in the hypothalamus of rats with T2DM after DJB surgery. DJB surgery significantly reduced (P < 0.05) hypothalamic inflammation in T2DM rats by inhibiting the activation of NF-κB and decreasing the expression of interleukin (IL)-1ß and IL-6. DJB surgery significantly reduced (P < 0.05) the expression of factors related to neuronal injury (glial fibrillary acidic protein and Caspase-3) in the hypothalamus of T2DM rats and upregulated (P < 0.05) the expression of neuroprotective factors (C-fos, Ki67, Bcl-2, and BDNF), thereby reducing hypothalamic injury in T2DM rats. CONCLUSION: DJB surgery improve oxidative stress and inflammation in the hypothalamus of T2DM rats and reduce neuronal cell injury by activating the glucagon-like peptide 1 receptor-mediated Nrf2/HO-1 signaling pathway.

Dysregulated inter-mitochondrial crosstalk in glioblastoma cells revealed by in situ cryo-electron tomography.

Glioblastomas (GBMs) are the most lethal primary brain tumors with limited survival, even under aggressive treatments. The current therapeutics for GBMs are flawed due to the failure to accurately discriminate between normal proliferating cells and distinctive tumor cells. Mitochondria are essential to GBMs and serve as potential therapeutical targets. Here, we utilize cryo-electron tomography to quantitatively investigate nanoscale details of randomly sampled mitochondria in their native cellular context of GBM cells. Our results show that compared with cancer-free brain cells, GBM cells own more inter-mitochondrial junctions of several types for communications. Furthermore, our tomograms unveil microtubule-dependent mitochondrial nanotunnel-like bridges in the GBM cells as another inter-mitochondrial structure. These quantified inter-mitochondrial features, together with other mitochondria-organelle and intra-mitochondrial ones, are sufficient to distinguish GBM cells from cancer-free brain cells under scrutiny with predictive modeling. Our findings decipher high-resolution inter-mitochondrial structural signatures and provide clues for diagnosis and therapeutic interventions for GBM and other mitochondria-related diseases.

Using autogenous tooth sticky bone graft repair mandibular third molar dentigerous cyst osseous defects.

BACKGROUND: Dentigerous cyst are most common odontogenic cyst and they frequently occur at the mandibular third molar. Their asymptomatic long medical history always resulted in severe bone resorption at the distal aspect of the adjacent second molar. BonMaker® ATB demonstrate an excellent autogenous bone graft candidacy. The aim of this study is to share a single team's experience of dentigerous cyst osseous defect repairing by applying autogenous tooth sticky bone graft. METHOD: In total, 18 patients with dentigerous cyst, which was arised from mandibular third molar unilaterally, were enrolled in this study. Enucleation of dentigerous cyst was performed extracting with involving teeth under general anesthesia. Autogenous tooth sticky bone graft was prepared using extracted tooth and autogenous fibrin glue. Subsequently, grafting was performed above covering with concentrate growth factors. Patients were followed up at sixth months. RESULTS: They were eleven male and seven female patients. Their ages ranged from 20 to 40 years, with a mean of 31 years. Primary wound healing of all sites was achieved in all the patients. Sixth months postoperative radiographic assessment show that dentigerous cysts osseous defects of seventeen patients were good bone filling and ossification. One patient occurred slight bone resorption at the distal aspect of the adjacent second molar. CONCLUSION: Within the limitation of sample size and retrospective nature of the present study, autogenous tooth sticky bone graft demonstrates one of the best alternative alveolar bones repairing graft.

Feasibility and Safety of Remazolam versus Propofol When Inserting Laryngeal Masks Without Muscle Relaxants During Hysteroscopy.

Purpose: This study aimed to evaluate the efficacy and safety of remazolam compared with propofol in patients who underwent laryngeal mask airway (LMA) insertion without the use of muscle relaxant agents during hysteroscopic surgery. Patients and Methods: A total of 72 patients undergoing hysteroscopy with LMA insertion were assigned to two groups. The patients in the remazolam group received 0.3 µg/kg sufentanil, 0.3 mg/kg remazolam and 1.2 mg/kg remifentanil, whereas the patients in the propofol group received 0.3 µg/kg sufentanil, 2.0 mg/kg propofol and 1.2 mg/kg remifentanil for insertion of the LMA. The primary endpoint was the summed score of the insertion conditions. The secondary endpoints included hemodynamics, the duration of induction, the duration of insertion, tidal volume, plateau pressure and adverse events. Results: No difference was identified between the propofol group and remazolam group in the median summed score [18.0 (18.0, 18.0), 18.0 (17.0, 18.0), respectively, P > 0.05]. The induction duration was significantly longer (P < 0.05) in the remazolam group than propofol group. The cost of dopamine (P < 0.05) was significantly lower in the remazolam group compared with the patients in the propofol group, while the plateau pressure (P < 0.05) and the incidence of transient mild laryngospasm (P < 0.05) were significantly higher in the remazolam group. No differences were identified between the two groups in terms of heart rate, tidal volume, injection pain or hiccups (P > 0.05). Conclusion: Remazolam provided similar insertion conditions and better hemodynamic stability than propofol during LMA insertion without the use of muscle relaxant agents. However, a higher incidence of transient mild laryngospasm was found in the remazolam group, which should be considered.

Identification of RAC1 in promoting brain metastasis of lung adenocarcinoma using single-cell transcriptome sequencing.

This study aims to give a new perspective to the biomarkers in the lung adenocarcinoma (LUAD) brain metastasis, pathways involved and potential therapeutics. We performed a comprehensive single-cell level transcriptomic analysis on one LUAD patient with circulating tumor cells (CTCs), primary tumor tissue and metastatic tumor tissue using scRNA-seq approach to identify metastasis related biomarkers. Further scRNA-seq were performed on 7 patients to validate the cancer metastatic hallmark. with single cells collected from either metastatic or primary LUAD tissues. Pathological and functional studies were also performed to evidence the critical role of RAC1 in the LUAD metastasis. Hallmark gene was verified based on immunohistochemistry staining, cytological experiment, survival information from The Cancer Genome Atlas (TCGA), and staining results from Human Protein Atlas (HPA) databases. PCA analysis revealed that CTCs were in the intermediate place between the metastatic group and primary group. In the unsupervised clustering analysis CTCs were closer to one of the metastatic tumor cells, implying heterogeneity of the metastatic tumor and origin of the CTCs were from metastatic site. Transitional phase related gene analysis identified RAC1 was enriched in metastatic tumor tissue (MTT) preferred gene set functioning as regulated cell death and apoptosis as well as promoted macromolecule organization. Compared with normal tissue, expression levels of RAC1 increased significantly in LUAD tissue based on HPA database. High expression of RAC1 predicts worse prognosis and higher-risk. EMT analysis identified the propensity of mesenchymal state in primary cells while epithelial signals were higher in the metastatic site. Functional clustering and pathway analyses suggested genes in RAC1 highly expressed cells played critical roles in adhesion, ECM and VEGF signaling pathways. Inhibition of RAC1 attenuates the proliferation, invasiveness and migration ability of lung cancer cells. Besides, through MRI T2WI results, we proved that RAC1 can promote brain metastasis in the RAC1-overexpressed H1975 cell burden nude mouse model. RAC1 and its mechanisms might promote drug design against LUAD brain metastasis.

A deep learning model based on contrast-enhanced computed tomography for differential diagnosis of gallbladder carcinoma.

BACKGROUND: Gallbladder carcinoma (GBC) is highly malignant, and its early diagnosis remains difficult. This study aimed to develop a deep learning model based on contrast-enhanced computed tomography (CT) images to assist radiologists in identifying GBC. METHODS: We retrospectively enrolled 278 patients with gallbladder lesions (> 10 mm) who underwent contrast-enhanced CT and cholecystectomy and divided them into the training (n = 194) and validation (n = 84) datasets. The deep learning model was developed based on ResNet50 network. Radiomics and clinical models were built based on support vector machine (SVM) method. We comprehensively compared the performance of deep learning, radiomics, clinical models, and three radiologists. RESULTS: Three radiomics features including LoG_3.0 gray-level size zone matrix zone variance, HHL first-order kurtosis, and LHL gray-level co-occurrence matrix dependence variance were significantly different between benign gallbladder lesions and GBC, and were selected for developing radiomics model. Multivariate regression analysis revealed that age ≥ 65 years [odds ratios (OR) = 4.4, 95% confidence interval (CI): 2.1-9.1, P < 0.001], lesion size (OR = 2.6, 95% CI: 1.6-4.1, P < 0.001), and CA-19-9 > 37 U/mL (OR = 4.0, 95% CI: 1.6-10.0, P = 0.003) were significant clinical risk factors of GBC. The deep learning model achieved the area under the receiver operating characteristic curve (AUC) values of 0.864 (95% CI: 0.814-0.915) and 0.857 (95% CI: 0.773-0.942) in the training and validation datasets, which were comparable with radiomics, clinical models and three radiologists. The sensitivity of deep learning model was the highest both in the training [90% (95% CI: 82%-96%)] and validation [85% (95% CI: 68%-95%)] datasets. CONCLUSIONS: The deep learning model may be a useful tool for radiologists to distinguish between GBC and benign gallbladder lesions.

[Application of nitrous oxide/oxygen inhalation comfort technique during tooth extraction of elderly hypertensive patients under electrocardiographic monitoring].

PURPOSE: To investigate the application value of nitrous oxide/oxygen inhalation comfort technique during tooth extraction in elderly patients with hypertension under electrocardiographic(ECG) monitoring. METHODS: According to the inclusion and exclusion criteria, sixty elderly patients (over 65 years old) with hypertension for tooth extraction were randomly divided into 2 groups: the experimental group(nitrous oxide/oxygen inhalation combined with ECG monitoring group, n=30) and the control group (routine ECG monitoring group, n=30). Mean arterial pressure (MAP) and heart rate (HR) at T0 (baseline values before surgery), T1 (on local anesthesia), T2 (during operation) and T3(5 minutes after operation) were recorded. SPSS 25.0 software package was used for statistical analysis. RESULTS: There was no significant difference in MAP and HR at each time point in the experimental group(P＞0.05). There was no significant difference in MAP and HR at T0 and T3 time points in the control group(P＞0.05). At other time points, MAP and HR were significantly different (P＜0.05). There was no significant differences in MAP and HR between the two groups at T0 and T3(P＞0.05). MAP and HR at T1 and T2 in the experimental group were significantly less than those in the control group(P＜0.05). CONCLUSIONS: Nitrous oxide/oxygen inhalation comfort technology can stabilize patients' emotions and maintain stable blood pressure and heart rate in elderly patients with hypertension during tooth extraction, thus improving the safety of tooth extraction.

The effects of altered DNA damage repair genes on mutational processes and immune cell infiltration in esophageal squamous cell carcinoma.

BACKGROUND: Defects in DNA damage repair (DDR) pathways lead to genomic instability and oncogenesis. DDR deficiency is prevalent in esophageal squamous cell carcinoma (ESCC), but the effects of DDR alterations on mutational processes and tumor immune microenvironment in ECSS remain unclear. METHODS: Whole-exome and transcriptome sequencing data of 45 ESCC samples from Taizhou, China, were used to identify genomic variations, gene expression modulation in DDR pathways, and the abundance of tumor-infiltrating immune cells. Ninety-six ESCC cases from The Cancer Genome Atlas (TCGA) project were used for validation. RESULTS: A total of 57.8% (26/45) of the cases in the Taizhou data and 70.8% (68/96) of the cases in the TCGA data carried at least one functional impact DDR mutation. Mutations in the DDR pathways were associated with a high tumor mutation burden. Several DDR deficiency-related mutational signatures were discovered and were associated with immune cell infiltration, including T cells, monocytes, dendritic cells, and mast cells. The expression levels of two DDR genes, HFM1 and NEIL1, were downregulated in ESCC tumor tissues and had an independent effect on the infiltration of mast cells. In the Taizhou data, increased expression of HFM1 was associated with a poor prognosis, and the increased expression of NEIL1 was associated with a good outcome, but no reproducible correlation was observed in the TCGA data. CONCLUSION: This research demonstrated that DDR alterations could impact mutational processes and immune cell infiltration in ESCC. The suppression of HFM1 and NEIL1 could play a crucial role in ESCC progression and may also serve as prognostic markers.

miR-138-5p inhibits the progression of colorectal cancer via regulating SP1/LGR5 axis.

Colorectal cancer (CRC) is one of the main malignancies that seriously threaten human health. Considering the high mortality and morbidity associated with this disease, even surgical resection and chemotherapy may not be sufficient in certain cases. This study aimed to explore the molecular mechanisms of miR-138-5p in regulating CRC progression. Quantitative reverse transcriptase polymerase chain reaction and western blot were performed to assess the levels of mRNA and proteins, including miR-138-5p, leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), SP1, ß-catenin, cyclin D1, and c-myc. The bioactivities of LoVo and HCT116 cells were assessed via MTT assay, flow cytometry, and transwell assay. StarBase was used to identify the downstream targets of genes. Double luciferase reporter and RIP assays revealed the direct binding of miR-138-5p to SP1 and of SP1 to LGR5. Our results illustrated that miR-138-5p was downregulated in CRC and its knockdown accelerated CRC progression. Conversely, SP1 was upregulated in CRC and its knockdown inhibited CRC progression. SP1 is also targeted by miR-138-5p and binds to LGR5. This study showed that miR-138-5p inhibits LoVo and HCT116 cell proliferation, migration, and invasion. Overall, miR-138-5p regulates CRC progression and promotes apoptosis via the SP1/LGR5 axis. This study indicates that miR-138-5p is involved in regulating CRC progression.

Cutaneous adverse events in lung cancer patients on the therapy based on PD-1/PD-L1 inhibitors: A prospective observational cohort study.

AIM: This is a prospective study of cutaneous adverse events (CAEs) in lung cancer patients treated by programmed cell death-1(PD-1) inhibitors and programmed cell death-ligand 1(PD-L1) inhibitors-based single or combination therapy. PATIENTS & METHODS: It were included that lung cancer patients who developed CAEs from January 2019 to July 2021 after applying PD-1/PD-L1 inhibitors in our institution. RESULTS: A total of 107 patients with 112 CAEs were enrolled, of which 71 patients received PD-1/PD-L1 inhibitors plus chemotherapy, 31 patients received PD-1/PD-L1 inhibitors plus anti-angiogenic/targeted therapy, and 5 patients received PD-1/PD-L1 inhibitors monotherapy. The median time to CAEs onset was 8.7w (0.3w-70.7w) for PD-1/PD-L1 inhibitors plus chemotherapy, 10.1w (0.4w-103.0w) for PD-1/PD-L1 inhibitors plus anti-angiogenic/targeted therapy, and 13.6w (0.7w-50.6w) for PD-1/PD-L1 inhibitors monotherapy. The most common CAEs were reactive cutaneous capillary endothelial proliferation (RCCEP) (30.8%, 33/107), followed by eczematous (21.5%, 23/107) and pruritus only (15.9%, 17/107). 7 patients (6.5%, 7/107) had grade 3-4 CAE. CONCLUSION: Most CAEs are mild to moderate and easily controlled. Early diagnosis and intervention for CAEs are important.

Antifungal activity of the repurposed drug disulfiram against Cryptococcus neoformans.

Fungal infections have become clinically challenging owing to the emergence of drug resistance in invasive fungi and the rapid increase in the number of novel pathogens. The development of drug resistance further restricts the use of antifungal agents. Therefore, there is an urgent need to identify alternative treatments for Cryptococcus neoformans (C. neoformans). Disulfiram (DSF) has a good human safety profile and promising applications as an antiviral, antifungal, antiparasitic, and anticancer agent. However, the effect of DSF on Cryptococcus is yet to be thoroughly investigated. This study investigated the antifungal effects and the mechanism of action of DSF against C. neoformans to provide a new theoretical foundation for the treatment of Cryptococcal infections. In vitro studies demonstrated that DSF inhibited Cryptococcus growth at minimum inhibitory concentrations (MICs) ranging from 1.0 to 8.0 µg/mL. Combined antifungal effects have been observed for DSF with 5-fluorocytosine, amphotericin B, terbinafine, or ketoconazole. DSF exerts significant protective effects and synergistic effects combined with 5-FU for Galleria mellonella infected with C. neoformans. Mechanistic investigations showed that DSF dose-dependently inhibited melanin, urease, acetaldehyde dehydrogenase, capsule and biofilm viability of C. neoformans. Further studies indicated that DSF affected C. neoformans by interfering with multiple biological pathways, including replication, metabolism, membrane transport, and biological enzyme activity. Potentially essential targets of these pathways include acetaldehyde dehydrogenase, catalase, ATP-binding cassette transporter (ABC transporter), and iron-sulfur cluster transporter. These findings provide novel insights into the application of DSF and contribute to the understanding of its mechanisms of action in C. neoformans.

Anatomical type analysis of right interlobar artery based on chest thin-slice CT scan and three-dimensional reconstruction.

PURPOSE: To analyse and summarize branching pattern types of the interlobar portion of right pulmonary arteries (RPA) through chest thin-slice CT scans and three-dimensional reconstruction. METHODS: A total of 179 patients (58 males and 121 females, with an average age of 53.9 years) at the Thoracic Surgery Department of Ningbo First Hospital were retrospectively included from December 2020 to December 2021. All patients completed preoperative thin-slice CT scans and three-dimensional reconstructions of the chest. The clinical data and branching patterns were collected. Data were analysed using SPSS 21.0. RESULTS: The branching pattern types of the interlobar portion of RPA were divided into 4 types according to the order and number of branches: Type I (145/179, 81.0%), Asc. A2, MA, A6; Type II (28/179, 15.6%), Asc. A2 deletion, MA, A6; Type III (5/179, 2.8%), Asc. A2, A6, MA; and Type IV (1/179, 0.6%), MA, Asc. A2, A6. Type I was the most common pattern. Furthermore, according to the number of branches of MA and A6, this pattern can be subdivided into 15 subcategories. CONCLUSION: Chest thin-slice CT scans and 3D reconstructions can provide surgeons with accurate lung anatomy, which helps surgeons perform preoperative planning and complete surgery successfully.

Cutaneous adverse events associated with PD-1 inhibitor-based therapy in patients with non-small-cell lung cancer.

Aim: To analyze the incidence and characteristics of cutaneous adverse events (CAEs) in non-small-cell lung cancer patients treated with PD-1 inhibitor-based therapy. Methods: A total of 150 non-small-cell lung cancer patients under PD-1 inhibitor-based therapy from February 2018 to September 2021 were included and were followed up with regularly. Results: Over one-half of patients (88/150; 58.7%) had CAEs. Reactive cutaneous capillary endothelial proliferation, maculopapular rash and pruritus were the most common CAEs. The incidences of CAEs were 50.0 (18/36), 67.0 (50/75) and 51.3% (20/39) with PD-1 inhibitor monotherapy, PD-1 inhibitor in combination with chemotherapy and PD-1 inhibitor in combination with antivascular/targeted therapy, respectively. Conclusion: CAEs occur frequently in PD-1 inhibitor-based therapy but are generally tolerable.

Molecular differences between younger versus older ER-positive and HER2-negative breast cancers.

The RxPONDER and TAILORx trials demonstrated benefit from adjuvant chemotherapy in patients age ≤ 50 with node-positive breast cancer and Recurrence Score (RS) 0-26, and in node-negative disease with RS 16-25, respectively, but no benefit in older women with the same clinical features. We analyzed transcriptomic and genomic data of ER+/HER2- breast cancers with in silico RS < 26 from TCGA (n = 530), two microarray cohorts (A: n = 865; B: n = 609), the METABRIC (n = 867), and the SCAN-B (n = 1636) datasets. There was no difference in proliferation-related gene expression between age groups. Older patients had higher mutation burden and more frequent ESR1 copy number gain, but lower frequency of GATA3 mutations. Younger patients had higher rate of ESR1 copy number loss. In all datasets, younger patients had significantly lower mRNA expression of ESR1 and ER-associated genes, and higher expression of immune-related genes. The ER- and immune-related gene signatures showed negative correlation and defined three subpopulations in younger women: immune-high/ER-low, immune-intermediate/ER-intermediate, and immune-low/ER-intermediate. We hypothesize that in immune-high cancers, the cytotoxic effect of chemotherapy may drive the benefit, whereas in immune-low/ER-intermediate cancers chemotherapy induced ovarian suppression may play important role.