CARMA3 Drives NF-κB Activation and Promotes Intervertebral Disc Degeneration: Involvement of CARMA3-BCL10-MALT1 Signalosome.

Intervertebral disc degeneration (IDD) diseases are common and frequent diseases in orthopedics. The caspase recruitment domain (CARD) and membrane-associated guanylate kinase-like protein 3 (CARMA3) is crucial in the activation of the NF-κB pathway. However, the biological function of CARMA3 in IDD remains unknown. Here, CARMA3 expression was elevated in nucleus pulposus (NP) tissues of IDD rats and nutrient deprivation (ND)-induced NP cells. The main pathological manifestations observed in IDD rats were shrinkage of the NP, reduction of NP cells, fibrosis of NP tissues, and massive reduction of proteoglycans. These changes were accompanied by a decrease in the expression of collagen II and aggrecan, an increase in the expression of the extracellular matrix (ECM) catabolic proteases MMP-3, MMP-13, and metalloprotease with ADAMTS-5, and an increase in the activity of the pro-apoptotic protease caspase-3. The expression of p-IκBαSer32/36 and p-p65Ser536 was also upregulated. However, these effects were reversed with the knockdown of CARMA3. Mechanistically, CARMA3 bound to BCL10 and MALT1 to form a signalosome. Knockdown of CARMA3 reduced the CARMA3-BCL10-MALT1 signalosome-mediated NF-κB activation. CARMA3 activated the NF-κB signaling pathway in a manner that bound to BCL10 and MALT1 to form a signalosome, which affects NP cell damage and is involved in the development of IDD. This supports CARMA3-BCL10-MALT1-NF-κB as a promising targeting axis for the treatment of IDD.

[Comparison of effectiveness between unilateral biportal endoscopic decompression and unilateral biportal endoscopic lumbar interbody fusion for degree â degenerative lumbar spondylolisthesis].

Objective: To compare the effectiveness of unilateral biportal endoscopic decompression and unilateral biportal endoscopic lumbar interbody fusion (ULIF) in the treatment of degreeⅠdegenerative lumbar spondylolisthesis (DLS). Methods: A clinical data of 58 patients with degreeⅠDLS who met the selection criteria between October 2021 and October 2022 was retrospectively analyzed. Among them, 28 cases were treated with unilateral biportal endoscopic decompression (decompression group) and 30 cases with ULIF (ULIF group). There was no significant difference between the two groups ( P>0.05) in the gender, age, lesion segment, and preoperative visual analogue scale (VAS) score of low back pain, VAS score of leg pain, Oswestry disability index (ODI), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), disk height (DH), segmental lordosis (SL), and other baseline data. The operation time, postoperative drainage volume, postoperative ambulation time, VAS score of low back pain, VAS score of leg pain, ODI, laboratory examination indexes (CRP, ESR), and imaging parameters (DH, SL) were compared between the two groups. Results: Compared with the ULIF group, the decompression group had shorter operation time, less postoperative drainage, and earlier ambulation ( P<0.05). All incisions healed by first intention, and no complication such as nerve root injury, epidural hematoma, or infection occurred. All patients were followed up 12 months. Laboratory tests showed that ESR and CRP at 3 days after operation in decompression group were not significantly different from those before operation ( P>0.05), while the above indexes in ULIF group significantly increased at 3 days after operation compared to preoperative values ( P<0.05). There were significant differences in the changes of ESR and CRP before and after operation between the two groups ( P<0.05). Except that the VAS score of low back pain at 3 days after operation was not significantly different from that before operation in decompression group ( P>0.05), there were significant differences in VAS score of low back pain and VAS score of leg pain between the two groups at other time points ( P<0.05). The VAS score of low back pain in ULIF group was significantly higher than that in decompression group at 3 days after operation ( P<0.05), and there was no significant difference in VAS score of low back pain and VAS score of leg pain between the two groups at other time points ( P>0.05). The ODI of the two groups significantly improved after operation ( P<0.05), but there was no significant difference between 3 days and 6 months after operation ( P>0.05). There was no significant difference between the two groups at the two time points after operation ( P<0.05). Imaging examination showed that there was no significant difference in DH and SL between pre-operation and 12 months after operation in decompression group ( P>0.05). However, the above two indexes in ULIF group were significantly higher than those before operation ( P<0.05). There were significant differences in the changes of DH and SL before and after operation between the two groups ( P<0.05). Conclusion: Unilateral biportal endoscopic decompression can achieve good effectiveness in the treatment of degree Ⅰ DLS. Compared with ULIF, it can shorten operation time, reduce postoperative drainage volume, promote early ambulation, reduce inflammatory reaction, and accelerate postoperative recovery. ULIF has more advantages in restoring intervertebral DH and SL.

Utility of Wnt family member 9b (Wnt9b) immunohistochemistry in the cytologic diagnosis of metastatic breast carcinoma.

Wnt family member 9b (Wnt9b) has been demonstrated as a valuable marker for breast cancer diagnosis in surgical pathology. In this study, we examined the utility of Wnt9b in diagnosing metastatic breast carcinoma in cytology samples. Cell blocks from fine needle aspirations (FNA) and fluid specimens of 96 metastatic breast carcinomas and 123 primary and metastatic non-breast neoplasms from various organ systems were evaluated by Wnt9b and GATA3 immunohistochemistry (IHC). Wnt9b and GATA3 were positive in 81.3% and 92.7% of metastatic breast carcinomas, respectively. Conversely, 93.5% and 90.0% of non-breast, non-urothelial carcinomas were negative for Wnt9b and GATA3, respectively. Wnt9b expression was positive in rare gastrointestinal, gynecological, lung, pancreas, and salivary gland tumors. All twenty-eight urothelial carcinomas were negative for Wnt9b, while twenty-six (92.9%) were positive for GATA3. Wnt9b was slightly less sensitive but more specific than GATA3 in diagnosing metastatic breast cancer in cytology samples. Particularly, Wnt9b shows higher specificity in differentiating breast and urothelial primaries. The combined use of Wnt9b and GATA3 may increase diagnostic accuracy.

Co-treatment of diamond-wire-saw silicon kerf and spent automotive catalysts for simultaneous recovery of PGMs, REEs, Zr, and high-purity Si.

Spent automotive catalysts (SACs) and diamond-wire-saw silicon kerf (DWSSK) are classified as hazardous wastes. Currently, the two wastes are treated separately using unrelated approaches. More than two independent approaches are required to recover platinum group metals (PGMs), Zr and rare earth elements (REEs) from SACs, and recover Si from DWSSK, which is time-consuming and laborious. In this study, a new approach was proposed to co-treat the two wastes based on the concept of using waste treats waste: using DWSSK (∼89.85 wt% Si) as a new metal collector to extract PGMs, REEs, and Zr simultaneously from SACs to obtain a Si-VM alloy (VM: valuable metal); meanwhile, using the carrier of SACs to form molten slag to eliminate the main impurity, O, from DWSSK. The largest recovery ratios of Pd, Rh, Zr, Ce, La, and Nd from SACs were 99.50 ± 0.10%, 99.14 ± 0.14 %, 96.19 ± 0.76%, 67.18 ± 4.57%, 61.24 ± 4.93% and 47.65 ± 7.27%, respectively, and the largest removal ratio of O from DWSSK was 99.96%. After smelting, the Si-VM alloy was separated into high-purity Si and VM-containing acid solutions via acid leaching. The leaching ratios of Pd, Rh, Ce, La, Nd, and Zr were 99.78%, 98.15%, 99.93%, ∼100%, 99.76% and 99.98%, respectively. The purity of Si was upgraded from 89.85 wt% (in DWSSK) to 99.98 wt% after acid leaching. The new approach proposed in this study is considered more environmentally friendly and cost-effective than the regular approaches that treat the two wastes separately.

Triple-negative Breast Carcinoma With Apocrine and Histiocytoid Features: A Clinicopathologic and Molecular Study of 18 Cases.

Triple-negative breast cancer (TNBC) is a heterogenous group of tumors. Most TNBCs are high-grade aggressive tumors, but a minority of TNBCs are not high grade, with relatively indolent behavior and specific morphologic and molecular features. We performed a clinicopathologic and molecular assessment of 18 non-high-grade TNBCs with apocrine and/or histiocytoid features. All were grade I or II with low Ki-67 (≤20%). Thirteen (72%) showed apocrine features, and 5 (28%) showed histiocytoid and lobular features. In all, 17/18 expressed the androgen receptor, and 13/13 expressed gross cystic disease fluid protein 15. Four (22.2%) patients were treated with neoadjuvant chemotherapy, but none achieved a pathologic complete response. In all, 2/18 patients (11%) had lymph node metastasis at the time of surgery. None of the cases had a recurrence or disease-specific death, with an average follow-up time of 38 months. Thirteen cases were profiled by targeted capture-based next-generation DNA sequencing. Genomic alterations (GAs) were most significant for PI3K-PKB/Akt pathway (69%) genes, including PIK3R1 (23%), PIK3CA (38%), and PTEN (23%), and RTK-RAS pathway (62%) including FGFR4 (46%) and ERBB2 (15%). TP53 GA was seen in only 31% of patients. Our findings support those on high-grade TNBCs with apocrine and/or histiocytoid features as a clinicopathologic and genetically distinct subgroup of TNBC. They can be defined by features including tubule formation, rare mitosis, low Ki-67 (≤20%), triple-negative status, expression of androgen receptor and/or gross cystic disease fluid protein 15, and GA in the PI3K-PKB/Akt and/or RTK-RAS pathway. These tumors are not sensitive to chemotherapy but have favorable clinical behavior. Tumor subtype definitions are the first step to implementing future trial designs to select these patients.

Direct fabrication of NbS2 nanoflakes on carbon fibers by atomic layer deposition for ultrasensitive cardiac troponin I detection.

The sensitive detection of cardiac troponin I (cTnI) is of great significance for the early diagnosis of acute myocardial infarction (AMI). Herein, in order to fabricate an electrochemical biosensor for ultrasensitive cTnI detection, atomic layer deposition (ALD) was employed to directly deposit NbS2 nanoflakes (NFs) on carbon fiber paper (CFP). Due to the self-limiting reaction of ALD, NbS2NFs were deposited uniformly and accurately on the surface of carbon fibers by controlling the number of ALD cycles, which ensured ultrasensitive detection. Precise regulation of the nanoscale morphology and electrochemical performance of NbS2 nanoflakes via ALD cycles was observed in depth. Owing to the high surface area and conductivity, an anodic/cathodic current of ∼3.01 mA of NbS2NFs/CFP can be obtained. Subsequently, an electrochemical biosensor based on the excellent performance of NbS2NFs/CFP was fabricated. The ultrasensitive detection of cTnI in a linear range of 1 fM to 0.1 nM with a detection limit of 0.32 fM was achieved.

Atomic layer deposition (ALD)-constructed TaS2nanoflakes for cancer-related nucleolin detection.

Sensitive detection of nucleolin (NCL) is of great significance for the early diagnosis of cancer. In this work, as a new type of two-dimensional (2D) transition metal dichalcogenides (TMDCs), TaS2nanoflakes (NFs) were precisely constructed by atomic layer deposition (ALD) on carbon fiber paper (CFP) with high specific surface area.In situobservation showed that the nucleation and growth of TaS2nanoflakes were precisely controlled by the number of ALD cycles, thereby regulating their electrochemical properties. The electrochemical performance of TaS2NFs was observed in depth, and compared with that of traditional 2D TMDCs. Due to the high surface area and conductivity, anodic/cathodic current of ∼1570µA of TaS2NFs/CFP can be obtained. Subsequently, an electrochemical biosensor based on ALD-constructed TaS2NFs/CFP for cancer-related NCL detection was fabricated. Due to the excellent electrochemical performance of TaS2NFs/CFP, ultrasensitive detection of NCL in the linear range of 0.1 pM-10 nM with a detection limit of 0.034 pM was achieved.

Stem cell phenotype predicts therapeutic response in glioblastomas with MGMT promoter methylation.

A growing body of evidence supports the presence of a population of cells in glioblastoma (GBM) with a stem cell-like phenotype which shares certain biological markers with adult neural stem cells, including expression of SOX2, CD133 (PROM1), and NES (nestin). This study was designed to determine the relationship between the expression of these stem cell markers and the clinical outcome in GBM patients. We quantified the intensity of expression of the proteins CD133 and SOX2 by immunohistochemistry (IHC) in a cohort of 86 patients with IDH-wildtype GBM, and evaluated patient outcomes using Kaplan-Meier and Cox proportional hazards analysis. In our patients, MGMT promoter methylation status and age were predictors of overall survival and progression free survival. The levels of SOX2 and CD133 were not associated with outcome in univariate analysis; however, stratification of tumors based on low or high levels of CD133 or SOX2 expression revealed that MGMT methylation was a predictor of progression-free survival and overall survival only for tumors with high levels of expression of CD133 or SOX2. Tumors with low levels of expression of CD133 or SOX2 did not show any relationship between MGMT methylation and survival. This relationship between MGMT and stem cell markers was confirmed in a second patient cohort, the TCGA dataset. Our results show that stratification of GBM by the level of expression of CD133 and SOX2 improved the prognostic power of MGMT promoter methylation status, identifying a low-expressing group in which the clinical outcome is not associated with MGMT promoter methylation status, and a high-expressing group in which the outcome was strongly associated with MGMT promoter methylation status. These findings support the concept that the presence of a high stem cell phenotype in GBM, as marked by expression of SOX2 or CD133, may be associated with the clinical response to treatment.

Utility of secretagogin as a marker for the diagnosis of lung neuroendocrine carcinoma.

Small-cell lung cancers (SCLC) and large-cell neuroendocrine carcinomas (LCNEC) are two types of high-grade pulmonary neuroendocrine carcinomas (NECs). Diagnostic neuroendocrine markers commonly include synaptophysin, chromogranin A, CD56, and insulinoma-associated protein 1 (INSM1). In this study, the utility of secretagogin (SCGN) was examined in the context of pulmonary NEC diagnosis. The study included 71 pulmonary NEC cases (18 SCLCs, 13 combined-SCLCs, 23 LCNECs, and 17 combined-LCNECs). Immunohistochemical stains of SCGN, synaptophysin, chromogranin A, CD56, and INSM1 were performed on whole tumor sections. The stains were evaluated based on combined staining intensity and the proportion of positive tumor cells. At least mild staining intensity in at least 1% of the cells was considered positive. Bioinformatic studies showed specific SCGN expression in neuroendocrine cells and NECs. SCGN showed diffuse nuclear and cytoplasmic staining in NECs with intra-tumoral heterogeneity. The non-neuroendocrine components were negative. The sensitivity of SCGN was no better than the other established neuroendocrine markers based on all NECs combined or LCNECs/c-LCNECs only. However, the sensitivity of SCGN (71%) was higher than chromogranin A (68%) for SCLCs/c-SCLCs only. The average proportion of SCGN positive tumor cells was 8% higher than chromogranin A (22% versus 14%, P = 0.0332) in all NECs and 18% higher for SCLC and c-SCLC cases only (32% versus 13%, P = 0.0054). The above data showed that SCGN could be used as a supplemental neuroendocrine marker to diagnose SCLC.

Diagnosis and Treatment of Cervical Spondylotic Radiculopathy Using Selective Nerve Root Block (SNRB): Where are We Now?

Cervical spondylotic radiculopathy (CSR) is one of the most common degenerative diseases of the spine that is commonly treated with surgery. The primary goal of surgery is to relieve symptoms through decompression or relieving pressure on compressed cervical nerves. Nevertheless, cutaneous pain distribution is not always predictable, making accurate diagnosis challenging and increasing the likelihood of inadequate surgical outcomes. With the widespread application of minimally invasive surgical techniques, the requirement for precise preoperative localization of the affected segments has become critical, especially when treating patients with multi-segmental CSR. Recently, the preoperative use of a selective nerve root block (SNRB) to localize the specific nerve roots involved in CSR has increased. However, few reviews discuss the currently used block approaches, risk factors, and other aspects of concern voiced by surgeons carrying out SNRB. This review summarized the main cervical SNRB approaches currently used clinically and the relevant technical details. Methods that can be used to decrease risk during cervical SNRB procedures, including choice of steroids, vessel avoidance, guidance with radiographs or ultra-sound, contrast agent usage, and other concerns, also are discussed. We concluded that a comprehensive understanding of the current techniques used for cervical SNRB would allow surgeons to perform cervical SNRB more safely.

Somatic mutations in collagens are associated with a distinct tumor environment and overall survival in gastric cancer.

BACKGROUND: Gastric cancer is a heterogeneous disease with poorly understood genetic and microenvironmental factors. Mutations in collagen genes are associated with genetic diseases that compromise tissue integrity, but their role in tumor progression has not been extensively reported. Aberrant collagen expression has been long associated with malignant tumor growth, invasion, chemoresistance, and patient outcomes. We hypothesized that somatic mutations in collagens could functionally alter the tumor extracellular matrix. METHODS: We used publicly available datasets including The Tumor Cancer Genome Atlas (TCGA) to interrogate somatic mutations in collagens in stomach adenocarcinomas. To demonstrate that collagens were significantly mutated above background mutation rates, we used a moderated Kolmogorov-Smirnov test along with combination analysis with a bootstrap approach to define the background accounting for mutation rates. Association between mutations and clinicopathological features was evaluated by Fisher or chi-squared tests. Association with overall survival was assessed by Kaplan-Meier and the Cox-Proportional Hazards Model. Gene Set Enrichment Analysis was used to interrogate pathways. Immunohistochemistry and in situ hybridization tested expression of COL7A1 in stomach tumors. RESULTS: In stomach adenocarcinomas, we identified individual collagen genes and sets of collagen genes harboring somatic mutations at a high frequency compared to background in both microsatellite stable, and microsatellite instable tumors in TCGA. Many of the missense mutations resemble the same types of loss of function mutations in collagenopathies that disrupt tissue formation and destabilize cells providing guidance to interpret the somatic mutations. We identified combinations of somatic mutations in collagens associated with overall survival, with a distinctive tumor microenvironment marked by lower matrisome expression and immune cell signatures. Truncation mutations were strongly associated with improved outcomes suggesting that loss of expression of secreted collagens impact tumor progression and treatment response. Germline collagenopathy variants guided interpretation of impactful somatic mutations on tumors. CONCLUSIONS: These observations highlight that many collagens, expressed in non-physiologically relevant conditions in tumors, harbor impactful somatic mutations in tumors, suggesting new approaches for classification and therapy development in stomach cancer. In sum, these findings demonstrate how classification of tumors by collagen mutations identified strong links between specific genotypes and the tumor environment.

Clinical efficacy and imaging outcomes of unilateral biportal endoscopy with unilateral laminotomy for bilateral decompression in the treatment of severe lumbar spinal stenosis.

Objective: To investigate the clinical efficacy and imaging outcomes of unilateral biportal endoscopy (UBE) with unilateral laminotomy for bilateral decompression (ULBD) in the treatment of severe lumbar spinal stenosis (SLSS). Methods: We retrospectively analyzed 50 patients with SLSS treated with UBE-ULBD from October 2018 to March 2021. Visual analog scale (VAS) for back and legs pain, Oswestry disability index (ODI), modified Macnab criteria, complications, hospital stay, preoperative and postoperative dural sac cross-sectional area (DSCA) and Schizas grade, mean angle of facetectomy and osseous lateral recess decompression rate were examined. Results: The mean follow-up period was 10.7 months. The mean hospital stay was 2.76 ± 1.02 days. At the final follow-up, VAS for back pain and legs pain decreased from 7.22 ± 0.95 to 1.26 ± 0.44 and from 7.88 ± 0.69 to 1.18 ± 0.39, respectively; ODI decreased from 69.88 ± 6.32% to 14.96 ± 2.75%. According to the modified Macnab criteria, the results were excellent in 24 (48%), good in 22 (44%), and fair in 4 (8%). Excellent or good results (a satisfactory outcome) were obtained in 92% of the patients. There were 2 cases of complications of dural sac tear. The postoperative DSCA was significantly enlarged compared with that before surgery, from 44.74 ± 9.85 to 126.86 ± 14.81 mm2. According to Schizas grade, the stenosis grade changes from preoperative grade C in 16 cases, grade D in 34 cases, to postoperative grade A in 40 cases, and grade B in 10 cases. The mean angle of facetectomy of the ipsilateral facet joint was 70.87 ± 5.68 ∘ , contralateral was 65.07 ± 4.98 ∘ . The decompression rate was 70.81 ± 4.43% (ipsilateral side) and 71.22 ± 3.68% (contralateral). Conclusions: UBE-ULBD has a good clinical effect in the treatment of SLSS, and has achieved satisfactory results in spinal canal enlargement, undercutting of facet joints, and decompression effect. It is a safe and effective surgical for SLSS.

Resveratrol inhibits inflammation after spinal cord injury via SIRT-1/NF-κB signaling pathway.

Spinal cord injury (SCI) can cause severe trauma to the central nervous system. Resveratrol has been widely studied for several of its medicinal properties, including anti-inflammatory, anti-aging and anti-oxidative effects. The regulation of SIRT-1 is thought to be related to the effects of resveratrol. As a downstream component of SIRT-1, NF-κB is one of the important signaling pathways that regulate the inflammatory response. Herein, we explored how treatment with resveratrol promoted recovery of motor function after SCI by activating the SIRT-1/NF-κB signaling pathway and inhibiting inflammation in rat models. Recovery of hind limb function was observed using the Basso, Beattie, and Bresnahan locomotor rating scale at different time points after SCI. Western blot analysis, immunofluorescence, Nissl staining and HE staining were utilized to observe the morphological characteristics of spinal cord tissue, as well as the expression of SIRT-1, NF-κB, TNF-α, IL-1ß, IL-6 and brain-derived neurotrophic factor. Resveratrol treatment promoted motor function recovery, increased the expression of brain-derived neurotrophic factor, and reduced loss of motor neurons and lesion size among rats after SCI. Meanwhile, inflammatory response was inhibited as the SIRT-1/NF-κB signaling pathway was modulated. These results suggest that resveratrol can help achieve neuroprotective effect by inhibiting inflammation, regulated by the SIRT-1/NF-κB signaling pathway.

Wnt Family Member 9b (Wnt9b) Is a New Sensitive and Specific Marker for Breast Cancer.

Confirming the tumor origin is often a diagnostic challenge in pathology and carries significant therapeutic impacts. Cytokeratin 7, estrogen receptor, and GATA binding protein 3 (GATA3) are well-established diagnostic markers frequently used to support a tumor's breast origin. However, their specificities still have room to improve. Many nonbreast tumors express cytokeratin 7 and estrogen receptor, and urothelial tumors frequently express GATA3. There is a practical need for a new breast lineage marker that is sensitive and specific. Wnt family member proteins play critical roles in embryo development, tissue homeostasis and tumor development through ß-catenin dependent and independent pathways. The current study evaluated Wnt9b and GATA3 expression in 163 primary breast cancers, 63 metastatic breast cancers, and 525 nonbreast epithelial tumors. The positive rates of Wnt9b and GATA3 in primary breast cancer were both 98.7%. The positive rates in metastatic breast cancer were 87.3% for Wnt9b and 96.8% for GATA3. For nonbreast tumors, including 64 cases of urothelial carcinoma, Wnt9b was negative in all except salivary gland carcinomas. The study demonstrated that Wnt9b is a breast cancer marker with similar sensitivity as GATA3 but with greater specificity than GATA3 and may ultimately become a useful diagnostic tool in routine surgical pathology practice.

A Vision-Based Social Distancing and Critical Density Detection System for COVID-19.

Social distancing (SD) is an effective measure to prevent the spread of the infectious Coronavirus Disease 2019 (COVID-19). However, a lack of spatial awareness may cause unintentional violations of this new measure. Against this backdrop, we propose an active surveillance system to slow the spread of COVID-19 by warning individuals in a region-of-interest. Our contribution is twofold. First, we introduce a vision-based real-time system that can detect SD violations and send non-intrusive audio-visual cues using state-of-the-art deep-learning models. Second, we define a novel critical social density value and show that the chance of SD violation occurrence can be held near zero if the pedestrian density is kept under this value. The proposed system is also ethically fair: it does not record data nor target individuals, and no human supervisor is present during the operation. The proposed system was evaluated across real-world datasets.

Knockdown of macrophage migration inhibitory factor (MIF), a novel target to protect neurons from parthanatos induced by simulated post-spinal cord injury oxidative stress.

Parthanatos is a form of regulated cell death (RCD) that is closely linked to DNA damage, which is a common consequence of oxidative stress due to central nervous trauma, such as spinal cord injury (SCI). The mechanism by which apoptosis-inducing factor (AIF) mediates DNA strand breaks in parthanatos was not clear until the discovery of the nuclease function of MIF. A previous study suggested that observed results may not be reliable if the oxidative stress induced in cells observed under experimental pathological conditions does not accurately replicate the specific pathologies being studied. According to an earlier direct measurement of extracellular oxidative stress in a rat SCI model, post-SCI oxidative stress was approximately the same as exposure to 150 µM H2O2. However, this concentration has been reported as sublethal oxidative stress in other cell types related to senescence, apoptosis, and parthanatos. Using sublethal H2O2 concentrations to induce oxidative stress is equivocal. Also, different cell types have diverse tolerances and responses to oxidative stress, and, therefore, exposure to H2O2. To avoid these limitations, the present study explored the mechanism of neuronal death under this simulated post-SCI oxidative stress and determined the effects of MIF knockdown in parthanatos associated with SCI. Immunofluorescence and flow cytometry were used to reveal typical characteristics of parthanatos that were blocked by PARP-1 inhibitors but not caspase inhibitors. In addition to classic features like PARP-1 and caspase-3 cleavage that were absent, we determined that parthanatos instead of apoptosis played a major role in the cell death caused by oxidative stress following SCI. Flow cytometry analysis of cells transfected by adenovirus with MIF-shRNA then exposed to H2O2 showed a significant decrease in cell death for MIF knockdown cells, even after AIF nuclear translocation. The comet assay also displayed significantly fewer DNA strand breaks after MIF knockdown. This is the first study has verified that MIF knockdown enables to protect neurons from parthanatos under a simulated in vivo oxidative stress following SCI. It suggests that MIF knockdown is a promising therapy to rescue neurons suffering from oxidative stress-induced SCI pathology.

Stromal ColXα1 expression correlates with tumor-infiltrating lymphocytes and predicts adjuvant therapy outcome in ER-positive/HER2-positive breast cancer.

BACKGROUND: The breast cancer microenvironment contributes to tumor progression and response to chemotherapy. Previously, we reported that increased stromal Type X collagen α1 (ColXα1) and low TILs correlated with poor pathologic response to neoadjuvant therapy in estrogen receptor and HER2-positive (ER+/HER2+) breast cancer. Here, we investigate the relationship of ColXα1 and long-term outcome of ER+/HER2+ breast cancer patients in an adjuvant setting. METHODS: A total of 164 cases with at least 5-year follow-up were included. Immunohistochemistry for ColXα1 was performed on whole tumor sections. Associations between ColXα1expression, clinical pathological features, and outcomes were analyzed. RESULTS: ColXα1 expression was directly proportional to the amount of tumor associated stroma (p = 0.024) and inversely proportional to TILs. Increased ColXα1 was significantly associated with shorter disease free survival and overall survival by univariate analysis. In multivariate analysis, OS was lower in ColXα1 expressing (HR = 2.1; 95% CI = 1.2-3.9) tumors of older patients (> = 58 years) (HR = 5.3; 95% CI = 1.7-17) with higher stage (HR = 2.6; 95% CI = 1.3-5.2). Similarly, DFS was lower in ColXα1 expressing (HR = 1.8; 95% CI = 1.6-5.7) tumors of older patients (HR = 3.2; 95% CI = 1.3-7.8) with higher stage (HR = 2.7; 95% CI = 1.6-5.7) and low TILs. In low PR+ tumors, higher ColXα1 expression was associated with poorer prognosis. CONCLUSION: ColXα1 expression is associated with poor disease free survival and overall survival in ER+/HER2+ breast cancer. This study provides further support for the prognostic utility of ColXα1 as a breast cancer associated stromal factor that predicts response to chemotherapy.

High pressure behavior of crystal [2,2'-bi(1,3,4-oxadiazole)]-5,5'-dinitramide: A DFT investigation.

Density functional theory (DFT) computation was carried out to investigate the crystal, molecular and electronic structures of high energy crystal [2,2'-bi(1,3,4-oxadiazole)]-5,5'-dinitramide (BODN) with the pressure 0-120 GPa. The relaxed crystal structure by the GGA/PBE-TS functional matches well with the experimental data at ambient pressure condition. With the intensifying of pressure, the lattice parameters, volumes, bond lengths, H-bond energies, atomic charges, bond populations, band gaps and density of states of crystal BODN change gently. Under the pressure of 48, 104, and 107 GPa, three pressure-induced transformations occurred. The intramolecular six membered rings pose strong affect in stabilizing systems in the pressure range 0-120 GPa. Between O1 and H2 atoms, the H-bond interaction transforms into covalent interaction under the circumstance of 48 GPa. At 104 GPa, structural transformation occurs with the distortion of the intramolecular six membered ring. In addition, O1⋅⋅⋅H2 and O2⋅⋅⋅H1 have the largest H-bond energies in comparison with the others. When the pressure reaches 107 GPa, the H-bond O1⋅⋅⋅H2 is formed again with the deformation and non-coplanarity of two oxadiazoles in crystal BODN. The electrons can be moved easily based on the density of states and energy bands under high pressure. Helpful information will be conveyed by this work in the field of further analysis connected the pressure effect on molecular transformations.

ColXα1 is a stromal component that colocalizes with elastin in the breast tumor extracellular matrix.

The tumor microenvironment regulates tissue development and homeostasis, and its dysregulation contributes to neoplastic progression. Increased expression of type X collagen α-1 (ColXα1) in tumor-associated stroma correlates with poor pathologic response to neoadjuvant chemotherapy in estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Evaluation of ColXα1 expression patterns suggests a potential connection with elastin fibers. To investigate the possible interaction between ColXα1 and elastin, we evaluated the expression of ColXα1 in relation to elastin fibers in normal breast tissue, ductal carcinoma in situ, and invasive breast carcinomas at cellular and subcellular levels. Our findings demonstrate that ColXα1 colocalizes with elastin in invasive breast cancer-associated stroma by immunohistochemistry, immunofluorescence, and electron microscopy. In 212 invasive breast carcinomas, this complex was aberrantly and selectively expressed in tumor extracellular matrix in 79% of ER+/HER2-, 80% of ER+/HER2+, 76% of ER-/HER2+, and 58% of triple negative breast cancers. In contrast, ColXα1 was generally absent, while elastin was present perivascularly in normal breast tissue. ColXα1 and elastin were coexpressed in 58% of ductal carcinoma in situ (DCIS) in periductal areas. In mass-forming DCIS with desmoplastic stroma, the complex was intensely expressed in periductal areas as well as within the tumor-associated stroma in all cases. Our data suggest that the breast carcinoma neoplastic process may involve aberrant expression of ColXα1 and elastin in the tumor microenvironment emerging early at the DCIS stage. Enrichment of these complexes in tumor-associated stroma may represent a stromal signature indicative of intrinsic differences between breast cancers. These findings shed light on investigation into the role of aberrant collagen complex expression in tumorigenesis and tumor progression which may be leveraged in therapeutic and theranostic applications.

Tailored Polyimide-Graphene Nanocomposite as Negative Electrode and Reduced Graphene Oxide as Positive Electrode for Flexible Hybrid Sodium-Ion Capacitors.

Redox-active polyimide materials hold a great promise for electrochemical energy storage applications, especially for flexible energy storage devices. However, the low utilization efficiency due to poor electrical conductivity of the materials remains one of the greatest challenges. In this work, we designed and prepared polyimide-graphene composite materials and tested their electrochemical properties in sodium-ion capacitors. By manipulating the interfacial chemistry and interactions between the polyimide and graphene, composite electrode materials with different polyimide particle sizes and morphologies were obtained. Sodium-ion storage capacity was significantly improved, from ∼50 mAh g-1 for pure polyimide to 225 mAh g-1 for a polyimide-graphene composite. A hybrid sodium-ion capacitor fabricated with freestanding polyimide-graphene composite as the negative electrode and reduced graphene oxide as the positive electrode delivered energy densities of 55.5 and 21.5 Wh kg-1 at power densities of 395 and 3400 W kg-1, respectively. A flexible sodium-ion capacitor with outstanding mechanical properties was also demonstrated.