CT-Based Deep-Learning Model for Spread-Through-Air-Spaces Prediction in Ground Glass-Predominant Lung Adenocarcinoma.

BACKGROUND: Sublobar resection is strongly associated with poor prognosis in early-stage lung adenocarcinoma, with the presence of tumor spread through air spaces (STAS). Thus, preoperative prediction of STAS is important for surgical planning. This study aimed to develop a STAS deep-learning (STAS-DL) prediction model in lung adenocarcinoma with tumor smaller than 3 cm and a consolidation-to-tumor (C/T) ratio less than 0.5. METHODS: The study retrospectively enrolled of 581 patients from two institutions between 2015 and 2019. The STAS-DL model was developed to extract the feature of solid components through solid components gated (SCG) for predicting STAS. The STAS-DL model was assessed with external validation in the testing sets and compared with the deep-learning model without SCG (STAS-DLwoSCG), the radiomics-based model, the C/T ratio, and five thoracic surgeons. The performance of the models was evaluated using area under the curve (AUC), accuracy and standardized net benefit of the decision curve analysis. RESULTS: The study evaluated 458 patients (institute 1) in the training set and 123 patients (institute 2) in the testing set. The proposed STAS-DL yielded the best performance compared with the other methods in the testing set, with an AUC of 0.82 and an accuracy of 74%, outperformed the STAS-DLwoSCG with an accuracy of 70%, and was superior to the physicians with an AUC of 0.68. Moreover, STAS-DL achieved the highest standardized net benefit compared with the other methods. CONCLUSION: The proposed STAS-DL model has great potential for the preoperative prediction of STAS and may support decision-making for surgical planning in early-stage, ground glass-predominant lung adenocarcinoma.

Deep-learning model to improve histological grading and predict upstaging of atypical ductal hyperplasia / ductal carcinoma in situ on breast biopsy.

AIMS: Risk stratification of atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS), diagnosed using breast biopsy, has great clinical significance. Clinical trials are currently exploring the possibility of active surveillance for low-risk lesions, whereas axillary lymph node staging may be considered during surgical planning for high-risk lesions. We aimed to develop a machine-learning algorithm based on whole-slide images of breast biopsy specimens and clinical information to predict the risk of upstaging to invasive breast cancer after wide excision. METHODS AND RESULTS: Patients diagnosed with ADH/DCIS on breast biopsy were included in this study, comprising 592 (740 slides) and 141 (198 slides) patients in the development and independent testing cohorts, respectively. Histological grading of the lesions was independently evaluated by two pathologists. Clinical information, including biopsy method, lesion size, and Breast Imaging Reporting and Data System (BI-RADS) classification of ultrasound and mammograms, were collected. Deep DCIS consisted of three deep neural networks to evaluate nuclear grade, necrosis, and stromal reactivity. Deep DCIS output comprised five parameters: total patches, lesion extent, Deep Grade, Deep Necrosis, and Deep Stroma. Deep DCIS highly correlated with the pathologists' evaluations of both slide- and patient-level labels. All five parameters of Deep DCIS were significantly associated with upstaging to invasive carcinoma in subsequent wide excisional specimens. Using multivariate logistic regression, Deep DCIS predicted upstaging to invasive carcinoma with an area under the curve (AUC) of 0.81, outperforming pathologists' evaluation (AUC, 0.71 and 0.69). After including clinical and hormone receptor status information, performance further improved (AUC, 0.87). This combined model retained its predictive power in two subgroup analyses: the first subgroup included unequivocal DCIS (excluding cases of ADH and DCIS suspicious for microinvasion) (AUC, 0.83), while the second excluded cases of high-grade DCIS (AUC, 0.81). The model was validated in an independent testing cohort (AUC, 0.81). CONCLUSION: This study demonstrated that deep-learning models can refine histological evaluation of ADH and DCIS on breast biopsies, which may help guide future treatment planning.

A novel computer-assisted tool for 3D imaging of programmed death-ligand 1 expression in immunofluorescence-stained and optically cleared breast cancer specimens.

BACKGROUND: Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are the two most common immune checkpoints targeted in triple-negative breast cancer (BC). Refining patient selection for immunotherapy is non-trivial and finding an appropriate digital pathology framework for spatial analysis of theranostic biomarkers for PD-1/PD-L1 inhibitors remains an unmet clinical need. METHODS: We describe a novel computer-assisted tool for three-dimensional (3D) imaging of PD-L1 expression in immunofluorescence-stained and optically cleared BC specimens (n = 20). The proposed 3D framework appeared to be feasible and showed a high overall agreement with traditional, clinical-grade two-dimensional (2D) staining techniques. Additionally, the results obtained for automated immune cell detection and analysis of PD-L1 expression were satisfactory. RESULTS: The spatial distribution of PD-L1 expression was heterogeneous across various BC tissue layers in the 3D space. Notably, there were six cases (30%) wherein PD-L1 expression levels along different layers crossed the 1% threshold for admitting patients to PD-1/PD-L1 inhibitors. The average PD-L1 expression in 3D space was different from that of traditional immunohistochemistry (IHC) in eight cases (40%). Pending further standardization and optimization, we expect that our technology will become a valuable addition for assessing PD-L1 expression in patients with BC. CONCLUSION: Via a single round of immunofluorescence imaging, our approach may provide a considerable improvement in patient stratification for cancer immunotherapy as compared with standard techniques.

COVID-19 vaccination: 2023 Taiwan Association of Gerontology and Geriatrics (TAGG) consensus statements.

The COVID-19 pandemic remains challenging due to the rapid evolution of the severe acute respiratory syndrome coronavirus 2. This article discusses recent findings on high-risk groups for COVID-19 mortality and morbidity, along with consensus statements from the 2023 Taiwan Association of Gerontology and Geriatrics (TAGG) meeting. It examines evidence on viral mutation mechanisms, emerging variants, and their implications for vaccination strategies. The article underscores advanced age, immunocompromised status, chronic medical conditions, occupational exposure, and socioeconomic disparities as significant risk factors for severe COVID-19 outcomes. TAGG's consensus emphasizes robust vaccination promotion, prioritizing elderly, and immunocompromised groups, individualized multi-dose regimens for immunocompromised patients, and simplified clinical guidelines. Discussions on global and regional recommendations for regular, variant-adapted boosters highlight the non-seasonal nature of COVID-19. Key agreements include escalating domestic preparedness, implementing vigorous risk-based vaccination, and adapting global guidelines to local contexts. Given ongoing viral evolution, proactive adjustment of vaccination policies is essential. Scientific consensus, tailored recommendations, and rapid knowledge dissemination are vital for optimizing COVID-19 protection among vulnerable groups in Taiwan. This article seeks to inform clinical practice and public health policy by summarizing expert-driven vaccination perspectives.

Sublabial excision versus transnasal endoscopic marsupialization for nasolabial cysts: A systematic review and meta-analysis.

OBJECTIVES: To compare the intraoperative and postoperative outcomes of sublabial excision and transnasal endoscopic marsupialization, the two primary surgical approaches for nasolabial cysts. DESIGN AND SETTING: A comprehensive meta-analysis of studies identified from PubMed, Embase, and the Cochrane Library. PARTICIPANTS: Patients diagnosed with nasolabial cysts who underwent surgical treatment. MAIN OUTCOME MEASURES: Operative time, postoperative pain, overall postoperative complications, admission rate, length of hospital stay, use of general anaesthesia, medical costs, and recurrence rate. RESULTS: The pooled analysis revealed that the transnasal endoscopic marsupialization group had shorter operative time (mean differences [MD], -32.51; 95% confidence interval [CI], -38.52 to -26.51), reduced postoperative pain (MD, -4.25; 95% CI, -7.62 to -0.89), fewer overall postoperative complications (risk difference [RD], -0.68; 95% CI, -0.90 to -0.46), lower admission rates (RD, -0.86; 95% CI, -1.11 to -0.61), shorter hospital stays (MD, -1.74; 95% CI, -2.58 to -0.89), decreased use of general anaesthesia (RD, -0.40; 95% CI, -0.76 to -0.03), and reduced medical costs (MD, -229.69; 95% CI, -338.64 to -120.75). The recurrence rate between the two groups showed no significant difference (RD, -0.01; 95% CI, -0.05 to 0.04). CONCLUSION: Transnasal endoscopic marsupialization presents as a promising alternative to sublabial excision in the treatment of nasolabial cysts. It offers advantages like reduced operative time, decreased postoperative pain, fewer complications, lower admission rates, shorter hospital stays, diminished need for general anaesthesia, and cost savings. Clinicians can leverage these findings to select the most suitable surgical approach for their patients.

Astrocytic aryl hydrocarbon receptor mediates chronic kidney disease-associated mental disorders involving GLT1 hypofunction and neuronal activity enhancement in the mouse brain.

Chronic kidney disease (CKD)-associated mental disorders have been attributed to the excessive accumulation of hemodialysis-resistant indoxyl-3-sulfate (I3S) in the brain. I3S not only induces oxidative stress but is also a potent endogenous agonist of the aryl hydrocarbon receptor (AhR). Here, we investigated the role of AhR in CKD-induced brain disorders using a 5/6 nephrectomy-induced CKD mouse model, which showed increased I3S concentration in both blood and brain, anxiety and impaired novelty recognition, and AhR activation in the anterior cortex. GFAP+ reactive astrocytes were increased accompanied with the reduction of glutamate transporter 1 (GLT1) on perineuronal astrocytic processes (PAPs) in the anterior cingulate cortex (ACC) in CKD mice, and these alterations were attenuated in both neural lineage-specific and astrocyte-specific Ahr conditional knockout mice (nAhrCKO and aAhrCKO). By using chronic I3S treatment in primary astrocytes and glia-neuron (GN) mix cultures to mimic the CKD brain microenvironment, we also found significant reduction of GLT1 expression and activity in an AhR-dependent manner. Chronic I3S treatment induced AhR-dependent pro-oxidant Nox1 and AhR-independent anti-oxidant HO-1 expressions. Notably, AhR mediates chronic I3S-induced neuronal activity enhancement and synaptotoxicity in GN mix, not neuron-enriched cortical culture. In CKD mice, neuronal activity enhancement was observed in ACC and hippocampal CA1, and these responses were abrogated by both nAhrCKO and aAhrCKO. Finally, intranasal AhR antagonist CH-223191 administration significantly ameliorated the GLT1/PAPs reduction, increase in c-Fos+ neurons, and memory impairment in the CKD mice. Thus, astrocytic AhR plays a crucial role in the CKD-induced disturbance of neuron-astrocyte interaction and mental disorders.

Radiotherapy versus low-dose tamoxifen following breast-conserving surgery for low-risk and estrogen receptor-positive breast ductal carcinoma in situ: an international open-label randomized non-inferiority trial (TBCC-ARO DCIS Trial).

BACKGROUND: Radiotherapy (RT) following breast-conserving surgery (BCS) is mainly used to decrease the rate of ipsilateral breast tumor recurrence (IBTR) in women with breast ductal carcinoma in situ (DCIS). Recent studies have demonstrated that low-dose tamoxifen significantly reduces IBTR in breast DCIS. Here, we aim to determine whether the administration of low-dose tamoxifen is non-inferior to RT in preventing IBTR in patients with low-risk characteristics of breast DCIS. METHODS/DESIGN: This is a prospective, international, open-label, randomized, non-inferiority trial. Patients with low-risk clinicopathologic features (> 40 years old, low risk of breast cancer susceptibility gene (BRCA) 1 and BRCA2 mutations, mammographically detected unicentric and non-mass lesions, low- or intermediate-grade without comedo or necrosis, measuring < 2.5 cm with margins ≥ 3 mm, and estrogen receptor-positive status) of DCIS who underwent BCS will be randomized at a 1:1 ratio to either receive tamoxifen (5 mg/day) for 5 years or undergo RT with conventional fractions (50 Gy in 25 fractions) or hypofractionations (40.05 Gy in 15 fractions). Randomization will be stratified by the Taiwan Breast Cancer Consortium. As approximately 5% of patients cannot tolerate the side effects of low-dose tamoxifen and will receive RT, we estimate that 405 patients will be randomized to a low-dose tamoxifen arm and 405 patients to the RT arm, according to a non-inferiority margin within 5% of IBTR difference and 90% ß-power noticing non-inferiority. The primary endpoints are breast tumor recurrence, including ipsilateral, regional, contralateral, and distant recurrence of breast DCIS or invasive cancer. The secondary endpoints are overall survival and adverse effects of RT and tamoxifen. Translational studies will also be conducted for this trial. DISCUSSION: This is the first non-inferiority trial on breast DCIS. This study will provide an important recommendation for clinical physicians on whether to use low-dose adjuvant tamoxifen for patients with low-risk breast DCIS who do not want to receive adjuvant RT. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT04046159, Registered on April 30, 2019.

Water-soluble copper pyrithione complexes with cytotoxic and antibacterial activity.

Copper Pyrithione, [Cu(PyS)2] has shown excellent biological activity against cancer cells and bacterial cells, however, it has extremely low aqueous solubility, limiting its applicability. Herein, we report a series of PEG-substituted pyrithione copper(II) complexes with significantly increased aqueous solubility. While long PEG chains lead to a decrease in bioactivity, the addition of short PEG chains leads to improved aqueous solubility with retention of activity. One novel complex, [Cu(PyS1)2], has particularly impressive anticancer activity, surpassing that of the parent complex.

Sex Differences and Positive Dose-Response Relationships between Serum Osteocalcin Levels and Low Muscle Strength.

INTRODUCTION: Impaired handgrip strength is an indication for sarcopenia and frailty screening, and is associated with increased osteoporotic risks and all-cause mortality. Osteocalcin, secreted by osteoblasts, is a versatile factor that participates in bone turnover and muscle adaptation. The role of osteocalcin in muscle strength has mainly been discussed in animal models and requires more human data. The study aimed to investigate the association between the serum osteocalcin level and handgrip strength in middle-aged individuals and older adults with diabetes. METHODS: Adult participants (aged 40 and above, N = 237) with diabetes were enrolled in a medical center in northern Taiwan. Subjects were divided into normal, low muscle mass without dynapenia, dynapenia without low muscle mass, and groups of low muscle mass with dynapenia according to their handgrip strength and muscle mass measurements. Physical performance, including handgrip strength, repeated sit-to-stand tests, walking speed, and short physical performance batteries, was documented. Body composition was measured by bioelectrical impedance analysis. RESULTS: The median serum osteocalcin level was highest in the dynapenic group without low muscle mass (median [Q1, Q3], 14.1 [11.2, 16.3] ng/mL). Multivariate logistic regression showed that a higher serum osteocalcin level was associated with worse handgrip strength (OR: 3.89, 95% CI: 1.66-9.10) after adjusting for body mass index (adiposity), skeletal muscle mass index (muscle), and medication with dipeptidyl peptidase-4 inhibitor. Further sex stratification revealed a more significant association between serum osteocalcin level and impaired handgrip strength in women but not in men. The female groups showed increases in the risk of impaired handgrip strength: 4.84-fold in the osteocalcin T2 group (11.4 ≤ osteocalcin <15.0 ng/mL) and 4.54-fold in the osteocalcin T3 group (osteocalcin ≥15.0 ng/mL). Moreover, after adjusting for various confounders, 8.41-fold and 8.03-fold increases in the risk of impaired handgrip strength were observed in the osteocalcin T2 group (11.4≤ osteocalcin <15.0 ng/mL) and osteocalcin T3 group (osteocalcin ≥14.5 ng/mL), respectively. CONCLUSION: Higher serum osteocalcin is associated with increased risks of impaired handgrip strength and impaired physical performance. Dose-dependent associations were found especially in postmenopausal women but not in men.

High rate of postoperative upstaging of ductal carcinoma in situ when prioritizing ultrasound evaluation of mammography-detected lesions: a single-center retrospective cohort study.

BACKGROUND: The initial diagnosis of ductal carcinoma in situ (DCIS) can be upstaged to invasive cancer after definitive surgery. This study aimed to identify risk factors for DCIS upstaging using routine breast ultrasonography and mammography (MG) and to propose a prediction model. METHODS: In this single-center retrospective study, patients initially diagnosed with DCIS (January 2016-December 2017) were enrolled (final sample size = 272 lesions). Diagnostic modalities included ultrasound-guided core needle biopsy (US-CNB), MG-guided vacuum-assisted breast biopsy, and wire-localized surgical biopsy. Breast ultrasonography was routinely performed for all patients. US-CNB was prioritized for lesions visible on ultrasound. Lesions initially diagnosed as DCIS on biopsy with a final diagnosis of invasive cancer at definitive surgery were defined as "upstaged." RESULTS: The postoperative upstaging rates were 70.5%, 9.7%, and 4.8% in the US-CNB, MG-guided vacuum-assisted breast biopsy, and wire-localized surgical biopsy groups, respectively. US-CNB, ultrasonographic lesion size, and high-grade DCIS were independent predictive factors for postoperative upstaging, which were used to construct a logistic regression model. Receiver operating characteristic analysis showed good internal validation (area under the curve = 0.88). CONCLUSIONS: Supplemental screening breast ultrasonography possibly contributes to lesion stratification. The low upstaging rate for ultrasound-invisible DCIS diagnosed by MG-guided procedures suggests that it is unnecessary to perform sentinel lymph node biopsy for lesions invisible on ultrasound. Case-by-case evaluation of DCIS detected by US-CNB can help surgeons determine if repeating biopsy with vacuum-assisted breast biopsy is necessary or if sentinel lymph node biopsy should accompany breast-preserving surgery. TRIAL REGISTRATION: This single-center retrospective cohort study was conducted with the approval of the institutional review board of our hospital (approval number 201610005RIND). As this was a retrospective review of clinical data, it was not registered prospectively.

Social network associated with depressed mood and sarcopenia among older adults in Taiwan.

BACKGROUND: Social isolation is increasing in aging societies; however, its relationship with depressed mood and sarcopenia is not well studied. This study aims to examine the influence of social network on depressed mood and sarcopenia among community-dwelling older adults in Taiwan. METHODS: We collected data from a sample of 981 older adults residing in the community. These individuals received government-subsidized preventive healthcare services for adults at a district hospital in Taipei in 2021. The social network of the older adults who participated was assessed using the Lubben Social Network Scale, while depressed mood was assessed using the Geriatric Depression Scale. The definition of sarcopenia used in this study was based on the 2019 Asian Working Group for Sarcopenia. RESULTS: According to this study, sarcopenia was present in approximately 15 % of older adults. Multiple logistic regression analysis showed that older adults who had poor social network and did not meet the recommended 150 min of regular physical activity per week were more likely to have depressed mood. Additionally, older adults who were older, underweight, did not engage in regular physical activity, and had poor social network were more likely to have sarcopenia. CONCLUSION: Poor social network was associated with increased risks of depressed mood and sarcopenia among older adults.

FKBP51 mediates resilience to inflammation-induced anxiety through regulation of glutamic acid decarboxylase 65 expression in mouse hippocampus.

BACKGROUND: Inflammation is a potential risk factor of mental disturbance. FKBP5 that encodes FK506-binding protein 51 (FKBP51), a negative cochaperone of glucocorticoid receptor (GR), is a stress-inducible gene and has been linked to psychiatric disorders. Yet, the role of FKBP51 in the inflammatory stress-associated mental disturbance remained unclear. METHODS: Fkbp5-deficient (Fkbp5-KO) mice were used to study inflammatory stress by a single intraperitoneal injection of lipopolysaccharide (LPS). The anxiety-like behaviors, neuroimaging, immunofluorescence staining, immunohistochemistry, protein and mRNA expression analysis of inflammation- and neurotransmission-related mediators were evaluated. A dexamethasone drinking model was also applied to examine the effect of Fkbp5-KO in glucocorticoid-induced stress. RESULTS: LPS administration induced FKBP51 elevation in the liver and hippocampus accompanied with transient sickness. Notably, Fkbp5-KO but not wild-type (WT) mice showed anxiety-like behaviors 7 days after LPS injection (LPS-D7). LPS challenge rapidly increased peripheral and central immune responses and hippocampal microglial activation followed by a delayed GR upregulation on LPS-D7, and these effects were attenuated in Fkbp5-KO mice. Whole-brain [18F]-FEPPA neuroimaging, which target translocator protein (TSPO) to indicate neuroinflammation, showed that Fkbp5-KO reduced LPS-induced neuroinflammation in various brain regions including hippocampus. Interestingly, LPS elevated glutamic acid decarboxylase 65 (GAD65), the membrane-associated GABA-synthesizing enzyme, in the hippocampus of WT but not Fkbp5-KO mice on LPS-D7. This FKBP51-dependent GAD65 upregulation was observed in the ventral hippocampal CA1 accompanied by the reduction of c-Fos-indicated neuronal activity, whereas both GAD65 and neuronal activity were reduced in dorsal CA1 in a FKBP51-independent manner. GC-induced anxiety was also examined, which was attenuated in Fkbp5-KO and hippocampal GAD65 expression was unaffected. CONCLUSIONS: These results suggest that FKBP51/FKBP5 is involved in the systemic inflammation-induced neuroinflammation and hippocampal GR activation, which may contribute to the enhancement of GAD65 expression for GABA synthesis in the ventral hippocampus, thereby facilitating resilience to inflammation-induced anxiety.

ICOS-Positive Regulatory T Cells in Hepatocellular Carcinoma: The Perspective from Digital Pathology Analysis.

INTRODUCTION: Inducible co-stimulator (ICOS), an important co-stimulatory receptor on effector T cells (Teffs), may also contribute to tumor growth due to its high expression on regulatory T cells (Tregs). This study explored the clinical significance of ICOS-expressing Tregs in hepatocellular carcinoma (HCC). METHODS: Tumor tissues from HCC patients who received curative hepatectomy were obtained at a referral center. Dual immunohistochemistry was performed to evaluate the expression of ICOS and Foxp3. The cell densities and proximities between stained cells in regions of interest were measured by digital pathology and the associations with clinical outcome were analyzed. RESULTS: A total of 142 patients (male:female = 112: 30, median age of 61.0 years) were enrolled. Among them, 87 (61.3%) had chronic hepatitis B virus infection and 33 (23.2%) had chronic hepatitis C infection. Low α-fetoprotein level (<20 ng/mL) and early-stage were significantly associated with improved overall survival (OS). The density of ICOS+Foxp3+ cells and the ratio of ICOS+Foxp3+/total Foxp3+ cells were significantly higher (p < 0.001) in the tumor center than in the peritumor area. Patients with a high density of ICOS+Foxp3+ cells or a high ratio of ICOS+Foxp3+/total Foxp3+ cells in the tumor center trended to have a shorter OS. A shorter distance between ICOS+Foxp3+ cells and ICOS+Foxp3- cells (likely Teffs) in the tumor center was significantly associated with a shorter OS (p = 0.030), suggesting active immunosuppression of ICOS+ Tregs on ICOS+ Teffs. CONCLUSION: An increased abundance of ICOS+ Tregs in the tumor center in comparison to the peritumor area indicates a strong immunosuppressive tumor microenvironment of HCC. A high proportion of ICOS+Foxp3+ cells and a shorter distance between ICOS+ Tregs and other ICOS+ cells were associated with a poor OS, suggesting that depleting ICOS+ Tregs might provide clinical benefit for patients with HCC.

SMARCB1(INI1)-deficient sinonasal adenocarcinoma: Report of a case previously diagnosed as high-grade non-intestinal-type sinonasal adenocarcinoma.

SMARCB1(INI1)-deficient sinonasal carcinoma is a recently recognized entity with wide histomorphologic spectrum. The classification of sinonasal adenocarcinoma (SNAC) is complex and yet to be redefined, especially the category of high-grade non-intestinal-type SNAC. Recently SMARCB1(INI1)-deficient SNACs with an unique oncocytoid/rhabdoid cytomorphology and variable degrees of glandular formation have been reported. Here we described a rare case of SMARCB1(INI1)-deficient SNAC composed of mainly oncocytoid/rhabdoid cells with mixed solid and cribriform patterns. This case was originally diagnosed as non-intestinal-type SNAC and was reclassified due to complete loss expression of SMARCB1(INI1) by immunohistochemistry (IHC). The SMARCB1(INI1) stain provides a valuable tool for identification of this specific type of SNAC. We compared this case with other SNACs diagnosed in our department and reviewed relevant literature for this specific type of SNAC.

FGF primes angioblast formation by inducing ETV2 and LMO2 via FGFR1/BRAF/MEK/ERK.

It is critical to specify a signal that directly drives the transition that occurs between cell states. However, such inferences are often confounded by indirect intercellular communications or secondary transcriptomic changes due to primary transcription factors. Although FGF is known for its importance during mesoderm-to-endothelium differentiation, its specific role and signaling mechanisms are still unclear due to the confounding factors referenced above. Here, we attempted to minimize the secondary artifacts by manipulating FGF and its downstream mediators with a short incubation time before sampling and protein-synthesis blockage in a low-density angioblastic/endothelial differentiation system. In less than 8 h, FGF started the conversion of KDRlow/PDGFRAlow nascent mesoderm into KDRhigh/PDGFRAlow angioblasts, and the priming by FGF was necessary to endow endothelial formation 72 h later. Further, the angioblastic conversion was mediated by the FGFR1/BRAF/MEK/ERK pathway in mesodermal cells. Finally, two transcription factors, ETV2 and LMO2, were the early direct functional responders downstream of the FGF pathway, and ETV2 alone was enough to complement the absence of FGF. FGF's selective role in mediating the first-step, angioblastic conversion from mesoderm-to-endothelium thus allows for refined control over acquiring and manipulating angioblasts. The noise-minimized differentiation/analysis platform presented here is well-suited for studies on the signaling switches of other mesodermal-lineage fates as well.

Delayed-onset radiculopathy caused by a retropulsed bone fragment after percutaneous kyphoplasty: report of four cases and literature review.

BACKGROUND: Vertebral compression fractures caused by osteoporosis are common in elderly patients and are often encountered by clinical physicians. Percutaneous balloon kyphoplasty (PKP) is widely accepted as a minimally invasive procedure for effectively relieving pain and correcting deformities, but complications may occur. Radiculopathy with a delayed onset caused by a retropulsed bone fragment has not been adequately described in the literature. Thus, this article presents a case report of four cases of retropulsed bone fragment-related radiculopathy after PKP. CASE PRESENTATION: In this article, we reported that four out of 251 patients developed radiculopathy after PKP between January 2012 and January 2019 despite experiencing substantial improvements in back pain. All patients with radiculopathy were female and diagnosed with osteoporosis, and their ages ranged from 68 to 89 years. Radiculopathy occurred from 2 to 16 weeks after PKP. All four patients underwent another operation (posterior decompression and instrumentation). Three patients recovered completely, and one died of postoperative intracranial haemorrhage. A detailed imaging study with pre- and postoperative magnetic resonance imaging (MRI) revealed that retropulsed bone fragments that impinged on the corresponding root after PKP were responsible for this complication, and all four patients developed a disrupted posterior vertebral rim preoperatively. No leakage of cement or pedicle track violations were observed. CONCLUSION: Although PKP is a safe and effective treatment for painful osteoporotic vertebral compression fractures, a risk of catastrophic neurological injury remains. Radiculopathy with delayed onset caused by a retropulsed bone fragment after kyphoplasty is rare and challenging to treat, and the integrity of the posterior vertebral cortex should be carefully evaluated preoperatively to prevent this complication.

The efficacy of incorporating ultrasound-guided core biopsy into the clinical workflow of indeterminate thyroid tumors.

BACKGROUND: Ultrasound-guided core biopsy (USCB) is a minimally invasive sampling procedure which may help to confirm the diagnoses of the thyroid tumors with indeterminate results of ultrasound-guided fine-needle aspiration (USFNA). Although with potential advantages, the working protocol of introducing USCB in the routine practice has not been established yet. This study aims to evaluate the efficacy of USCB when it is included in the clinical workflow of assessing the thyroid tumors with indeterminate USFNA results after a long-term follow up. METHODS: Between 2009 and 2016, consecutive patients receiving thyroid USFNA were reviewed retrospectively in the tertiary referral hospital. The patients, who finally received USCB for their thyroid tumors after repeated indeterminate USFNA results, were recruited. The important sonographic features in facilitating specific diagnoses by USCB, differentiating malignancy from benignity, and confirming origins of thyroid tumors were analyzed and the role of USCB was investigated. RESULTS: Thirty-nine patients met the inclusion criteria were analyzed. The specific diagnoses were confirmed in 23 patients (59%) by USCB. Taller than wide, ill-defined margin and hypoechogenicity helped in differentiating malignant tumors and the latter two features were pertinent to the success of applying USCB for specific diagnosis. No sonographic features were able to differentiate the thyroid malignancy from extra-thyroid origins exclusively. Thyroid USCB facilitated clinical decision making in 37 of the 39 patients (94.9%) with indeterminate USFNA results. CONCLUSION: The USCB is a cost-effective sampling procedure for confirming the diagnosis of indeterminate thyroid tumors and their clinical management, especially for those malignancies from extra-thyroid origins.

Neoadjuvant afatinib with paclitaxel for triple-negative breast cancer and the molecular characteristics in responders and non-responders.

BACKGROUND: The prognosis of triple-negative breast cancer (TNBC) is worse and a major proportion of TNBC expresses epidermal growth factor receptor (EGFR). Afatinib can inhibit EGFR signal pathway; however, its treatment effect for TNBC is unknown. Thus, we aimed to assess the efficacy and biomarkers of afatinib in combination with paclitaxel in a neoadjuvant setting. METHODS: Patients with stage II to III TNBC were enrolled. They received 40 mg of afatinib daily for 14 days, followed by daily afatinib and weekly paclitaxel (80 mg/m2) every 21 days for four to six cycles. To explore the mechanisms of responsiveness and non-responsiveness, 409 cancer-associated genes were sequenced. RESULTS: Twenty-one patients were enrolled and one patient achieved a complete clinical response; however, a 2 mm residual tumor was noted in the surgical specimen. Overall, 33.0% patients were responders. Fifteen patients received molecular testing. No activated mutation of EGFR or Her2 were found. Activated PI3K or JAK2 pathway were trended to associate with non-responder (p = 0.057). Mutation of homologous recombination (HR) genes were correlated with non-responsiveness (p = 0.005). Seven patients did not have altered PI3K, JAK2 or HR pathway; six (85.7%) of them were responder. Patients with the amplified DAXX gene was associated with a favorable trend of response (p = 0.109). CONCLUSION: Adding afatinib to neoadjuvant paclitaxel generated a modest effect in TNBC. Exploratory molecular analysis suggested that activated PI3K, JAK2 pathways and mutation of HR genes were associated with therapeutic non-responsiveness, and amplification of DAXX genes was associated with responsiveness to afatinib in combination with paclitaxel.

Epoxyeicosatrienoic acids and soluble epoxide hydrolase in physiology and diseases of the central nervous system.

Epoxyeicosatrienoic acids (EETs) are fatty acid signaling molecules synthesized by cytochrome P450 epoxygenases from arachidonic acid. The biological activity of EETs is terminated when being metabolized by soluble epoxide hydrolase (sEH), a process that serves as a key regulator of tissue EETs levels. EETs act through several signaling pathways to mediate various beneficial effects, including anti-inflammation, anti-apoptosis, and anti-oxidation with relieve of endoplasmic reticulum stress, thereby sEH has become a potential therapeutic target in cardiovascular disease and cancer therapy. Enzymes for EET biosynthesis and metabolism are both widely detected in both neuron and glial cells in the central nervous system (CNS). Recent studies discovered that astrocyte-derived EETs not only mediate neurovascular coupling and neuronal excitability by maintaining glutamate homeostasis but also glia-dependent neuroprotection. Genetic ablation as well as pharmacologic inhibition of sEH has greatly helped to elucidate the physiologic actions of EETs, and maintaining or elevating brain EETs level has been demonstrated beneficial effects in CNS disease models. Here, we review the literature regarding the studies on the bioactivity of EETs and their metabolic enzyme sEH with special attention paid to their action mechanisms in the CNS, including their modulation of neuronal activity, attenuation of neuroinflammation, regulation of cerebral blood flow, and improvement of neuronal and glial cells survival. We further reviewed the recent advance on the potential application of sEH inhibition for treating cerebrovascular disease, epilepsy, and pain disorder.

Curcumin Facilitates Aryl Hydrocarbon Receptor Activation to Ameliorate Inflammatory Astrogliosis.

Curcumin is an anti-inflammatory and neuroprotective compound in turmeric. It is a potential ligand of the aryl hydrocarbon receptor (AhR) that mediates anti-inflammatory signaling. However, the AhR-mediated anti-inflammatory effect of curcumin within the brain remains unclear. We investigated the role of AhR on the curcumin effect in inflammatory astrogliosis. Curcumin attenuated lipopolysaccharide (LPS)-induced proinflammatory IL-6 and TNF-α gene expression in primary cultured rat astrocytes. When AhR was knocked down, LPS-induced IL-6 and TNF-α were increased and curcumin-decreased activation of the inflammation mediator NF-κB p65 by LPS was abolished. Although LPS increased AhR and its target gene CYP1B1, curcumin further enhanced LPS-induced CYP1B1 and indoleamine 2,3-dioxygenase (IDO), which metabolizes tryptophan to AhR ligands kynurenine (KYN) and kynurenic acid (KYNA). Potential interactions between curcumin and human AhR analyzed by molecular modeling of ligand-receptor docking. We identified a new ligand binding site on AhR different from the classical 2,3,7,8-tetrachlorodibenzo-p-dioxin site. Curcumin docked onto the classical binding site, whereas KYN and KYNA occupied the novel one. Moreover, curcumin and KYNA collaboratively bound onto AhR during molecular docking, potentially resulting in synergistic effects influencing AhR activation. Curcumin may enhance the inflammation-induced IDO/KYN axis and allosterically regulate endogenous ligand binding to AhR, facilitating AhR activation to regulate inflammatory astrogliosis.