Hypoxia-preconditioned bone marrow-derived mesenchymal stem cells protect neurons from cardiac arrest-induced pyroptosis.

JOURNAL/nrgr/04.03/01300535-202504000-00027/figure1/v/2024-07-06T104127Z/r/image-tiff Cardiac arrest can lead to severe neurological impairment as a result of inflammation, mitochondrial dysfunction, and post-cardiopulmonary resuscitation neurological damage. Hypoxic preconditioning has been shown to improve migration and survival of bone marrow-derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest, but the specific mechanisms by which hypoxia-preconditioned bone marrow-derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown. To this end, we established an in vitro co-culture model of bone marrow-derived mesenchymal stem cells and oxygen-glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis, possibly through inhibition of the MAPK and nuclear factor κB pathways. Subsequently, we transplanted hypoxia-preconditioned bone marrow-derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia. The results showed that hypoxia-preconditioned bone marrow-derived mesenchymal stem cells significantly reduced cardiac arrest-induced neuronal pyroptosis, oxidative stress, and mitochondrial damage, whereas knockdown of the liver isoform of phosphofructokinase in bone marrow-derived mesenchymal stem cells inhibited these effects. To conclude, hypoxia-preconditioned bone marrow-derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest, and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.

Characteristics of atypical Pulmonary Tuberculosis without typical clinical features diagnosed by pathology.

PURPOSE: Some patients with pulmonary tuberculosis (PTB) do not display typical clinical features, leading to delays in diagnosis and treatment. METHODS: We retrospectively analyzed PTB patients admitted to the Second Affiliated Hospital of Chongqing Medical University between 2017 and 2020. They are divided into pathological group (diagnosed through pathological biopsy) and control group (diagnosed via sputum or lavage fluid). Clinical data of both groups were compared. Based on radiographic features, the pathological group was further divided into the inflammation group, peripheral nodule group, and central occupancy group. We then statistically analyzed the computed tomography (CT) signs, bronchoscopic manifestations and results of pathological biopsy for each subgroup. RESULTS: The pathological group consisted of 75 patients, while the control group had 338 patients. Multivariate logistic regression analysis showed that the pathological group had more diabetes (OR = 3.266, 95% CI = 1.609-6.630, P = 0.001), lower ESR (OR = 0.984, 95% CI = 0.971-0.998, P = 0.022), and lower CRP (OR = 0.990, 95% CI = 0.980-0.999, P = 0.036). In the three subgroups, the exudative lesions in the inflammation group were mostly located in atypical areas of PTB. The lobulation sign and spiculation sign were frequently observed in the peripheral nodule group. All presented with significant hilar mediastinal lymphadenopathy in the central occupancy group. In the pathological group, bronchoscopic manifestations typically included mucosal edema and bronchial stenosis. CONCLUSION: Diabetes is an independent risk factor for atypical PTB. Expression of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in atypical PTB is low. Radiologically, it is most easily misdiagnosed when presented as peripheral solid nodules or masses, so a biopsy is recommended.

Treatment of primary epididymal adenocarcinoma: a case report and review of the literature.

BACKGROUND: Epididymal tumors, especially malignant tumors, have low incidence and are rare in our clinical work. However, they may progress quickly and have poor prognosis. For such rare clinical cases with extremely low incidence rates, and as they are prone to misdiagnosis and missed diagnosis and have a very poor prognosis, clinical workers need to pay special attention and consider the possibility of primary epididymal malignant tumors. CASE REPORT: A 63-year-old Chinese male patient from Asia was admitted due to scrotal pain. Upon examination, an abnormal lesion was found in the right epididymal region. After thorough evaluation, surgical resection was performed, and the postoperative pathological result confirmed the presence of epididymal adenocarcinoma. After further ruling out secondary lesions, primary epididymal adenocarcinoma was considered. Right retroperitoneal lymph node dissection was performed under laparoscopic for treatment, and 1/11 lymph node metastasis was detected after surgery. The patient is currently under close follow-up. CONCLUSIONS: The number of clinical cases of primary epididymal malignant tumors is very limited, there is currently no standardized diagnosis and treatment process, and there is a lack of systematic evaluation methods regarding the effectiveness of different treatment options such as chemotherapy, radiotherapy, immunotherapy, and targeted therapy. In addition, the outcome is difficult to predict. In this article, we reviewed relevant literature and systematically elaborated on the diagnosis and treatment of epididymal malignant tumors, hoping to provide useful information for relevant experts.

Serum IgA as a Prognostic Beacon: Anticipating Systemic Therapy Efficacy in Metastatic Clear Cell Renal Cell Carcinoma.

OBJECTIVE: Immunotherapy-tyrosine kinase inhibitor (IO-TKI) therapy has revolutionized the treatment landscape for metastatic clear cell renal cell carcinoma (mccRCC); however, the absence of effective biomarkers poses a challenge in predicting the efficacy of these regimens. This study aims to explore the predictive and prognostic value of serum immunoglobulin A (IgA) in mccRCC patients undergoing IO-TKI therapy. METHODS: Ninety-six mccRCC patients treated with IO-TKI therapy from 2019 to 2023 were enrolled and serum IgA levels were assessed at the pretreatment baseline and after 3 months of treatment. RESULTS: Notably, baseline levels of IgA showed no correlation with the objective response rate. However, patients achieving complete or partial responses exhibited a remarkable decrease in IgA levels, while those with stable or progressive disease displayed an increase in IgA levels after 3 months of treatment. Furthermore, the dynamic alteration in IgA levels after 3 months of treatment demonstrated predictive value for both progression-free survival (PFS) and overall survival (OS). The time-dependent receiver operating characteristic curves exhibited outstanding performance in predicting PFS (AUC 0.793) and OS (AUC 0.738). CONCLUSION: Taken together, this study demonstrates that dynamic alteration of serum IgA after 3 months of treatment was significantly correlated with prognosis and therapeutic efficacy in mccRCC patients.

Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosis.

The damage of integrated epithelial epithelium is a key pathogenic factor and closely associated with the recurrence of ulcerative colitis (UC). Here, we reported that vanillic acid (VA) exerted potent therapeutic effects on DSS-induced colitis by restoring intestinal epithelium homeostasis via the inhibition of ferroptosis. By the CETSA assay and DARTS assay, we identified carbonic anhydrase IX (CAIX, CA9) as the direct target of VA. The binding of VA to CA9 causes insulin-induced gene-2 (INSIG2) to interact with stromal interaction molecule 1 (STIM1), rather than SREBP cleavage-activating protein (SCAP), leading to the translocation of SCAP-SREBP1 from the endoplasmic reticulum (ER) to the Golgi apparatus for cleavage into mature SREBP1. The activation of SREBP1 induced by VA then significantly facilitated the transcription of stearoyl-CoA desaturase 1 (SCD1) to exert an inhibitory effect on ferroptosis. By inhibiting the excessive death of intestinal epithelial cells caused by ferroptosis, VA effectively preserved the integrity of intestinal barrier and prevented the progression of unresolved inflammation. In conclusion, our study demonstrated that VA could alleviate colitis by restoring intestinal epithelium homeostasis through CA9/STIM1-mediated inhibition of ferroptosis, providing a promising therapeutic candidate for UC.

Prognosis of uterine and extrauterine low-grade endometrial stromal sarcoma: an observational cohort study.

OBJECTIVE: Little is known about the survival differences between uterine and extrauterine low-grade endometrial stromal sarcoma (LGESS). Survival outcomes, consisting of disease-free survivals and overall survivals (OS), were compared in these two entities. METHODS: From February 2012 to June 2019, all primary LGESS cases and LGESS cases with first recurrence in the study center were reviewed. The clinicopathological characteristics and survival outcomes of extrauterine and uterine LGESS patients were compared for both primary and recurrent diseases. RESULTS: During the study period, 143 patients with primary LGESS and 56 patients with recurrent LGESS were included and followed up to 1 June 2020, among whom 8 (5.6%) and 10 (17.8%) patients were identified as having extrauterine LGESS. Patients with primary and recurrent extrauterine LGESS had similar clinicopathological characteristics to those of patients with uterine LGESS. In primary or in recurrent LGESS cases, in univariate analysis, patients with uterine and extrauterine LGESS had similar disease-free intervals after the last treatment, and they also had similar OSs after the diagnosis. Ovarian preservation led to significantly increased recurrence for primary LGESS [hazard ratio (HR) 4.9, 95% CI: 2.3-10.1, P <0.001) and repeated recurrence for recurrent LGESS (HR 3.1, 95% CI: 1.3-7.3, P =0.009). Surgical treatment for recurrent LGESS decreased repeated recurrence after the first recurrence (HR 0.2, 95% CI: 0.1-0.7, P =0.006). No factors were found to be associated with the OS of primary or recurrent LGESS. CONCLUSION: The clinical characteristics and survival outcomes of extrauterine LGESS are similar to those of uterine LGESS. Surgery is the treatment of choice for recurrent LGESS. Ovarian preservation is detrimental to disease-free survival but not to OS in both uterine and extrauterine LGESS.

Cronkhite‒Canada syndrome as inflammatory hamartomatous polyposis: new evidence from whole transcriptome sequencing of colonic polyps.

BACKGROUND: Cronkhite-Canada syndrome (CCS) is a rare, nonhereditary disease characterized by diffuse gastrointestinal polyposis and ectodermal abnormalities. Although it has been proposed to be a chronic inflammatory condition, direct evidence of its pathogenesis is lacking. This study aims to investigate the pathophysiology of CCS by analyzing transcriptomic changes in the colonic microenvironment. METHODS: Next-generation sequencing-based genome-wide transcriptional profiling was performed on colonic hamartomatous polyps from four CCS patients and normal colonic mucosa from four healthy volunteers. Analyses of differential expression and multiple enrichment analyses were conducted from the molecular level to the cellular level. Quantitative real-time PCR (qRT-PCR) was carried out to validate the sequencing accuracy in samples from six CCS patients and six healthy volunteers. RESULTS: A total of 543 differentially expressed genes were identified, including an abundance of CC- and CXC-chemokines. Innate immune response-related pathways and processes, such as leukocyte chemotaxis, cytokine production, IL-17, TNF, IL-1 and NF-kB signaling pathways, were prominently enhanced in CCS colonic polyps. Upregulation of wound healing, epithelial-mesenchymal transition, Wnt, and PI3K-Akt signaling pathways were also observed. Enrichment analyses at different levels identified extracellular structure disorganization, dysfunction of the gut mucosal barrier, and increased angiogenesis. Validation by qRT-PCR confirmed increased expression of the LCN2, IL1B, CXCL1, and CXCL3 genes in CCS colonic polyps. CONCLUSIONS: This case-control whole transcriptome analysis of active CCS colonic hamartomatous polyps revealed intricate molecular pathways, emphasizing the role of the innate immune response, extracellular matrix disorganization, inflammatory cell infiltration, increased angiogenesis, and potential epithelial to mesenchymal transition. These findings supports CCS as a chronic inflammatory condition and sheds light on potential therapeutic targets, paving the way for more effective and personalized management of CCS in the future.

Microwave-responsive gadolinium metal-organic frameworks nanosystem for MRI-guided cancer thermotherapy and synergistic immunotherapy.

The clinical application of cancer immunotherapy is unsatisfied due to low response rates and systemic immune-related adverse events. Microwave hyperthermia can be used as a synergistic immunotherapy to amplify the antitumor effect. Herein, we designed a Gd-based metal-organic framework (Gd-MOF) nanosystem for MRI-guided thermotherapy and synergistic immunotherapy, which featured high performance in drug loading and tumor tissue penetration. The PD-1 inhibitor (aPD-1) was initially loaded in the porous Gd-MOF (Gd/M) nanosystem. Then, the phase change material (PCM) and the cancer cell membrane were further sequentially modified on the surface of Gd/MP to obtain Gd-MOF@aPD-1@CM (Gd/MPC). When entering the tumor microenvironment (TME), Gd/MPC induces immunogenic death of tumor cells through microwave thermal responsiveness, improves tumor suppressive immune microenvironment and further enhances anti-tumor ability of T cells by releasing aPD-1. Meanwhile, Gd/MPC can be used for contrast-enhanced MRI. Transcriptomics data revealed that the downregulation of MSK2 in cancer cells leads to the downregulation of c-fos and c-jun, and ultimately leads to the apoptosis of cancer cells after treatment. In general, Gd/MPC nanosystem not only solves the problem of system side effect, but also achieves the controlled drug release via PCM, providing a promising theranostic nanoplatform for development of cancer combination immunotherapy.

Endoscopic and histopathological hints on infections in patients of common variable immunodeficiency disorder with gastrointestinal symptoms.

BACKGROUND AND AIMS: Common variable immunodeficiency disorder (CVID) patients may have gastrointestinal (GI) involvement and suffer from infections, which are poorly understood. This study aimed to evaluate the clinical, endoscopic, and histopathological features of CVID patients with GI symptoms and determine their correlation with infections. METHODS: We performed a retrospective study on 21 CVID patients with GI symptoms who underwent endoscopic examination in Peking Union Medical College Hospital from 2000 to 2020. The clinical, infectious, endoscopic, and histopathological features were reassessed. RESULTS: Chronic diarrhea was the most prevalent GI symptom, observed in 95.2% of our CVID cohort. Over 85% of patients had low body weight and malabsorption. Small bowel villous atrophy was found in 90.5% of patients under endoscopy and mostly confirmed by histopathology. GI infections were identified in 9 (42.9%) patients. Of these, 7 patients with diffuse and obvious nodular lymphoid hyperplasia (NLH) of small bowel under endoscopy had significantly higher infection rate (85.7% vs 21.4%, p < 0.05), predominantly with Giardia and bacteria. Small bowel biopsies showed 95% of patients lacked plasma cells and 60% had increased intraepithelial lymphocytes (IELs), but not significantly different between GI infection and non-infection group. Most patients improved after intravenous immunoglobulin and anti-infection therapy. CONCLUSIONS: CVID could involve GI tract, particularly small bowel. Obvious NLH under endoscopy could be a hint for GI infection in CVID patients. Comprehensive endoscopic and histopathological evaluation may be helpful in CVID diagnosis and identification of potential co-infection, leading to proper treatment.

Fusobacterium nucleatum-triggered neutrophil extracellular traps facilitate colorectal carcinoma progression.

BACKGROUND: Fusobacterium nucleatum (Fn) acts as a procarcinogenic bacterium in colorectal carcinoma (CRC) by regulating the inflammatory tumor microenvironment (TME). Neutrophil extracellular traps (NETs), which can be generated by persistent inflammation, have been recently considered to be significant contributors in promoting cancer progression. However, whether NETs are implicated in Fn-related carcinogenesis is still poorly characterized. Here, we explored the role of NETs in Fn-related CRC as well as their potential clinical significance. METHODS: Fn was measured in tissue specimens and feces samples from CRC patients. The expression of NET markers were also detected in tissue specimens, freshly isolated neutrophils and blood serum from CRC patients, and the correlation of circulating NETs levels with Fn was evaluated. Cell-based experiments were conducted to investigate the mechanism by which Fn modulates NETs formation. In addition, we clarified the functional mechanism of Fn-induced NETs on the growth and metastasis of CRC in vitro and in vivo experiments. RESULTS: Tissue and blood samples from CRC patients, particularly those from Fn-infected CRC patients, exhibited greater neutrophil infiltration and higher NETs levels. Fn infection induced abundant NETs production in in vitro studies. Subsequently, we demonstrated that Fn-induced NETs indirectly accelerated malignant tumor growth through angiopoiesis, and facilitated tumor metastasis, as manifested by epithelial-mesenchymal transition (EMT)-related cell migration, matrix metalloproteinase (MMP)-mediated basement membrane protein degradation, and trapping of CRC cells. Mechanistically, the Toll-like receptor (TLR4)-reactive oxygen species (ROS) signaling pathway and NOD-like receptor (NOD1/2)-dependent signaling were responsible for Fn-stimulated NETs formation. More importantly, circulating NETs combined with carcinoembryonic antigen (CEA) could predict CRC occurrence and metastasis, with areas under the ROC curves (AUCs) of 0.92 and 0.85, respectively. CONCLUSIONS: Our findings indicated that Fn-induced NETs abundance by activating TLR4-ROS and NOD1/2 signalings in neutrophils facilitated CRC progression. The combination of circulating NETs and CEA was identified as a novel screening strategy for predicting CRC occurrence and metastasis.

Calcineurin inhibitors or cyclophosphamide in the treatment of membranous nephropathy superimposed with FSGS lesions: a retrospective study from China.

BACKGROUND: Cyclophosphamide (CTX) and calcineurin inhibitors (CNIs) based regimens are recommended as immunosuppressive therapies for patients with idiopathic membranous nephropathy (IMN). Focal and segmental glomerular sclerosis (FSGS) lesions, which are common in membranous nephropathy (MN), are poor predictors of outcome. This study compared the differences of prognosis between two regimens in patients with IMN combined with FSGS lesions. METHODS: This retrospective study enrolled 108 patients with biopsy-proven IMN, accompanied with FSGS lesions, nephrotic syndrome and an estimated glomerular filtration rate (eGFR)≥60 mL/min/1.73 m2 who were treated with CTX or CNIs. We used propensity score matching (PSM) for balancing the confounding variables. RESULTS: During follow-up, 10 patients (10/55 [18.2%]; nine males) in the CNIs group showed a 50% decline in eGFR; eight had a not otherwise specified variant. Patients initially treated with CNIs had a significantly higher risk of progression to the primary outcome and a lower probability of complete or total remission. The relapse rate was higher in patients who initially received CNIs- than in those who received CTX-based treatment. Before PSM, age and 24-h urine protein level differed significantly between the groups. The PSM model included data from 72 patients. Worse outcomes were also noted among patients who initially received CNIs than those who received CTX-based treatments after matching. CONCLUSIONS: Patients with MN combined with FSGS lesions have a higher risk of renal functional decline and a higher rate of relapse after CNIs than after CTX therapy.

Cytological DNA methylation for cervical cancer screening: a validation set.

Background: In a previous training set with a case-controlled design, cutoff values for host EPB41L3 and JAM3 gene methylation were obtained for the detection of cervical intraepithelial neoplasia (CIN) 2 or more severe lesions (CIN2+). This validation trial was conducted to evaluate the role of DNA methylation in screening for CIN2+ by cervical cytology among unselected participants. Methods: From June 1, 2019, to September 1, 2019, in our study center, we collected liquid-based samples from cervical swabs for methylation assays and hrHPV testing in eligible patients. The primary endpoint was the diagnostic accuracy of DNA methylation and hrHPV genotyping for CIN2+ according to confirmed histology results. Results: Among 307 participants, compared with hrHPV testing, the methylation assay for CIN2+ had lower sensitivity (68.7% versus 86.1%, p=0.002) but higher specificity (96.7% versus 0.696, p<0.001). The methylation assay also had favorable sensitivity and specificity in patients with negative hrHPV testing (56.3% and 96.9%) and in patients with cervical adenocarcinoma (73.7% and 92.7%). DNA methylation had higher specificity than the hrHPV assay (100.0% versus 44.4%, p<0.001) for identifying residual CIN2+ in patients without residual lesions. Positive cervical DNA methylation was associated with a diagnostic probability of endometrial carcinoma (odds ratio 15.5 [95% confidence interval 4.1-58.6]) but not of ovarian epithelial carcinoma (1.4 [0.3-6.5]). Conclusions: The host EPB41L3 and JAM3 gene methylation assay in cervical cytology had favorable diagnostic accuracy for CIN2+ and was highly specific for residual CIN2+ lesions The methylation assay is a promising triage tool in hrHPV+ women, or even an independent tool for cervical cancer screening. The methylation status in cervical cytology could also serve as a prognostic biomarker. Its role in detecting endometrial carcinomas is worthy of further exploration.

Endoscopic features help to identify the histopathological patterns of colorectal polyps in Cronkhite-Canada syndrome.

OBJECTIVES: Cronkhite-Canada syndrome (CCS) is a rare nonhereditary gastrointestinal hamartomatous polyposis syndrome with a high risk of colorectal cancerogenesis. It is challenging to discriminate adenomas from nonneoplastic colorectal polyps macroscopically. This study aimed to explore the endoscopic features of different histopathological patterns of colorectal polyps in CCS. METHODS: Sixty-seven lesions from 23 CCS patients were prospectively biopsied or resected during the colonoscopic examination for histopathological analysis. The Fisher's exact test and multivariate logistical analysis were conducted to reveal the predictive endoscopic features of CCS polyps with low-grade dysplasia (LGD) and adenomas. RESULTS: There were seven (10.4%) adenomas, 20 (29.9%) CCS-LGD, and 40 (59.7%) nonneoplastic CCS polyps. Polyps were large (>20 mm) in none of the adenomas, 30.0% of CCS-LGD polyps, and 2.5% of nonneoplastic CCS polyps (P < 0.001). The color of the polyps was whitish for 71.4% of adenomas, 10.0% of CCS-LGD polyps, and 15.0% of nonneoplastic CCS polyps (P = 0.004). Pedunculated polyps were detected in 42.9% of adenomas, 45.0% of CCS-LGD polyps, and 5.0% of nonneoplastic CCS polyps (P < 0.001). The proportions of types IV and VI in the Kudo classification were 42.9%, 95.0%, and 35.0% in adenomatous, CCS-LGD, and nonneoplastic CCS polyps, respectively (P = 0.002). The endoscopic activity was in remission for 71.4% of adenomas, 5.0% of CCS-LGD polyps, and 10.0% of nonneoplastic CCS polyps (P < 0.001). CONCLUSION: Endoscopic features, including the size, color, sessility, Kudo's pit pattern classification of polyps, and endoscopic activity, help identify the histopathological patterns of colorectal polyps in CCS.

Pulmonary benign metastasizing leiomyoma in patients aged 45 years and younger: clinical features and novelty in treatment.

BACKGROUND: Pulmonary benign metastasizing leiomyoma (PBML) is the most common extrauterine spread of uterine leiomyoma, and its biological behavior is traditionally thought to be hormone dependent. Studies on older PBML patients have been previously reported, but limited literature has been published regarding the clinical features and treatment of PBML in young women. METHODS: A total of 65 cases of PBML in women aged 45 years and younger were reviewed, including 56 cases selected from PubMed and 9 cases from our hospital. The clinical characteristics and management of these patients were analyzed. RESULTS: The median age of all the patients at diagnosis was 39.0 years. PBML most commonly presented as bilateral solid lesions (60.9%), with other rare imaging manifestations. The median interval time from a pertinent gynecologic procedure to diagnosis was 6.0 years. A total of 16.7% of patients received careful observation, and all achieved stable status in a median follow-up time of 18.0 months. A total of 71.4% of patients were administered anti-estrogen therapies, including surgical castration (33.3%), gonadotropin-releasing hormone analog (23.8%) and anti-estrogen drugs (14.3%). Eight of 42 patients underwent surgical resection of metastatic lesions. Patients who underwent curative surgery for the removal of pulmonary lesions combined with adjuvant anti-estrogen therapies had favorable outcomes compared with those who only underwent surgical resection. The disease control rates of surgical castration, gonadotropin-releasing hormone analog, and anti-estrogen drugs were 85.7%, 90.0%, and 50.0%, respectively. For two patients, sirolimus (rapamycin) achieved successful relief of symptoms and control of pulmonary lesions without lowering hormone levels and causing estrogen deficiency symptoms. CONCLUSIONS: In the absence of standard treatment guidelines for PBML, maintaining a low-estrogen environment using different kinds of antiestrogen therapies has been the mainstream strategy and has satisfying curative effects. A wait-and-see strategy might be an option, but therapeutic approaches must be contemplated when complications or symptoms progress. For PBML in young women, the negative effect on ovarian function of anti-estrogen treatment, especially surgical castration, should be considered. Sirolimus might be a new treatment option for young PBML patients, especially for those who want to preserve ovarian function.

Hypoxic preconditioned mesenchymal stem cells ameliorate rat brain injury after cardiopulmonary resuscitation by suppressing neuronal pyroptosis.

Cardiac arrest (CA) can result in cerebral ischaemia-reperfusion injury and poor neurological outcomes. While bone marrow-derived mesenchymal stem cells (BMSCs) have been shown to have protective effects in brain ischaemic disease, their efficacy can be reduced by the poor oxygen environment. In this study, we investigated the neuroprotective effects of hypoxic preconditioned BMSCs (HP-BMSCs) and normoxic BMSCs (N-BMSCs) in a cardiac arrest rat model by examining their ability to ameliorate cell pyroptosis. The mechanism underlying the process was also explored. Cardiac arrest was induced in rats for 8 min and surviving rats received 1 × 106 normoxic/hypoxic BMSCs or PBS via intracerebroventricular (ICV) transplantation. Neurological function of rats was evaluated using neurological deficit scores (NDSs) and examined for brain pathology. Serum S100B and neuron-specific enolase (NSE) levels and cortical proinflammatory cytokines were measured to evaluate brain injury. Pyroptosis-related proteins in the cortex after cardiopulmonary resuscitation (CPR) were measured using western blotting and immunofluorescent staining. Transplanted BMSCs were tracked using bioluminescence imaging. Results showed significantly better neurological function and neuropathological damage after transplantation with HP-BMSCs. In addition, HP-BMSCs reduced levels of pyroptosis-related proteins in the rat cortex after CPR and significantly reduced levels of biomarkers for brain injury. Mechanistically, HP-BMSCs alleviated brain injury by reducing the expressions of HMGB1, TLR4, NF-κB p65, p38 MAPK and JNK in the cortex. Our study demonstrated that hypoxic preconditioning could enhance the efficacy of BMSCs in alleviating post-resuscitation cortical pyroptosis. This effect may be related to the regulation of the HMGB1/TLR4/NF-κB, MAPK signalling pathways.

Research trends and prospects on brain metastasis from breast cancer: A bibliometric analysis.

Introduction: Brain metastasis is the terminal event of breast cancer with poor prognoses. Therefore, this article aimed to provide an updated summary on the development, hotspots, and research trends of brain metastasis from breast cancer based on bibliometric analysis. Method: Publications on breast cancer with brain metastasis retrieved from the Web of Science Core Collection. CiteSpace, VOSviewer, and other online bibliometric analysis platforms were used to analyze and visualize the result. Result: In totality, 693 researchers from 3,623 institutions across 74 counties and regions published a total of 2,790 papers in 607 journals. There was a noticeable increase in publications in 2006. The United States was the dominant country with the most publications followed by China. University Texas MD Anderson Cancer Center was the most productive institution, while Dana Farber Cancer Institution was the most cited. Journal of Neuro-Oncology published the most papers, while Journal of Clinical Oncology ranked first based on cocited analysis. Nancy U. Lin was the most productive and cited author with high influence. There was a focus on basic research, clinical trials, local therapy, treatment optimization, and epidemiological studies regarding brain metastases from breast cancer. References focused on pathogenesis, prevention, treatment, and prognosis were cited most frequently, among which the clinical trial of novel treatment attracted most attention from researchers. Reference citation burst detection suggested that new therapies such as the novel tyrosine kinase inhibitor and antibody-drug conjugate may lead the research trends in the future. Conclusion: High-income countries contributed more to the field of breast cancer with brain metastasis, while developing countries like China developed quickly. Furthermore, the success of novel therapies in recent years may lead to the new era of treatment of breast cancer with brain metastasis in the future.

Global burden of common cancers attributable to metabolic risks from 1990 to 2019.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is usually accompanied by metabolic syndrome, which is associated with increased risk of cancer. To inform a tailored cancer screen in patients at higher risks, we estimated the global burden of cancer attributable to metabolic risks. METHODS: Data of common metabolism-related neoplasms (MRNs) were derived from the Global Burden of Disease (GBD) 2019 database. Age-standardized, disability-adjusted life year (DALY) rates and death rates of patients with MRNs were extracted from the GBD 2019 database and stratified by metabolic risk, sex, age, and level of socio-demographic index (SDI). The annual percentage changes of age-standardized DALYs and death rates were calculated. FINDINGS: Metabolic risks, consisting of high body mass index and fasting plasma glucose, contributed substantially to the burden of neoplasms, including colorectal cancer (CRC), tracheal, bronchus, and lung cancer (TBLC), etc. Globally, in 2019, there was an estimated age-standardized DALY rate (ASDR) of 234 (95% confidence interval [CI] 124-376) per 100,000 person years for neoplasms attributable to metabolic risks. ASDRs of MRNs were higher for CRC, TBLC, men, patients aged ≥50 years, and patients with high or high-middle SDI. CONCLUSIONS: The findings of this study further underpin the correlation between NAFLD and intrahepatic and extrahepatic cancers and highlight the possibility of tailored cancer screening for the NAFLD population at higher risks. FUNDING: This work was supported by the National Natural Science Foundation of China and Natural Science Foundation of Fujian Province of China.

Expression of DDB1 is associated with subtypes of epithelial ovarian cancer and predicts clinical outcomes.

BACKGROUND: Ovarian cancer is the most lethal gynaecological malignancy. Damage specific DNA-binding protein 1 (DDB1) functions in nucleotide-excision repair and has been reported to be involved in cancer development. In this study, we aimed to determine the expression levels of DDB1 and their association with the clinical outcomes of patients with ovarian cancer. METHODS: Tissue arrays were performed on 54 epithelial ovarian cancer (EOC) samples. Immunohistochemistry was performed to determine DDB1 expression. DDB1 expression levels among different EOC subtypes were analysed via one-way analysis of variance using SPSS Statistics 19.0. Correlation between DDB1 expression and chemotherapy course/progression-free survival (PFS) of patients was determined via Kaplan-Meier survival analysis using GraphPad Prism 5. Moreover, knockdown of DDB1 in ovarian cancer cells ES2 and OVCAR3 was used to preliminarily validate the role of DDB1. RESULTS: DDB1 was detected in the cytoplasm, especially in the nucleus, of all subtypes of EOC. However, DDB1 expression levels were significantly different between clear cell carcinoma and low-grade serous carcinoma (P = 0.022) and clear cell carcinoma and endometrioid cancer (P = 0.016). In addition, DDB1 expression was not significantly correlated with chemotherapy course (P = 0.433) or PFS (P = 0.566). High expression levels of DDB1 were correlated with significantly worse overall survival (P = 0.017) in patients with EOC. In addition, DDB1 knockdown in ovarian cancer cells decreased their proliferation in vitro. CONCLUSION: Our results revealed that DDB1 expression is heterogeneous in ovarian cancer, suggesting its use as a potential biomarker for poor survival in ovarian cancer.