FluoroFusion: NHC-Catalyzed Nucleophilic Aromatic Substitution Reaction Unveils Functional Perfluorinated Diarylmethanones.

A mild, facile, and metal-free approach via the N-heterocyclic carbene-catalyzed SNAr reaction between aryl aldehydes with perfluoroarenes to obtain the coveted functional perfluorinated diarylmethanones is disclosed. This method accommodates a diverse substrate range and exhibits notable tolerance toward various functional groups. Our success in modifying biologically relevant molecules, crafting a fully fluorinated bioisosteric analogue of drug candidate D1, and highlighting the potential of these ketones as valuable electrolyte additives for lithium-ion batteries (LIBs) underscores the versatility of our methodology.

Pro-aromatic Dihydroquinazolinones - From Multigram Synthesis to Reagents for Gram-scale Metallaphotoredox Reactions.

Dihydroquinazolinone (DHQZ) has recently been harnessed as a ketone-derived pro-aromatic reagent extensively employed in (metalla)photoredox reactions as versatile group transfer agents. In this work, we outline a column chromatography-free protocol for the multigram-scale synthesis of pro-aromatic DHQZs as well as its use in a gram-scale nickel/photoredox dual-catalyzed cross-coupling in single-batch, photoflow, and simultaneous multiple smaller batches. While the single-batch approach leveraged moderate yields, a simple plug-flow photoreactor also exhibited amenable productivity (up to 45 % yield) despite the use of a heterogeneous base. Meanwhile, performing the metallaphotoredox-catalyzed reaction in multiple smaller batches in an improvised photoreactor facilitated high yields of up to 59 % and good reproducibility, implying a convenient alternative in the absence of photoflow setups.

A Randomised Trial Comparing Drug Coated Balloons and Conventional Balloons for the Treatment of Stent Graft Stenosis in Dialysis Vascular Access.

OBJECTIVE: Previous studies on arteriovenous fistulas have demonstrated the potential benefit of drug coated balloons (DCBs) in maintaining the patency of dialysis access. However, stenoses involving stent grafts were excluded from these studies. Therefore, the aim was to evaluate the effectiveness of DCBs in treating stent graft stenosis. METHODS: This was a prospective, single blinded, randomised controlled study. From March 2017 to April 2021, 40 patients with dysfunctional vascular access owing to stent graft stenosis were randomised to treatment with a DCB or conventional balloon. Clinical follow up was scheduled at one, three, and six months, and angiographic follow up was performed six months after the intervention. The primary outcome was angiographic late luminal loss at six months, and secondary outcomes included target lesion and access circuit primary patency at six months. RESULTS: Thirty-six participants completed follow up angiography. The DCB group had a superior mean late luminal loss at six months compared with the control group (1.82 mm ± 1.83 mm vs. 3.63 mm ± 1.08 mm, respectively, p = .001). All 40 patients completed clinical follow up. The DCB group had a superior six month target lesion primary patency compared with the control group [hazard ratio (HR) 0.23, 95% confidence interval (CI) 0.07 - 0.71; p = .005). Additionally, the DCB group had a numerically higher six month access circuit primary patency rate than the control group, although the difference was not statistically significant (HR 0.54, 95% CI 0.26 - 1.11, p = .095). CONCLUSION: Conventional balloon angioplasty is not durable in stent graft stenosis treatment. Treatment with DCBs provides less angiographic late luminal loss and potentially superior primary patency of the target lesion than treatment with conventional balloons. [ClinicalTrials ID: NCT03360279.].

Change in Activities of Daily Living in the Year Following a Stroke: A Latent Growth Curve Analysis.

BACKGROUND: Early prediction of future functional capability is crucial for stroke survivors' care management. OBJECTIVES: The purposes of this study were to test the trajectory of change across time in activities of daily living (ADLs) and to determine whether the National Institutes of Health Stroke Scale (NIHSS) score within 24 hours poststroke, gender, and age predict ADLs at 1, 3, 6, and 12 months poststroke. METHODS: A prospective cohort design was used. Baseline characteristics and neurological deficits were measured in 1,021 stroke survivors. The 13-item NIHSS was used to examine neurological status within 24 hours poststroke. ADLs were measured with the Barthel index at 1, 3, 6, and 12 months poststroke. A latent growth curve model was used to analyze how the dynamic changes in ADLs were related to NIHSS score, gender, and age. RESULTS: The latent growth curve model analyses revealed that, as the time following a stroke increases, survivors tend to gradually improve with regard to ADLs. In addition, lower levels of initial ADLs were associated with higher growth in ADLs over time. However, after 6 months poststroke, further gains in ADLs slowed. Based on further analysis, the findings indicate that a lower NIHSS score, being male, and a young age at time of stroke were associated with higher initial levels of ADLs. Having a higher NIHSS score, being female, and a young age at time of stroke predicted an increase in ADLs over time. DISCUSSION: To promote ADLs of stroke patients, NIHSS score at admission, gender, and age should be included as important predictors of stroke care management. The results highlight that the rehabilitation of stroke patients should be focused more on ADLs at 1-6 months poststroke.

Publisher Correction: EFHD2 promotes epithelial-to-mesenchymal transition and correlates with postsurgical recurrence of stage I lung adenocarcinoma.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

EFHD2 promotes epithelial-to-mesenchymal transition and correlates with postsurgical recurrence of stage I lung adenocarcinoma.

Surgery is the only curative treatment for early-stage non-small cell lung cancer (NSCLC) patients. However, approximately one-third of these patients develop recurrence, which remains the main cause of mortality in the postsurgical treatment of NSCLC. Many molecular markers have been proposed to predict recurrence of early-stage disease, but no marker has demonstrated sufficient reliability for clinical application. In the present study, the novel protein EF-hand domain-containing protein D2 (EFHD2) was identified as expressed in highly metastatic tumor cells. EFHD2 increased the formation of protrusive invadopodia structures and cell migration and invasion abilities and promoted the epithelial-to-mesenchymal transition (EMT) character of lung adenocarcinoma cells. We demonstrated that the mechanism of EFHD2 in enhancing EMT occurs partly through inhibition of caveolin-1 (CAV1) for cancer progression. The expression of EFHD2 was significantly correlated with postsurgical recurrence of patients with stage I lung adenocarcinoma in the Kaplan-Meier-plotter cancer database search and our retrospective cohort study (HR, 6.14; 95% CI, 2.40-15.74; P < 0.001). Multivariate Cox regression analysis revealed that EFHD2 expression was an independent clinical predictor for this disease. We conclude that EFHD2 expression is associated with increased metastasis and EMT and could serve as an independent marker to predict postsurgical recurrence of patients with stage I lung adenocarcinoma.

Auramine O, an incense smoke ingredient, promotes lung cancer malignancy.

Burning incense to worship deities is a popular religious ritual in large parts of Asia, and is a popular custom affecting more than 1.5 billion adherents. Due to incomplete combustion, burning incense has been well recognized to generate airborne hazards to human health. However, the correlation between burning incense and lung cancer in epidemiological studies remains controversy. Therefore, we speculated that some unknown materials in incense smoke are involved in the initiation or progression of lung cancer. Based on this hypothesis, we identified a major compound auramine O (AuO) from the water-soluble fraction of incense burned condensate using mass spectrometry. AuO is commonly used in incense manufacture as a colorant. Due to thermostable, AuO released from burned incenses becomes an unexpected air pollutant. AuO is classified as a Group 2B chemical by the International Agency of Research on Cancer (IARC), however, the damage of AuO to the respiratory system remains elusive. Our study revealed that AuO has no apparent effect on malignant transformation; but, it dramatically promotes lung cancer malignancy. AuO accumulates in the nucleus and induces the autophagy activity in lung tumor cells. AuO significantly enhances migration and invasive abilities and the in vitro and in vivo stemness features of lung tumor cells through activating the expression of aldehyde dehydrogenase family 1 member A1 (ALDH1A1), and ALDH1A1 knockdown attenuates AuO-induced autophagy activity and blocks AuO-induced lung tumor malignancy. In conclusion, we found that AuO, an ingredient of incense smoke, significantly increases the metastatic abilities and stemness characters of lung tumor cells through the activation of ALDH1A1, which is known to be associated with poor outcome and progression of lung cancer. For public health, reducing or avoiding the use of AuO in incense is recommended.

Sciellin mediates mesenchymal-to-epithelial transition in colorectal cancer hepatic metastasis.

Hepatic metastasis is the major cause of mortality in colorectal cancer (CRC) patients. Using proteomic analysis, we found sciellin (SCEL) to be specifically expressed in hepatic metastatic CRC cell lines. SCEL knockdown increased CRC cell migration and invasion, while overexpression had the opposite effect. SCEL knockdown also caused cancer cells to form more invasive structures within 3D cultures, increased the mesenchymal marker vimentin, and attenuated the epithelial marker E-cadherin. SCEL increased WNT signaling by activating ß-catenin and its downstream target c-myc, and activated mesenchymal-to-epithelial transition (MET) through a SCEL-ß-catenin-E-cadherin axis. SCEL showed higher expression in late stage primary CRC than in its hepatic metastatic counterpart. SCEL expression is dynamically modulated by TGF-ß1 and hypoxia, revealing a plastic MET mechanism for tumor colonization. Intrahepatic injection in immunodeficient mice revealed that SCEL is necessary for metastatic CRC tumor growth in the liver. These results demonstrate that SCEL is a MET inducer dynamically regulated through the metastasis process. They suggest SCEL may be a useful therapeutic target for preventing or eliminating CRC hepatic metastasis.

ICAM1 Is a Potential Cancer Stem Cell Marker of Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of esophageal cancer diagnosed in Asian countries, with its incidence on the rise. Cancer stem cell (CSC; also known as tumor-initiating cells, TIC) is inherently resistant to cytotoxic chemotherapy and radiation and associates with poor prognosis and therapy failure. Targeting therapy against cancer stem cell has emerged as a potential therapeutic approach to develop effective regimens. However, the suitable CSC marker of ESCC for identification and targeting is still limited. In this study, we screened the novel CSC membrane protein markers using two distinct stemness characteristics of cancer cell lines by a comparative approach. After the validation of RT-PCR, qPCR and western blot analyses, intercellular adhesion molecule 1 (ICAM1) was identified as a potential CSC marker of ESCC. ICAM1 promotes cancer cell migration, invasion as well as increasing mesenchymal marker expression and attenuating epithelial marker expression. In addition, ICAM1 contributes to CSC properties, including sphere formation, drug resistance, and tumorigenesis in mouse xenotransplantation model. Based on the analysis of ICAM1-regulated proteins, we speculated that ICAM1 regulates CSC properties partly through an ICAM1-PTTG1IP-p53-DNMT1 pathway. Moreover, we observed that ICAM1 and CD44 could have a compensation effect on maintaining the stemness characteristics of ESCC, suggesting that the combination of multi-targeting therapies should be under serious consideration to acquire a more potent therapeutic effect on CSC of ESCC.

Feasibility and Safety of Coronary Procedures via an Arteriovenous Graft Approach in Patients on Maintenance Hemodialysis.

BACKGROUND: Traditionally, a radial or brachial arterial approach is unadvisable in hemodialysis patients. Consequently, coronary angiography or angioplasty is usually performed via a femoral artery approach in these patients, who carry a higher risk of vascular access complications. In hemodialysis patients, arteriovenous grafts (AVG) are created for repeated punctures; however, the feasibility and safety of a trans-AVG approach for coronary angiography or angioplasty remains unclear. METHODS: In our institution, cardiac catheterizations were attempted via AV grafts in hemodialysis patients with a U-shaped forearm AVG. We retrospectively identified coronary angiography or angioplasty procedures in hemodialysis patients from a computer-based database in our hospital. The procedure details and outcomes were obtained from review of the clinical, angiographic and hemodialysis records. RESULTS: From 2008 to 2013, 167 procedures in hemodialysis patients were identified from 2866 diagnostic or interventional coronary procedures in our institution. Out of these, 24 procedures in 17 patients were performed via a trans-AVG approach. In all AVG procedures, a 6F 16-cm or 7F 10-cm sheath was placed from the AVG into the brachial artery. All diagnostic procedures were successfully performed. In 14 procedures, the patients also underwent angioplasty and all of the angioplasty procedures were successful. There was no arterial spasm, arterial dissection, puncture site hematoma, or acute thrombosis of the AVG during or after the procedures. CONCLUSIONS: A trans-AVG approach appears to be a feasible and safe route for coronary angiography or angioplasty in hemodialysis patients with a U-shaped forearm AVG. However, further studies with a larger patient number are necessary. KEY WORDS: Arteriovenous graft; Hemodialysis; Percutaneous coronary intervention.

Terpinen-4-ol Induces Apoptosis in Human Nonsmall Cell Lung Cancer In Vitro and In Vivo.

Terpinen-4-ol, a monoterpene component of the essential oils of several aromatic plants, exhibits antitumor effects. In this study, the antitumor effects of terpinen-4-ol and the cellular and molecular mechanisms responsible for it were evaluated and studied, respectively on human nonsmall cell lung cancer (NSCLC) cells. Our results indicated that terpinen-4-ol elicited a dose-dependent cytotoxic effect, as determined by MTT assay. Increased sub-G1 population and annexin-V binding, activation of caspases 9 and 3, cleavage of poly(ADPribose) polymerase (PARP), and a decrease of mitochondrial membrane potential (MMP) indicated involvement of the mitochondrial apoptotic pathway in terpinen-4-ol-treated A549 and CL1-0 cells. Elevation of the Bax/Bcl-2 ratio and a decrease in IAP family proteins XIAP and survivin were also observed following terpinen-4-ol treatment. Notably, terpinen-4-ol was able to increase p53 levels in A549 and CL1-0 cells. Diminution of p53 by RNA interference induced necrosis instead of apoptosis in A549 cells following terpinen-4-ol treatment, indicating that terpinen-4-ol-elicited apoptosis is p53-dependent. Moreover, intratumoral administration of terpinen-4-ol significantly suppressed the growth of s.c. A549 xenografts by inducing apoptosis, as confirmed by TUNEL assay. Collectively, these data provide insight into the molecular mechanisms underlying terpinen-4-ol-induced apoptosis in NSCLC cells, rendering this compound a potential anticancer drug for NSCLC.

The effects of DNA formulation and administration route on cancer therapeutic efficacy with xenogenic EGFR DNA vaccine in a lung cancer animal model.

BACKGROUND: Tyrosine kinase inhibitor gefitinib is effective against lung cancer cells carrying mutant epidermal growth factor receptor (EGFR); however, it is not effective against lung cancer carrying normal EGFR. The breaking of immune tolerance against self epidermal growth factor receptor with active immunization may be a useful approach for the treatment of EGFR-positive lung tumors. Xenogeneic EGFR gene was demonstrated to induce antigen-specific immune response against EGFR-expressing tumor with intramuscular administration. METHODS: In order to enhance the therapeutic effect of xenogeneic EGFR DNA vaccine, the efficacy of altering routes of administration and formulation of plasmid DNA was evaluated on the mouse lung tumor (LL2) naturally overexpressing endogenous EGFR in C57B6 mice. Three different combination forms were studied, including (1) intramuscular administration of non-coating DNA vaccine, (2) gene gun administration of DNA vaccine coated on gold particles, and (3) gene gun administration of non-coating DNA vaccine. LL2-tumor bearing C57B6 mice were immunized four times at weekly intervals with EGFR DNA vaccine. RESULTS: The results indicated that gene gun administration of non-coating xenogenic EGFR DNA vaccine generated the strongest cytotoxicity T lymphocyte activity and best antitumor effects. CD8(+) T cells were essential for anti-tumor immunity as indicated by depletion of lymphocytes in vivo. CONCLUSION: Thus, our data demonstrate that administration of non-coating xenogenic EGFR DNA vaccine by gene gun may be the preferred method for treating EGFR-positive lung tumor in the future.