Mismatch between the titanium mesh cage and cervical geometries is an important factor that induces subsidence in anterior cervical corpectomy and fusion (ACCF). The aim of the present study was to ...construct a new quadrate anatomically adaptive titanium mesh cage (AA-TMC) that matches well with the cervical geometries and segmental alignment in one- and two-level ACCF. Computed tomography (CT) scans of 54 individuals were used to measure the cervical endplate geometries. X-rays of 74 young individuals were used to measure the intervertebral body angle (IBA) and intervertebral body height (IBH) of the surgical segments. The AA-TMC was designed based on these measured parameters. A total of 18 cervical cadaveric specimens underwent successive one- and two-level ACCF using the AA-TMC. Postoperatively, the specimens underwent CT scanning to assess the degree of matching of the TMC-endplate interface (TEI), IBA and IBH. A TEI interval <0.5 mm was considered well matching. In the sagittal plane, 93.8% of the inferior endplates were arched, whereas 94.8% of the superior endplates were flat. In the coronal plane, 82.9% of the inferior endplates and 93.8% of the superior endplates were flat. A total of 91.7 and 94.4% of the TEIs were well matched in one- and two-level ACCF, respectively. The postoperative IBA and IBH values were consistent with the values of young individuals. The AA-TMC achieved good matching with cervical geometries and segmental alignment in one- and two-level ACCF, and is proposed for use in ACCF to increase the contact at the TEI and achieve sufficient lordosis restoration.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
All terminally differentiated organs face two challenges, maintaining their cellular identity and restricting organ size. The molecular mechanisms responsible for these decisions are of critical ...importance to organismal development, and perturbations in their normal balance can lead to disease. A hallmark of heart failure, a condition affecting millions of people worldwide, is hypertrophic growth of cardiomyocytes. The various forms of heart failure in human and animal models share conserved transcriptome remodeling events that lead to expression of genes normally silenced in the healthy adult heart. However, the chromatin remodeling events that maintain cell and organ size are incompletely understood; insights into these mechanisms could provide new targets for heart failure therapy. Using a quantitative proteomics approach to identify muscle-specific chromatin regulators in a mouse model of hypertrophy and heart failure, we identified upregulation of the histone methyltransferase Smyd1 during disease. Inducible loss-of-function studies in vivo demonstrate that Smyd1 is responsible for restricting growth in the adult heart, with its absence leading to cellular hypertrophy, organ remodeling, and fulminate heart failure. Molecular studies reveal Smyd1 to be a muscle-specific regulator of gene expression and indicate that Smyd1 modulates expression of gene isoforms whose expression is associated with cardiac pathology. Importantly, activation of Smyd1 can prevent pathological cell growth. These findings have basic implications for our understanding of cardiac pathologies and open new avenues to the treatment of cardiac hypertrophy and failure by modulating Smyd1.
LBA3
Background: About 55% of mBC typically categorized as HER2 negative, express low levels of HER2 (IHC 1+ or IHC 2+/ISH− by ASCO/CAP 2018 guidelines) with poor outcomes in later lines (Tarantino ...2020). T-DXd has shown promising efficacy in HER2-low mBC in a phase 1 study (NCT02564900; Modi 2020). This is the primary report from DESTINY-Breast04 (NCT03734029), the first randomized, multicenter, open-label, phase 3 study comparing efficacy and safety of T-DXd vs TPC in pts with HER2-low mBC treated with 1-2 prior lines of chemotherapy in the metastatic setting. Methods: 557 pts with centrally confirmed HER2-low mBC were randomly assigned 2:1 to T-DXd 5.4 mg/kg or TPC (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). The primary endpoint was progression-free survival (PFS) determined by blinded independent central review (BICR) in pts with hormone receptor–positive (HR+) mBC. Key secondary endpoints (hierarchically tested after the primary endpoint) include PFS by BICR in the full analysis set (FAS; HR+/−) and overall survival (OS) in pts with HR+ mBC and in FAS. Other endpoints were objective response rate, duration of response, safety, and an exploratory analysis of pts with HR− mBC. Results: As of Jan 11, 2022, 373 and 184 pts (88.7% and 88.6% HR+ mBC) were assigned to T-DXd and TPC, respectively. Median follow-up was 18.4 months (mo; 95% CI, 17.9-19.1). Median treatment duration was 8.2 mo (range, 0.2-33.3) with T-DXd and 3.5 mo (range, 0.3-17.6) with TPC. Efficacy results are in the Table. 52.6% of pts with T-DXd vs. 67.4% of pts with TPC had grade (G) ≥ 3 treatment-emergent adverse events (TEAEs). With T-DXd, 45 pts (12.1%; 10.0% G1/2, 1.3% G3/4, 0.8% G5) had independently adjudicated drug-related interstitial lung disease ILD/pneumonitis vs. 1 pt (0.6% G1) with TPC. Conclusions: DESTINY-Breast04 is the first phase 3 trial of a HER2-directed therapy in pts with HER2-low mBC to show a statistically significant and clinically meaningful benefit in PFS and OS compared to standard-of-care treatment, regardless of HR status, with a generally manageable safety profile. Funding: Daiichi Sankyo, Inc., and AstraZeneca. Clinical trial information: NCT03734029. Table: see text
Background
Diffusion-weighted imaging (DWI) is a functional modality that indirectly represents the biological characteristics of cancer. However, the correlation of apparent diffusion coefficients ...(ADCs) to HPV type in patients with cervical cancer is still unknown.
Purpose
To explore the relationship between apparent diffusion coefficients calculated by DW-magnetic resonance imaging (MRI) and high-risk human papilloma virus (HR-HPV) infection in cervical squamous cell carcinoma (CSCC) patients.
Material and Methods
A total of 315 patients with histologically proven CSCC and who underwent pretreatment MRI were retrospectively analyzed. ADCs on the primary tumor were calculated. Receiver operating characteristic (ROC) curves were employed to determine the cut-off values of ADCmean and accuracy of prediction. Pearson correlation and multivariate logistic regression models were adopted to show the association of HR-HPV infection with clinical and imaging variables.
Results
ADCmean for HR-HPV+ CSCC was significantly lower than those for HR-HPV- CSCC. The area under the curve was 0.805 for predicting HR-HPV+ infection using mean ADCs. A cut-off value of 0.885 × 10−3 mm2/s for mean ADCS could distinguish HR-HPV+ from HR-HPV- CSCC with 83.3% sensitivity, 73.9% specificity, and 80.8% accuracy. Regression analysis revealed that the HR-HPV infection was closely associated with tumor ADC value (odds ratio OR = 5.588, 95% confidence interval CI = 3.371–9.262), FIGO stage (OR = 2.789, 95% CI = 1.631–4.769), and histological grade (OR = 2.333, 95% CI = 1.676–3.247).
Conclusion
ADC value is related with the HR-HPV infection in patients with CSCC and DWI may be used for predicting HR-HPV infection in patients with CSCC.
Abstract only The maturation of stem cell derived cardiomyocytes (iCMs) is incomplete relative to the fully matured adult myocytes. Lack of maturation represents a major limitation to the ...applications of iCMs as heart disease models or heart failure therapies. Current attempts to promote iCMs maturation, such as prolonged culture, mechanical stretching and electronic pacing, are often based on empirical methods with poor reproducibility or little mechanistic basis. In order to better understand the molecular mechanisms driving cardiomyocyte maturation, we performed extensive transcriptome analyses in neonatal vs. adult hearts. In addition to metabolic and cell cycle regulatory pathways, Gene Ontology analysis revealed RNA splicing regulation is significantly enriched in the transcriptome reprogramming during postnatal maturation in heart. Specifically, we find a cardiomyocyte enriched RNA splicing factor Rbfox1 is dramatically induced in the perinatal maturating mouse hearts. Ectopic expression of Rbfox1 in neonatal cardiomyocytes markedly promotes the cellular and molecular features of adult cardiomyocyte, including contractility, calcium handling, sarcomere organization, morphology, electrophysiology and gene expression. Most remarkably, expression of RBFox1 in human iPSC derived cardiomyocytes promotes similar maturation process as observed in the neonatal rat myocytes. At mechanistic level, RBFox1 expression in the iCMs enhances transcriptome maturation as indicated by targeted RNA splicing in genes involved in muscle contraction, gene expression, RNA processing and sarcomere organization. In summary, we have uncovered a novel molecular path towards neonatal myocyte maturation in perinatal murine hearts by targeted modulation of cardiomyocyte transcriptome via RNA-splicing. This approach has potential to be employed as a molecular approach to promote human iCMs maturation.
Traumatic brain injury (TBI) and ethanol intoxication (EI) frequently coincide, particularly in young subjects. However, the mechanisms of their interaction remain poorly understood. Among other ...pathogenic pathways, TBI induces glial activation and neuroinflammation in the hippocampus, resulting in acute and chronic hippocampal dysfunction. In this regard, we investigated the role of EI affecting these responses unfolding after TBI.
We used a blunt, weight-drop approach to model TBI in mice. Male mice were pre-administered with ethanol or vehicle to simulate EI. The neuroinflammatory response in the hippocampus was assessed by monitoring the expression levels of >20 cytokines, the phosphorylation status of transcription factors and the phenotype of microglia and astrocytes. We used AS1517499, a brain-permeable STAT6 inhibitor, to elucidate the role of this pathway in the EI/TBI interaction.
We showed that TBI causes the elevation of IL-33, IL-1β, IL-38, TNF-α, IFN-α, IL-19 in the hippocampus at 3 h time point and concomitant EI results in the dose-dependent downregulation of IL-33, IL-1β, IL-38, TNF-α and IL-19 (but not of IFN-α) and in the selective upregulation of IL-13 and IL-12. EI is associated with the phosphorylation of STAT6 and the transcription of STAT6-controlled genes. Moreover, ethanol-induced STAT6 phosphorylation and transcriptional activation can be recapitulated in vitro by concomitant exposure of neurons to ethanol, depolarization and inflammatory stimuli (simulating the acute trauma). Acute STAT6 inhibition prevents the effects of EI on IL-33 and TNF-α, but not on IL-13 and negates acute EI beneficial effects on TBI-associated neurological impairment. Additionally, EI is associated with reduced microglial activation and astrogliosis as well as preserved synaptic density and baseline neuronal activity 7 days after TBI and all these effects are prevented by acute administration of the STAT6 inhibitor concomitant to EI.
EI concomitant to TBI exerts significant immunomodulatory effects on cytokine induction and microglial activation, largely through the activation of STAT6 pathway, ultimately with beneficial outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract only Background: Cardiovascular disease is the leading cause of death in the world with a dearth of effective therapies. Heart undergoes a complex differentiation and maturation process ...throughout embryonic and post-natal stages. Intense efforts have been made in the study of cardiomyocyte differentiation, maturation and pathological remodeling. With the aid of stem cells, investigators are able to recapitulate events in early cardiac development and gain valuable insight in transcriptional regulatory networks directing early cardiomyocyte differentiation. However, the molecular network that determine myocyte maturation in postnatal development, which are especially important for understanding diseases and developing cell based clinical applications, are far less well characterized. Human induced pluripotent stem cell derived cardiomyocytes (hIPSC-CMs) are lineage committed but remain immature and fetal-like in molecular, morphological and functional characteristics. Their application in cell based therapy or serving as a disease model for heart failure is limited, in part due to the lack of sufficient insight to promote their maturation into adult myocytes. Results: We find from previous studies that postnatal cardiomyocyte development is marked by global alternative splicing (AS) programming. In mouse heart, we find RNA splicing regulator RBFox1 is markedly induced in heart only in post-natal period and functions as a key regulator to post-natal global RNA alternative splicing reprogramming during cardiomyocyte maturation. Transcriptome analysis revealed that exogenous expression of RBFox1 promotes gene expression in neonatal ventricular myocytes reminiscent of mature adult heart, and results in cellular maturation based on sarcomere organization and calcium cycling characteristics. Furthermore, ectopic expression of rodent RBFox1 in human iPSC derived CMs resulted in similar maturation effects, implicating a conserved mechanism in human and rodent myocytes. Conclusion: RBFox1 mediated RNA splicing is an important contributor to post-natal myocyte maturation and it can be manipulated to promote cardiomyocyte maturation for cell-based therapy or disease modeling.
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