Case report: Successful bronchoscopic interventional treatment of endobronchial leiomyomas.

Endobronchial leiomyomas are rare benign neoplasms of the lungs that arise from the smooth muscle cells of the bronchi and bronchioles. While surgical resection is the mainstay of treatment for these tumors, bronchoscopic interventional therapies are also effective and can help preserve lung function in certain cases. A 40-year-old male patient presented with a persistent cough and sputum production for over 4 months. A chest computed tomography scan revealed nodular lesions in the lower lobe bronchus, later confirmed as an endobronchial leiomyoma. The patient refused surgical intervention and opted for minimally invasive bronchoscopic treatments, including electric snare resection, argon plasma coagulation, and balloon dilation, resulting in a successful outcome with no recurrence during follow-up. Clinicians should consider bronchoscopic interventions as a viable treatment option for endobronchial leiomyomas patients who are either ineligible for surgical resection or opt not to undergo surgery.

Nicotine improves DSS-induced colitis by inhibiting NLRP3 and altering gut microbiota.

Ulcerative colitis (UC) is a chronic recurrent inflammatory disease affecting the rectum and colon. Numerous epidemiological studies have identified smoking as a protective factor for UC. Dysbiosis of intestinal microbiota and release of inflammatory factors are well-established characteristics associated with UC. Therefore, we have observed that nicotine exhibits the potential to ameliorate colitis symptoms in UC mice. Additionally, it exerts a regulatory effect on colonic microbiota dysbiosis by promoting the growth of beneficial bacteria while suppressing harmful bacteria. Combined in vivo and in vitro investigations demonstrate that nicotine primarily impedes the assembly of NLRP3, subsequently inhibiting downstream IL-1ß secretion.

Genomic heterogeneity of multiple synchronous lung cancers in Chinese population.

INTRODUCTION: It is clinically challenging to infer the phylogenetic relationship between different tumor lesions of patients with multiple synchronous lung cancers (MSLC), whether these lesions are the result of independently evolved tumor or intrapulmonary metastases. METHODS: We used the Illumina X10 platform to sequence 128 stage I lung cancer samples collected from 64 patients with MSLC. All samples were analyzed for mutation spectra and phylogenetic inference. RESULTS: We detected genetic aberrations within genes previously reported to be recurrently altered in lung adenocarcinoma including, EGFR, ERBB2, TP53, BRAF, and KRAS. Other putative driver mutations identified were enriched in RTK-RAS signaling, TP53 signaling, and cell cycle. Also, we found some interesting cases, two cases that carried EGFR L858R and T790M co-mutation in one tumor and another tumor with only EGFR 19del, and 1 case with two KRAS hotspots in the same tumor. Due to the short follow-up time and early stage, further investigation is needed to determine whether this unique mutation profile will affect their progression-free survival (PFS) and overall survival (OS). Regarding genetic evolution analysis among 64 tumor samples, 50 of them display distinct mutational profiles, suggesting these are independently evolved tumors, which is consistent with histopathological assessment. On the other hand, six patients were identified to be intrapulmonary metastasis as the mutations harbored in different lesions are clonally related. CONCLUSION: In summary, unlike intrapulmonary metastases, patients with MSLC harbor distinct genomic profiles in different tumor lesions, and we could distinguish MSLC from intrapulmonary metastases via clonality estimation.

A comprehensive analysis of immunotherapy in advanced endometrial cancer (Review).

The morbidity and mortality rates of endometrial cancer (EC) are increasing yearly. Early-stage EC can be effectively treated through surgery or surgery combined with radiotherapy and chemotherapy. Advanced and recurrent EC is treated with chemotherapy and comprehensive treatment; however, the prognosis for patients at this disease stage is poor. Consequently, novel and effective treatment strategies are urgently required for these patients. Breakthrough progress has been made with the use of immunosuppressants in the treatment of EC, which have been included in treatment guidelines. In the present review, the etiology and classification of EC was outlined and the relevant scientific basis for the application of immunosuppressants in advanced and recurrent EC was discussed. The relevant published and ongoing clinical trials are also summarized. As such, the present review aimed to provide a scientific summary of immunotherapy of EC.

Concentrated ultrasound-processed fat (CUPF): More than a mechanically emulsified graft.

INTRODUCTION: Autologous fat grafting is still an evolving technique. Researchers have attempted to increase the survival rate of grafts by concentrating adipose-derived stem cells (ASCs). In this study, we investigate a novel method that combines ultrasonic processing and centrifugation to generate small fat particles termed concentrated ultrasound-processed fat (CUPF) for grafting. METHODS: The standard approach for obtaining CUPF is described. The properties of processed fat, including CUPF, microfat, centrifuged fat, and nanofat, were investigated using histological observation. Comparative analyses were conducted on the cell number, viability, and immunophenotypic profile of stromal vascular fraction cells (SVFs). Cultured ASCs were evaluated for cell proliferation and adipogenic, osteogenic, and chondrogenic potential. The processed fats were transplanted and evaluated using in vivo and histological studies. RESULTS: Compared with microfat, centrifuged fat, and nanofat, CUPF had a condensed tissue content and higher concentration of viable cells in a small tissue structure and could smoothly pass through a 27-gauge cannula. In the CUPF group, SVFs were isolated in great numbers, with high viability and a high proportion of CD29- and CD105-positive cells. ASCs from the CUPF group exhibited high proliferation and multilineage differentiation potential. The grafts from the CUPF group were well preserved, and histological quantification revealed an increase in the abundance of Ki67- and CD31-positive cells in the tissue. CONCLUSIONS: Our study established a new fat processing strategy that combines ultrasonic processing and centrifugation to harvest small particle grafts named CUPF. CUPF concentrated a large number of ASCs and has great potential for regenerative therapy.

Adipose tissue aging is regulated by an altered immune system.

Adipose tissue is a widely distributed organ that plays a critical role in age-related physiological dysfunctions as an important source of chronic sterile low-grade inflammation. Adipose tissue undergoes diverse changes during aging, including fat depot redistribution, brown and beige fat decrease, functional decline of adipose progenitor and stem cells, senescent cell accumulation, and immune cell dysregulation. Specifically, inflammaging is common in aged adipose tissue. Adipose tissue inflammaging reduces adipose plasticity and pathologically contributes to adipocyte hypertrophy, fibrosis, and ultimately, adipose tissue dysfunction. Adipose tissue inflammaging also contributes to age-related diseases, such as diabetes, cardiovascular disease and cancer. There is an increased infiltration of immune cells into adipose tissue, and these infiltrating immune cells secrete proinflammatory cytokines and chemokines. Several important molecular and signaling pathways mediate the process, including JAK/STAT, NFκB and JNK, etc. The roles of immune cells in aging adipose tissue are complex, and the underlying mechanisms remain largely unclear. In this review, we summarize the consequences and causes of inflammaging in adipose tissue. We further outline the cellular/molecular mechanisms of adipose tissue inflammaging and propose potential therapeutic targets to alleviate age-related problems.

The Value of the Alvarado Score for the Diagnosis of Acute Appendicitis in Children: A Systematic Review and Meta-Analysis.

BACKGROUND: Relevant guidelines recommend the use of the Alvarado score (AS) to assist in the diagnosis of acute appendicitis (AA) in children. To provide reference evidence for the clinical application of AS, we performed a meta-analysis of studies related to the diagnostic accuracy of AS in children with AA. METHODS: We searched the relevant literature from databases including CNKI, WanFangdata, VIP, CBM, the Cochrane Library, PubMed, Embase, and Web of Science databases from the date of database creation to April 30, 2022, and screened them according to nadir criteria, followed by data extraction and then combined effect sizes to assess the accuracy of AS for diagnosis in children. RESULTS: Twenty-six studies involving 2579 cases were finally included, including 19 studies with Alvarado score and 8 studies with modified Alvarado Score (1 study included both Alvarado Score and modified Alvarado Score). The combined sensitivity (SE) of AS for diagnosing AA in children was 76.0% (95% CI 74.0-78.0%; I2 = 95.1%); combined specificity (SP) was 71.0% (95% CI 68.0-74.0%; I2 = 86.4%); combined positive likelihood ratio (LR+) was 2.43 (95% CI 1.92- 3.07; I2 = 78.7%); combined negative likelihood ratio (LR-) was 0.28 (95% CI 0.20-0.41; I2 = 94.2%); combined AUC = 0.8092, Q∗ = 0.7439; combined diagnostic ratio (DOR) was 8.96 (95% CI 5.65 -14.21; I2 = 76.2%). The combined effect size I2 was greater than 50% for all children with a modified AS diagnosis of AA, so all analyses used a random-effects model, which showed a combined SE of 87.0% (95% CI 85.0 - 88.0%; I2 = 85.5%); the combined SP was 47.0% (95% CI 43.0 - 51.0%. I2 = 88.7%); combined LR+ was 1.68 (95% CI 1.31-2.17; I2 = 85.9%); combined LR-was 0.28 (95% CI 0.20-0.39; I2 = 74.3%); combined AUC = 0.8672 and Q∗ = 0.7978. The combined DOR was 6.43 (95% CI 3.38-12.26; I2 = 80.0%). CONCLUSION: The results of this meta-analysis suggest that the accuracy of AS in diagnosing AA in children is moderate, and AS can be an auxiliary tool for the diagnosis of AA in children, relying on AS alone for the diagnosis of AA is not recommended; AS can be further improved scientifically to increase its diagnostic value.

Loss of Wdr5 attenuates MLL-rearranged leukemogenesis by suppressing Myc targets.

WD repeat domain 5 (WDR5) is a prominent target for pharmacological inhibition in cancer through its scaffolding role with various oncogenic partners such as MLL and MYC. WDR5-related drug discovery efforts center on blocking these binding interfaces or degradation have been devoted to developing small-molecule inhibitors or degraders of WDR5 for cancer treatment. Nevertheless, the precise role of WDR5 in these cancer cells has not been well elucidated genetically. Here, by using an MLL-AF9 murine leukemia model, we found that genetically deletion of Wdr5 impairs cell growth and colony forming ability of MLL-AF9 leukemia cells in vitro or ex vivo and attenuates the leukemogenesis in vivo as well, which acts through direct regulation of ribosomal genes. Pharmacological inhibition of Wdr5 recapitulates genetic study results in the same model. In conclusion, our current study demonstrated the first genetic evidence for the indispensable role of Wdr5 in MLL-r leukemogenesis in vivo, which supports therapeutically targeting WDR5 in MLL-rearranged leukemia by strengthening its disease linkage genetically and deepening insights into its mechanism of action.

Mayo adhesive probability score is associated with perioperative outcomes in retroperitoneal laparoscopic adrenalectomy.

BACKGROUNDS: This study aimed to determine whether the Mayo adhesive probability score (MAP), which evaluated adherent perinephric fat (APF), is useful in evaluating the difficulty of retroperitoneal laparoscopic adrenalectomy (RLA), and to analyse the correlation between MAP and perioperative parameters. METHODS: Clinical data of 104 patients with adrenal adenoma who underwent RLA were collected for retrospective analysis. According to the CT images obtained before surgery, patients were divided into two groups: High MAP group (2-5 points) and Low MAP group (0-1 points). Comparison of the general clinical characteristics and the perioperative data between the two groups was made. RESULTS: There were more male patients (73.7% versus 34.3%), more patients with a smoking history (24.3% versus 7.5%), higher BMI (25.7 versus 23.2, kg/m2 ), and bigger (23.8 versus 18.5, mm) neoplasm in the high MAP group (P < 0.05). Significant difference was observed in operative time (128.8 versus 102.3, min), estimated blood loss (47.2 versus 25.2, ml) and drainage tube removal time (4.0 versus 3.2, d) between the two groups (P < 0.05). A high MAP score (P < 0.001) and the size of tumour (P = 0.024) were independent risk factors for extended operative time. A higher BMI (OR = 1.525, P < 0.001) and larger tumour size (OR = 2.862, P = 0.004) were independent risk factors for a high MAP score. CONCLUSIONS: MAP score was associated with the perioperative outcomes of RLA. BMI and tumour size were better indicators of MAP score, which can influence the difficulty of RLA.

[Retracted] MicroRNA-199b targets the regulation of ZEB1 expression to inhibit cell proliferation, migration and invasion in non­small cell lung cancer.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that cell migration assay data shown in Figs. 2D and 4D were strikingly similar to data that had appeared in different form in other articles by different authors (in addition to the apparent duplication of some of these data within this paper itself). Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 16: 5007­5014, 2017; DOI: 10.3892/mmr.2017.7195].

MicroRNA-584 inhibits cell proliferation and invasion in non-small cell lung cancer by directly targeting MTDH.

[This retracts the article DOI: 10.3892/etm.2017.5624.].

Alboserpin, the Main Salivary Anticoagulant from the Disease Vector Aedes albopictus, Displays Anti-FXa-PAR Signaling In Vitro and In Vivo.

Blood-feeding arthropods secrete potent salivary molecules, which include platelet aggregation inhibitors, vasodilators, and anticoagulants. Among these molecules, Alboserpin, the major salivary anticoagulant from the mosquito vector Aedes albopictus, is a specific inhibitor of the human coagulation factor Xa (FXa). In this study, we investigated the anti-inflammatory properties of Alboserpin, in vitro and in vivo. In vitro, Alboserpin inhibited FXa-induced protease-activated receptor (PAR)-1, PAR-2, PAR-3, VCAM, ICAM, and NF-κB gene expression in primary dermal microvascular endothelial cells. Alboserpin also prevented FXa-stimulated ERK1/2 gene expression and subsequent inflammatory cytokine release (MCP-1, TNF-α, IL-6, IL-8, IL-1ß, IL-18). In vivo, Alboserpin reduced paw edema induced by FXa and subsequent release of inflammatory cytokines (CCL2, MCP-1, IL-1α, IL-6, IL-1ß). Alboserpin also reduced FXa-induced endothelial permeability in vitro and in vivo. These findings show that Alboserpin is a potent anti-inflammatory molecule, in vivo and in vitro, and may play a significant role in blood feeding.

SLC1A1-mediated cellular and mitochondrial influx of R-2-hydroxyglutarate in vascular endothelial cells promotes tumor angiogenesis in IDH1-mutant solid tumors.

Mutant isocitrate dehydrogenase 1 (mIDH1) drives tumorigenesis via producing oncometabolite R-2-hydroxyglutarate (R-2-HG) across various tumor types. However, mIDH1 inhibitors appear only effective in hematological tumors. The therapeutic benefit in solid tumors remains elusive, likely due to the complex tumor microenvironment. In this study, we discover that R-2-HG produced by IDH1-mutant tumor cells is preferentially imported into vascular endothelial cells and remodels mitochondrial respiration to promote tumor angiogenesis, conferring a therapeutic vulnerability in IDH1-mutant solid tumors. Mechanistically, SLC1A1, a Na+-dependent glutamate transporter that is preferentially expressed in endothelial cells, facilitates the influx of R-2-HG from the tumor microenvironment into the endothelial cells as well as the intracellular trafficking of R-2-HG from cytoplasm to mitochondria. R-2-HG hijacks SLC1A1 to promote mitochondrial Na+/Ca2+ exchange, which activates the mitochondrial respiratory chain and fuels vascular endothelial cell migration in tumor angiogenesis. SLC1A1 deficiency in mice abolishes mIDH1-promoted tumor angiogenesis as well as the therapeutic benefit of mIDH1 inhibitor in solid tumors. Moreover, we report that HH2301, a newly discovered mIDH1 inhibitor, shows promising efficacy in treating IDH1-mutant cholangiocarcinoma in preclinical models. Together, we identify a new role of SLC1A1 as a gatekeeper of R-2-HG-mediated crosstalk between IDH1-mutant tumor cells and vascular endothelial cells, and demonstrate the therapeutic potential of mIDH1 inhibitors in treating IDH1-mutant solid tumors via disrupting R-2-HG-promoted tumor angiogenesis.

Correlation of PD-L1 Expression with Clinicopathological and Genomic Features in Chinese Non-Small-Cell Lung Cancer.

Programmed cell death 1 ligand 1 (PD-L1) has been approved as predictive biomarker for non-small-cell lung cancer (NSCLC) patients treated with PD-(L)1 blockade therapy. The clinical/genomic features associated with PD-L1 are not well studied. Genomic profiling of tumor biopsies from 883 Chinese NSCLC patients was performed by targeted next-generation sequencing. Immunohistochemical analysis was conducted to evaluate PD-L1 expression levels using antibodies Dako 22C3 and 28-8, respectively. Our study showed distinct correlation between PD-L1 expression and clinical/genomic characteristics when using different PD-L1 antibodies and in different histological subtypes including adenocarcinoma (ADC) and squamous cell carcinoma (SCC), respectively. PD-L1 high expression (22C3) was associated with male and lymph node metastasis only in ADC patients. Furthermore, mutations of TP53 and KRAS, KIF5B-RET fusion, copy number gains of PD-L1 and PD-L2, and arm-level amplifications of chr.12p were significantly associated with PD-L1 positive status in ADC patients. For SCC patients, the gain of EGFR and MDM2 and loss of PTPRD were negatively associated with PD-L1 expression. We also compared our results with other studies and found conflicting results presumably because of the multiplicity of antibody clones and platforms, the difference of cutoffs for assigning PD-L1 expression levels, and the variation in study populations. Our study can help to understand the utility and validity of PD-L1 as biomarker of response to immune checkpoint inhibitors.

Deciphering the mechanism of processive ssDNA digestion by the Dna2-RPA ensemble.

Single-stranded DNA (ssDNA) commonly occurs as intermediates in DNA metabolic pathways. The ssDNA binding protein, RPA, not only protects the integrity of ssDNA, but also directs the downstream factor that signals or repairs the ssDNA intermediate. However, it remains unclear how these enzymes/factors outcompete RPA to access ssDNA. Using the budding yeast Saccharomyces cerevisiae as a model system, we find that Dna2 - a key nuclease in DNA replication and repair - employs a bimodal interface to act with RPA both in cis and in trans. The cis-activity makes RPA a processive unit for Dna2-catalyzed ssDNA digestion, where RPA delivers its bound ssDNA to Dna2. On the other hand, activity in trans is mediated by an acidic patch on Dna2, which enables it to function with a sub-optimal amount of RPA, or to overcome DNA secondary structures. The trans-activity mode is not required for cell viability, but is necessary for effective double strand break (DSB) repair.

Large mediastinal mass diagnosed as Nocardia infection by endobronchial ultrasound-guided transbronchial needle aspiration in a ceramic worker: A case report.

Background: Nocardia is a ubiquitous soil saprophyte transmitted through airborne or direct cutaneous inoculation routes. Although Nocardia is more common in immunocompromised patients, Nocardia may also arise in apparently immunocompetent patients. Case presentation: We report a rare case of Nocardia infection presenting as a large mediastinal mass in an immunocompetent ceramic worker. A 54-year-old man with no previous history of immune dysfunction, a ceramic worker by profession, was referred and admitted to our hospital because of a persistent fever for 19 days. Chest CT showed a large middle mediastinal mass. However, conventional anti-infective treatment was ineffective. Under the guidance of the Virtual bronchoscopic navigation (VBN) system, he underwent Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). The purulent exudate obtained by EBUS-TBNA was further identified as Nocardia by weak acid-fast and metagenomic next-generation sequencing (mNGS). He was subsequently treated with intravenous imipenem/amikacin, switched to intravenous imipenem and oral trimethoprim/sulfamethoxazole, and the clinical symptoms were significantly improved. Conclusions: Even in immunocompetent patients, Nocardiosis cannot be excluded. For the public, especially soil contact workers, precautions should be taken to avoid Nocardia infection from occupational exposure. This rare case may provide a diagnosis and treatment reference for clinicians.

A Retrospective Study on Using a Novel Single Needle Cone Puncture Approach for the Iodine-125 Seed Brachytherapy in Treating Patients With Thoracic Malignancy.

BACKGROUND: Patients with progressive thoracic malignancy characterized by large irregular tumors with necrosis and life-threatening symptoms lack effective treatments. We set out to develop a single needle cone puncture method for the Iodine-125 seed (SNCP-125I) brachytherapy, and aim to report the initial results. METHODS: 294 patients with advanced thoracic malignancy were treated with local SNCP-125I brachytherapy between March 2009 and July 2020, followed by thorough evaluation of clinical outcome, overall survival (OS), progression-free survival (PFS) and procedure-related complications after treatment. RESULTS: The overall response rate (ORR) among the treated patients was 81.0% (238/294). Life-threatening symptoms due to tumor oppression, hemoptysis and large irregular tumor with necrosis were successfully alleviated after the SNCP-125I treatment with a remission rate at 91% to 94%. The median OS and PFS were 13.6 months and 5.8 months, respectively. Procedure-related side effects including pneumothorax (32/294), blood-stained sputum (8/294), subcutaneous emphysema (10/294), puncture site bleeding (16/294) and chest pain (6/294) were observed. Patients who were able to follow with chemotherapy or immunotherapy experienced extended OS and PFS, as compared with patients who opted to receive hospice care (16.5 months Vs. 11.2 months). Further pathological and immunological analysis showed that SNCP-125I induced tumor lymphocytes infiltration and long-term tumor necrosis. CONCLUSION: SNCP-125I brachytherapy effectively eliminates life-threatening symptoms due to local tumor oppression, hemoptysis and large irregular and necrotic tumors in patients with unresectable chest malignancy and significantly induces local tumor regression. SNCP-125I brachytherapy combines with chemotherapy significantly prolong OS and PFS compare with SNCP-125I brachytherapy alone.

High-fat diet impairs ferroptosis and promotes cancer invasiveness via downregulating tumor suppressor ACSL4 in lung adenocarcinoma.

BACKGROUND: Long-chain acyl-CoA synthetase-4 (ACSL4) is involved in fatty acid metabolism, and aberrant ACSL4 expression could be either tumorigenic or tumor-suppressive in different tumor types. However, the function and clinical significance of ACSL4 in lung adenocarcinoma remain elusive. RESULTS: ACSL4 was frequently downregulated in lung adenocarcinoma when analyzing both the TCGA database and the validation samples, and the lower ACSL4 expression was correlated with a worse prognosis. Using gene set enrichment analysis, we found that high ACSL4 expression was frequently associated with the oxidative stress pathway, especially ferroptosis-related proteins. In vitro functional studies showed that knockdown of ACSL4 increased tumor survival/invasiveness and inhibited ferroptosis, while ACSL4 overexpression exhibited the opposite effects. Moreover, high-fat treatment could also inhibit erastin-induced ferroptosis by affecting ACSL4 expression. The anti-tumor effects of ferroptosis inducers and the anti-ferroptosis effects of the high-fat diet were further validated using the mouse xenograft model. CONCLUSIONS: ACSL4 plays a tumor-suppressive role in lung adenocarcinoma by suppressing tumor survival/invasiveness and promoting ferroptosis. Our study provided a theoretical reference for the application of ferroptotic inducers and dietary guidance for lung adenocarcinoma patients.

Deciphering the structure, function, expression and regulation of aquaporin-5 in cancer evolution.

In recent years, the morbidity rate resulting from numerous types of malignant tumor has increased annually, and the treatment of tumors has been attracting an increasing amount of attention. A number of recent studies have revealed that the water channel protein aquaporin-5 (AQP5) has become a major player in multiple types of cancer. AQP5 is abnormally expressed in a variety of tumor tissues or cells and has multiple effects on certain biological functions of tumors, such as regulating the proliferation, apoptosis and migration of tumor cells. It has been suggested that AQP5 may play an important role in the process of tumor development, opening up a new field of tumor research. The present review highlighted the structure of AQP5 and its role in tumor progression. Furthermore, the expression of AQP5 in different malignant neoplasms was summarized. In addition, the influence of not only drugs, but also different compounds on AQP5 were summarized. In conclusion, according to the findings in the present review, AQP5 has potential as a novel therapeutic target in human cancer, and other AQPs should be similarly investigated.