Perioperative circulating tumor DNA as a potential prognostic marker for operable stage I to IIIA non-small cell lung cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a noninvasive biomarker for dynamically monitoring tumors. However, published data on perioperative ctDNA in patients with operable non-small cell lung cancer (NSCLC) are currently limited. METHODS: This prospective study recruited 123 patients with resectable stage I to IIIA NSCLC. Preoperative and postoperative plasma samples and tumor tissue samples were subjected to next-generation sequencing with a panel of 425 cancer-related genes. Peripheral blood samples were collected before surgery, postoperatively within 1 month, and every 3 to 6 months for up to 3 years. RESULTS: After 4 exclusions, 119 eligible patients were enrolled from June 2016 to February 2019. Presurgical ctDNA was detectable in 29 of 117 patients (24.8%) and was associated with inferior recurrence-free survival (RFS; hazard ratio [HR], 2.42; 95% CI, 1.11-5.27; P = .022) and inferior overall survival (OS; HR, 5.54; 95% CI, 1.01-30.35; P = .026). Similarly, ctDNA was detected in 12 of 116 first postsurgical samples (10.3%) and was associated with shorter RFS (HR, 3.04; 95% CI, 1.22-7.58; P = .012). During surveillance after surgery, longitudinal ctDNA-positive patients (37 of 119; 31.1%) had significantly shorter RFS (HR, 3.46; 95% CI, 1.59-7.55; P < .001) and significantly shorter OS (HR, 9.99; 95% CI, 1.17-85.78; P = .010) in comparison with longitudinal ctDNA-negative patients. Serial ctDNA detection preceded radiologic disease recurrence by a median lead time of 8.71 months. CONCLUSIONS: These results suggest that perioperative ctDNA analyses can predict recurrence and survival, and serial ctDNA analyses can identify disease recurrence/metastasis earlier than routine radiologic imaging in patients with resectable NSCLC. LAY SUMMARY: The utility of serial circulating tumor DNA (ctDNA) monitoring for predicting disease recurrence and survival for early-stage non-small cell lung cancer (NSCLC) has not been well characterized. The detection of ctDNA before and after surgery is associated with the identification of a high risk of disease recurrence and long-term patient outcomes for resectable NSCLC. Perioperative ctDNA analyses identify disease recurrence earlier than routine radiologic imaging. ctDNA analyses can detect minimal residual disease for resectable NSCLC and thus can facilitate early intervention.

Tongue acupuncture for the treatment of post-stroke dysphagia: a meta-analysis of randomized controlled trials.

Objectives: Post-stroke dysphagia is the most common neurological impairment after stroke. The swallowing process is controlled by a network made up of the cerebral cortex, subcortical area, and brainstem structure. The disruption of the swallowing network after stroke leads to dysphagia. The affected swallowing muscles after stroke mainly include the laryngeal muscles (suprahyoid muscle and thyrohyoid muscle) and infrahyoid muscle. These muscles experience kinematic effects and muscle strength weakens, resulting in reduced movement in the swallowing process. Acupuncture can change the excitability of cerebral cortical nerve cells, promote the recovery of neurological function, and enhance neuromuscular excitability, ultimately improving the control of swallowing-related nerves and muscles and promoting swallowing functional recovery. In this meta-analysis, we systematically evaluate the clinical efficacy of acupuncture in the treatment of post-stroke dysphagia. Methods: Randomized controlled trials of tongue acupuncture therapy for post-stroke dysphagia were searched and selected from seven electronic databases (PubMed, CBM, Cochrane, Embase, CNKI, VPCS, and Wan fang). The Cochrane Collaboration tool was used to conduct methodological quality assessment. Rev. Man 5.4 software was utilized to perform data analysis. Results: A total of 15 studies with 1,094 patients were included. Meta-analysis Showed that WST score WST score (MD = -0.56, 95% CI (-1.23, 0.12), Z = 1.62, p < 0.00001), SSA score (MD = -1.65, 95% CI (-2.02, -1.28), Z = 8.77, p < 0.00001). These results suggested that the treatment group (tongue acupuncture or tongue acupuncture combined with other therapies) was superior to the control group in reducing WST scores and SSA scores. The clinical efficacy of the tongue acupuncture group was better compared with the control group (MD = 3.83, 95% CI (2.61, 5.62), Z = 6.88, p < 0.00001). Conclusion: The meta-analysis showed that the total effective rate of patients with dysphagia after stroke in the treatment group (acupuncture, tongue acupuncture, and acupuncture combined with other therapy) was higher than that in the control group. These results indicated that acupuncture, tongue acupuncture, and acupuncture combined with other therapy can improve post-stroke dysphagia.

Current evidence, clinical applications, and future directions of transcranial magnetic stimulation as a treatment for ischemic stroke.

Transcranial magnetic stimulation (TMS) is a non-invasive brain neurostimulation technique that can be used as one of the adjunctive treatment techniques for neurological recovery after stroke. Animal studies have shown that TMS treatment of rats with middle cerebral artery occlusion (MCAO) model reduced cerebral infarct volume and improved neurological dysfunction in model rats. In addition, clinical case reports have also shown that TMS treatment has positive neuroprotective effects in stroke patients, improving a variety of post-stroke neurological deficits such as motor function, swallowing, cognitive function, speech function, central post-stroke pain, spasticity, and other post-stroke sequelae. However, even though numerous studies have shown a neuroprotective effect of TMS in stroke patients, its possible neuroprotective mechanism is not clear. Therefore, in this review, we describe the potential mechanisms of TMS to improve neurological function in terms of neurogenesis, angiogenesis, anti-inflammation, antioxidant, and anti-apoptosis, and provide insight into the current clinical application of TMS in multiple neurological dysfunctions in stroke. Finally, some of the current challenges faced by TMS are summarized and some suggestions for its future research directions are made.

Dendritic cells mediated by small extracellular vesicles derived from MSCs attenuated the ILC2 activity via PGE2 in patients with allergic rhinitis.

BACKGROUND: Mesenchymal stromal cells-derived small extracellular vesicles (MSC-sEVs) have recently attracted considerable attention because of their therapeutic potential in various immune diseases. We previously reported that MSC-sEVs could exert immunomodulatory roles in allergic airway inflammation by regulating group 2 innate lymphoid cell (ILC2) and dendritic cell (DC) functions. Therefore, this study aimed to investigate the indirect effects of MSC-sEVs on ILC2s from patients with allergic rhinitis (AR) via DCs. METHODS: Here, we isolated sEVs from induced pluripotent stem cells-MSCs using anion-exchange chromatography and mature DCs (mDCs) were treated with MSC-sEVs. sEV-mDCs were co-cultured with peripheral blood mononuclear cells from patients with AR or purified ILC2s. The levels of IL-13 and GATA3 in ILC2s were examined by flow cytometry. Bulk RNA sequence for mDCs and sEV-mDCs was employed to further probe the potential mechanisms, which were then validated in the co-culture systems. RESULTS: sEV-mDCs showed impaired capacity in priming the levels of IL-13 and GATA3 in ILC2s when compared with mDCs. Furthermore, there was higher PGE2 and IL-10 production from sEV-mDCs, and the blockade of them especially the former one reversed the inhibitory effects of sEV-mDCs. CONCLUSIONS: We demonstrated that MSC-sEVs were able to dampen the activating effects of mDCs on ILC2s in patients with AR. Mechanismly, the PGE2-EP2/4 axis played an essential role in the immunomodulatory effects of sEV-mDCs on ILC2s. Herein, we provided new insights into the mechanism underlying the therapeutic effects of MSC-sEVs in allergic airway inflammation.

Mesenchymal stem cells overexpressing interleukin-10 prevent allergic airway inflammation.

BACKGROUNDS: Allergic airway inflammation is prevalent worldwide and imposes a considerable burden on both society and affected individuals. This study aimed to investigate the therapeutic advantages of mesenchymal stem cells (MSCs) overexpressed interleukin-10 (IL-10) for the treatment of allergic airway inflammation, as both IL-10 and MSCs possess immunosuppressive properties. METHODS: Induced pluripotent stem cell (iPSC)-derived MSCs were engineered to overexpress IL-10 via lentiviral transfection (designated as IL-10-MSCs). MSCs and IL-10-MSCs were administered intravenously to mice with allergic inflammation induced by ovalbumin (OVA), and the features of allergic inflammation including inflammatory cell infiltration, Th cells in the lungs, and T helper 2 cell (Th2) cytokine levels in bronchoalveolar lavage fluid (BALF) were examined. MSCs and IL-10-MSCs were co-cultured with CD4+ T cells from patients with allergic rhinitis (AR), and the levels of Th2 cells and corresponding type 2 cytokines were studied. RNA-sequence was performed to further investigate the potential effects of MSCs and IL-10-MSCs on CD4+ T cells. RESULTS: Stable IL-10-MSCs were established and characterised by high IL-10 expression. IL-10-MSCs significantly reduced inflammatory cell infiltration and epithelial goblet cell numbers in the lung tissues of mice with allergic airway inflammation. Inflammatory cell and cytokine levels in BALF also decreased after the administration of IL-10-MSCs. Moreover, IL-10-MSCs showed a stronger capacity to inhibit the levels of Th2 after co-cultured with CD4+ T cells from patients with AR. Furthermore, we elucidated lower levels of IL-5 and IL-13 in IL-10-MSCs treated CD4+ T cells, and blockade of IL-10 significantly reversed the inhibitory effects of IL-10-MSCs. We also reported the mRNA profiles of CD4+ T cells treated with IL-10-MSCs and MSCs, in which IL-10 played an important role. CONCLUSION: IL-10-MSCs showed positive effects in the treatment of allergic airway inflammation, providing solid support for the use of genetically engineered MSCs as a potential novel therapy for allergic airway inflammation.

Using PIM-Taiwan, PRISCUS, and Beers criteria to assess potentially inappropriate medication use among older adults with 90-day rehospitalization: a population-based study in Taiwan.

Background: Multimorbidity and polypharmacy increase the risk of hospitalization in older adults receiving potentially inappropriate medication (PIM). The current study compared the ability of PIM-Taiwan, PRISCUS, and Beers criteria to predict 90-day rehospitalization in older patients with and without PIM. Methods: The retrospective cohort study used Taiwan's Longitudinal Health Insurance Database to retrieve quarterly information about prescribed medication for adults aged ≥65 years hospitalized between 2001 and 2018. We analyzed the association of PIM with 90-day rehospitalization using logistic regression. Results: The study cohort included 206,058 older adults (mean age: 72.5 years). In the analysis, 133,201 (64.6%), 97,790 (47.5%), and 147,450 (71.6%), were identified as having PIM exposure in PIM-Taiwan, PRICUS, and Beers criteria, respectively. PIM-Taiwan criteria found exposure to PIM affecting the cardiovascular (adjusted OR [aOR] 1.37, 95% confidence interval [CI] = 1.32-1.41), gastrointestinal (aOR 1.26, 95% CI = 1.23-1.30), central nervous (aOR 1.11, 95% CI = 1.08-1.14), and respiratory (aOR 1.16, 95% CI = 1.12-1.20) systems significantly increased the risk of 90-day rehospitalization, after adjustment for covariates. In PRISCUS criteria, exposure to PIM affecting the respiratory (aOR 1.48, 95% CI = 1.41-1.56), central nervous (aOR 1.12, 95% CI = 1.09-1.15), and cardiovascular (aOR 1.20, 95% CI = 1.16-1.24) systems significantly increased the risk. In Beers criteria, exposure to PIM affecting the cardiovascular (aOR 1.37, 95% CI = 1.32-1.41), gastrointestinal (aOR 1.38, 95% CI = 1.35-1.42), central nervous (aOR 1.18, 95% CI = 1.15-1.21), endocrine (aOR 1.10, 95% CI = 1.06-1.15), and respiratory (aOR 1.09, 95% CI = 1.04-1.13) systems significantly increased the risk. Patients with 90-day rehospitalization had higher rates of the potentially harmful drug-drug interaction (DDI) pairs of serotonin syndrome (n = 19; 48.8%), QT prolongation (n = 4; 30.8%), extrapyramidal symptoms (EPS) (n = 102; 24.5%), and hypokalemia (n = 275; 20.1%). Conclusion: Beers criteria was more efficient in predicting 90-day rehospitalization among older adults experiencing PIM in Taiwan than either PIM-Taiwan or PRISCUS. The risk of 90-day rehospitalization was associated with the potentially harmful DDI classes of serotonin syndrome, QT prolongation, EPS, and hypokalemia.

Association of EGFR mutation or ALK rearrangement with expression of DNA repair and synthesis genes in never-smoker women with pulmonary adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement may predict the outcome of targeted drug therapy and also are associated with the efficacy of chemotherapy in patients with nonsmall cell lung cancer (NSCLC). The authors of this report investigated the relation of EGFR mutation or ALK rearrangement status and the expression of DNA repair or synthesis genes, including excision repair cross-complementing 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), thymidylate synthetase (TS), and breast cancer-early onset (BRCA1), as a potential explanation for these observations. METHODS: In total, 104 resected lung adenocarcinomas from women who were nonsmokers were analyzed concurrently for EGFR mutations, ALK rearrangements, and mRNA expression of the ERCC1, RRM1, TS, and BRCA1 genes. EGFR mutations were detected with a proprietary detection kit, ALK rearrangements were detected by polymerase chain reaction analysis, and genetic mRNA expression was detected by real-time polymerase chain reaction analysis. RESULTS: Of 104 patients, 73 (70.2%) had EGFR mutations, and 10 (9.6%) had ALK rearrangements. ERCC1 mRNA levels in patients who had EGFR mutations were 3.44 ± 1.94 × 10(-3) , which were significantly lower than the levels in patients who were positive for ALK rearrangements and in patients who were negative for both biomarkers (4.60 ± 1.95 × 10(-3) and 4.95 ± 2.33 × 10(-3) , respectively; P = .010). However, TS mRNA levels were significantly lower in patients who had EGFR mutations (1.15 ± 1.38 × 10(-3) vs 2.69 ± 3.97 × 10(-3) ; P = .006) or ALK rearrangements (1.21 ± 0.78 × 10(-3) vs 2.69 ± 3.97 × 10(-3) ; P = .020) than in patients who were negative for both biomarkers. CONCLUSIONS: NSCLC specimens that harbored activating EGFR mutations were more likely to express low ERCC1 and TS mRNA levels, whereas patients with NSCLC who had ALK rearrangement were more likely to express low TS mRNA levels.

GTP-binding protein Di-RAS3 diminishes the migration and invasion of non-small cell lung cancer by inhibiting the RAS/extracellular-regulated kinase pathway.

The GTP-binding protein Di-Ras3 (DIRAS3) has been established as a maternally imprinted tumor suppressor gene. Growing evidence has correlated the DIRAS3 gene with tumor progression, but its role in non-small cell lung cancer (NSCLC) is rarely reported. Accordingly, the current study sought to evaluate the role and mechanism of DIRAS3 in NSCLC cell progression. First, we uncovered that DIRAS3 was poorly expressed in NSCLC tissues and cells. Subsequently, we examined the effect of DIRAS3 over-expression or knockdown in different lung cancer cells on their malignant phenotypes, with the help of transwell cell migration and invasion assays, and Western blot analyses. It was found that the over-expression of DIRAS3 inhibited the migration and invasion of A549 cells or H520 cells, whereas knockdown of DIRAS3 led to opposing trends. In addition, over-expression of DIRAS3 attenuated the tumor growth and reduced the number of lung tumor nodules. Mechanistically, DIRAS3 may inhibit the migration and invasion of NSCLC cells by inhibiting the RAS/extracellular-regulated kinase (ERK) signaling pathway. Collectively, our findings indicate that DIRAS3 could serve as a potential therapeutic target biomarker for NSCLC.

Tongue Acupuncture for the Treatment of Poststroke Aphasia: A Systematic Review and Meta-Analysis.

Objective: This review evaluated the efficacy of tongue acupuncture for the clinical treatment of poststroke aphasia. Methods: PubMed, Medline, Cochrane, Embase, CNKI, VIP, and Wanfang databases were searched from their inception to 1st June 2022. The dataset included randomized controlled trials (RCTs) with tongue acupuncture for the treatment of poststroke aphasia. Data aggregation and risk of bias evaluation were conducted on Review Manager Version 5.4.1 and Stata16.0. The main outcome measures included the Aphasia Battery of Chinese (ABC), the Chinese Functional Communication Profile (CFCP), the Boston Diagnostic Aphasia Examination (BDAE), and clinical efficiency. Then, comparing the effectiveness of tongue acupuncture, tongue acupuncture combined with conventional therapies, conventional therapies with head acupuncture, language training, body acupuncture, and Jie Yu Dan. Results: A total of 20 studies with 1355 patients were included. Meta-analysis showed that compared with conventional treatments, tongue acupuncture has a significant improvement in clinical efficacy score (MD = 1.25, 95% CI (1.09, 1.43), P=0.001) and CFCP of poststroke aphasia (MD = 39.78, 95% CI (26.59, 52.97), P < 0.00001), but was not significant in improving ABC (MD = 5.95, 95% CI (2.85, 9.04), P=0.06). Compared to the conventional treatments, tongue acupuncture combined with conventional therapies promoted the ABC (MD = 11.48, 95% CI (2.20, 20.75), P < 0.00001), clinical efficacy score (MD = 1.22, 95% CI (1.14, 1.30), P < 0.00001), and CFCP score (MD = 29.80, 95% CI (19.08, 40.52), P < 0.00001) of poststroke aphasia. Conclusion: This systematic review indicated that tongue acupuncture or tongue acupuncture combined with conventional treatments was an effective therapy for treating poststroke aphasia. However, stricter evaluation standards and rigorously designed RCTs are needed.

Aurora-A/FOXO3A/SKP2 axis promotes tumor progression in clear cell renal cell carcinoma and dual-targeting Aurora-A/SKP2 shows synthetic lethality.

Renal cell carcinoma (RCC) is a common malignant tumor in the world. Histologically, most of RCC is classified as clear cell renal cell carcinoma (ccRCC), which is the most prevalent subtype. The overall survival of patients with ccRCC is poor, thus it is urgent to further explore its mechanism and target. S-phase kinase-associated protein 2 (SKP2) is overexpressed in a variety of human cancers and is associated with poor prognosis by enhancing tumor progression. However, it is unclear whether or how SKP2 is involved in ccRCC progression. Here, we reported that overexpression of SKP2 enhanced cell proliferation of ccRCC, while SKP2 depletion exhibited the opposite effect. Bioinformatic analyses found that SKP2 was positively correlated with Aurora-A (Aur-A) in ccRCC. The protein and mRNA levels of SKP2 were elevated or reduced by Aur-A overexpression or silencing, respectively. It was further found that Aur-A caused an increase phosphorylation of FOXO3A, which is a negatively transcription factor for SKP2. Interestingly, SKP2 mediated ubiquitylation and degradation of FOXO3A depend on the kinase activity of Aur-A. The combination of Aur-A inhibitor MLN8237 and SKP2 inhibitor SZL P1-41 showed a synergistic tumor growth inhibition in vivo and in vitro of ccRCC models. Thus, our data reveal that Aurora-A/FOXO3A/SKP2 axis promotes tumor progression in ccRCC, and the double inhibition of SKP2 and Aur-A shows significant synergistic effect, which indicates a potential new therapeutic strategy for ccRCC.

Homogenizing Li2CO3 Nucleation and Growth through High-Density Single-Atomic Ru Loading toward Reversible Li-CO2 Reaction.

The high activation barrier and sluggish kinetics of Li2CO3 decomposition impose a severe challenge on the development of a Li-CO2 battery with high Coulombic efficiency. To tackle this issue, herein we devise a novel synthetic tactic by combining electrostatic assembly with in situ polycondensation to obtain a single-atomic Ru catalyst of high density up to ∼5 wt %. When deployed to the CO2 cathode, the catalyst delivered an extraordinary capacity of 44.7 Ah g-1, an ultralow charge/discharge polarization of 0.97 V at 0.1 A g-1 (1.90 V at 2 A g-1), and a long-term cycling stability up to 367 cycles at 1 Ah g-1 (196 cycles at 2 Ah g-1), outshining most of the state-of-the-art CO2 cathode catalysts reported today. Further through extensive in situ and ex situ electroanalytical, spectroscopic, and microscopic characterizations, we attribute the superb battery performance mainly to the highly reversible Li2CO3 formation/decomposition, facilitated by the homogenized and downsized Li2CO3 nucleation and growth on account of the high density single-atomic Ru loading. This work not only offers a facile method to fabricate single-atom catalysts with high mass loading but also sheds light on promoting the reversible Li-CO2 reaction by mediating product morphology.

Effect of Vacancy Behavior on Precipitate Formation in a Reduced-Activation V-Cr-Mn Medium-Entropy Alloy.

In this work, we studied the evolution of vacancy-like defects and the formation of brittle precipitates in a reduced-activation V-Cr-Mn medium-entropy alloy. The evolution of local electronic circumstances around Cr and Mn enrichments, the vacancy defects, and the CrMn3 precipitates were characterized by using scanning electron microscopy with energy-dispersive spectroscopy, X-ray diffraction, and positron annihilation spectroscopy. The microstructure measurements showed that the Mn and Cr enrichments in the as-cast sample significantly evolved with temperature, i.e., from 400 °C, the Cr/Mn-segregated regions gradually dissolved into the matrix and then disappeared, and from 900 °C to 1000 °C, they existed as CrMn3 precipitates. The crystallite size of the phase corresponding to CrMn3 precipitates was about 29.4 nm at 900 °C and 43.7 nm at 1000 °C. The positron annihilation lifetime results demonstrated that the vacancies mediated the migration of Cr and Mn, and Cr and Mn segregation finally led to the formation of CrMn3 precipitates. The coincidence Doppler broadening results showed that the characteristic peak moved to the low-momentum direction, due to an increase in the size of the vacancy defects at the interface and the formation of CrMn3 precipitates.

[Functional reconstruction of the medial collateral ligament with double-bundle allograft technique].

OBJECTIVE: To discuss a new technique about reconstruction of medial collateral ligament (MCL) with double bundle allograft and to evaluate the short-term clinical efficacy. METHODS: All 53 patients who suffered from valgus instability of the knee were selected. All cases were diagnosed of MCL injury because the medial gap of the knee widened more than 5 mm compared with collateral knee by the stress X-ray, MRI displayed discontinuity of MCL and valgus stress test was positive. All patients were accepted arthroscopic evaluation through inferomedial and inferolateral arthroscopy portal incisions to ascertain whether there were intra-articular injuries. An 8 cm incision was made from 1 cm superior adductor tubercle to 5 cm proximal medial tibia joint line in a longitudinal fashion. The anterior tibia insertion was defined as 15 mm lateral from the medial tibia edge and 45 mm under the medial tibia joint line. The posterior tibia insertion was defined as 15 mm lateral from the medial tibia edge and 20 mm under the medial tibia joint line. We used 5 mm or 6 mm reamer to drill the tibia tunnel along with guide pin, and then drill the femur tunnel with 6 mm or 7 mm drill in the top of the adductor tubercle about 25 mm or 30 mm length. The allograft was pulled into the tunnel from tibia to the femur and fixed with absorbable interference screw. Patients carried out active rehabilitation program after operation. One year after the operation, IKDC score, Lysholm score were used to evaluate the clinical effect. RESULTS: The IKDC score (A or B, 86.78% vs. 0), Lysholm scores (89.7 ± 3.4 vs. 51.8 ± 4.9, t = -79.724, P < 0.05) were significantly improved compared with preoperative in all patients. Medial joint widened gap decreased from (10.4 ± 2.4) mm preoperative to (2.8 ± 1.5) mm postoperative from X ray and the differences were significant (t = 41.727, P < 0.05). Among these patients, the medial joint widened gap of 46 cases were less than 3 mm, 7 cases were from 3 mm to 5 mm. The range of motion was 135.4° ± 2.5° preoperative and 132.7° ± 3.7° postoperative. The 9 patients still had medial tenderness 1 year after operation. CONCLUSION: Application double bundle allograft technique to reconstruct MCL can significantly improve the stability of the knee and the short-term clinical efficacy was sure.

Regulation of ERα Stability and Estrogen Signaling in Breast Cancer by HOIL-1.

Estrogen receptor α (ERα) is the major driver for breast tumor carcinogenesis and progression, while ERα positive breast cancer is the major subtype in breast malignancies, which account for 70% breast cancers in patients. The success of endocrine therapy such as tamoxifen is one of the biggest breakthroughs in breast cancer treatments. However, the endocrine therapy resistance is a headache problem in breast cancer. Further mechanisms need to be identified to the effect of ERα signaling in controlling breast cancer progression and drug resistance. HOIL-1 was firstly identified as the ERα transcriptional co-activator in modulating estrogen signaling in breast cancer. In our current study, we showed that HOIL-1, which was elevated in breast cancer, related to good prognosis in ERα positive breast cancer, but correlated with poor outcome in endocrine-treated patients. HOIL-1 was required for ERα positive breast cancer proliferation and clone formation, which effect could be rescued by further ERα overexpression. Further mechanism studies showed that HOIL-1 is required for ERα signaling activity in breast cancer cells. HOIL-1 could interact with ERα in the cytosol and modulate ERα stability via inhibiting ERα K48-linked poly-ubiquitination. Thus, our study demonstrated a novel post-translational modification in ERα signaling, which could provide novel strategy for ERα-driven breast cancer therapy.

TMED3 promotes the progression and development of lung squamous cell carcinoma by regulating EZR.

Lung squamous cell carcinoma (LUSC) has a poor clinical prognosis and lacks effective targeted therapy. The transmembrane emp24 trafficking protein 3 (TMED3) belongs to the TMED family, which is responsible for the transport of intracellular proteins. This study was to explore the clinicopathological significance and biological effects of TMED3 in LUSC. Expression of TMED3 in LUSC was detected by immunohistochemical (IHC). The loss-of-function assays were used to investigate the effects of TMED3 on proliferation, apoptosis, cell cycle, and migration of LUSC cells. The influence of TMED3 knockdown on tumor growth in vivo was evaluated by mice xenograft models. In addition, the downstream target of TMED3 was recognized by RNA sequencing and Ingenuity Pathway Analysis (IPA). Moreover, TMED3 was upregulated in LUSC tissue, which was positively correlated with pathological grade. TMED3 knockdown was involved in the regulation of LUSC cell function, such as inhibition of proliferation, reduction of colony formation, induction of apoptosis, and reduction of migration. TMED3 knockdown induced abnormalities in apoptosis-related proteins in LUSC cells. In addition, the inhibition of cell migration by TMED3 knockdown was achieved by regulating EMT. Mechanically, EZR was considered as a potential target for TMED3 to regulate the progress of LUSC. Inhibition of EZR can inhibit the progression of LUSC, and even reduce the promoting effects of TMED3 overexpression on LUSC. In conclusion, TMED3 promoted the progression and development of LUSC by EZR, which may be a novel therapeutic target for LUSC.

mRNA Network: Solution for Tracking Chemotherapy Insensitivity in Small-Cell Lung Cancer.

Background: Small-cell lung cancer (SCLC) has poor prognosis and is prone to drug resistance. It is necessary to search for possible influencing factors for SCLC chemotherapy insensitivity. Therefore, we proposed an mRNA network to track the chemotherapy insensitivity in SCLC. Methods: Six samples of patients with SCLC were recruited for RNA sequencing. TopHat2 and Cufflinks were used to make differential analysis. Functional analysis was applied as well. Finally, multidimensional validation was applied for verifying the results we obtained by experiment. Results: This study was a trial of drug resistance in 6 SCLC patients after first-line chemotherapy. The top 10 downregulated genes differentially expressed in the chemo-insensitive group were SERPING1, DRD5, PARVG, PRAME, NKX1-1, MCTP2, PID1, PLEKHA4, SPP1, and SLN. Cell-cell signaling by Wnt (p=6.98E - 21) was the most significantly enriched GO term in biological process, while systemic lupus erythematosus (p=6.97E - 10), alcoholism (p=1.01E - 09), and transcriptional misregulation in cancer (p=0.00227988) were the top three ones of KEGG pathways. In multiple public databases, we also highlighted and verified the vital role of glycolysis/gluconeogenesis pathway and corresponding genes in chemo-insensitivity in SCLC. Conclusion: Our study confirmed some SCLC chemotherapy insensitivity-related genes, biological processes, and pathways, thus constructing the chemotherapy-insensitive network for SCLC.

A 64-week, multicenter, open-label study of aripiprazole effectiveness in the management of patients with schizophrenia or schizoaffective disorder in a general psychiatric outpatient setting.

OBJECTIVE: To evaluate the overall long-term effectiveness of aripiprazole in patients with schizophrenia in a general psychiatric practice setting in Taiwan. METHODS: This was a prospective, open-label, multicenter, post-market surveillance study in Taiwanese patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of schizophrenia or schizoaffective disorder requiring a switch in antipsychotic medication because current medication was not well tolerated and/or clinical symptoms were not well controlled. Eligible patients were titrated to aripiprazole (5-30 mg/day) over a 12-week switching phase, during which their previous medication was discontinued. Patients could then enter a 52-week, long-term treatment phase. Aripiprazole was flexibly dosed (5-30 mg/day) at the discretion of the treating physicians. Efficacy was assessed using the Clinical Global Impression scale Improvement (CGI-I) score, the Clinical Global Impression scale Severity (CGI-S) score, The Brief Psychiatry Rating Scale (BPRS), and the Quality of Life (QOL) scale, as well as Preference of Medicine (POM) ratings by patients and caregivers. Safety and tolerability were also assessed. RESULTS: A total of 245 patients were enrolled and switched from their prior antipsychotic medications, and 153 patients entered the 52-week extension phase. In all, 79 patients (32.2%) completed the study. At week 64, the mean CGI-I score was 3.10 and 64.6% of patients who showed response. Compared to baseline, scores of CGI-S, QOL, and BPRS after 64 weeks of treatment also showed significant improvements. At week 12, 65.4% of subjects and 58.9% of caregivers rated aripiprazole as better than the prestudy medication on the POM. The most frequently reported adverse events (AEs) were headache, auditory hallucinations and insomnia. A total of 13 patients (5.3%) discontinued treatment due to AEs. No statistically significant changes were noted with respect to fasting plasma glucose, lipid profile, body weight, and body mass index after long-term treatment with aripiprazole. CONCLUSIONS: Although the discontinuation rate was high, aripiprazole was found to be effective, safe and well tolerated in the long-term treatment of Taiwanese patients with schizophrenia who continued to receive treatment for 64 weeks.

Circulating Tumor DNA Analyses as a Potential Marker of Recurrence and Effectiveness of Adjuvant Chemotherapy for Resected Non-Small-Cell Lung Cancer.

BACKGROUND: Although adjuvant chemotherapy is established for patients with non-small-cell lung cancer (NSCLC), the long-term survival remains to be improved. Postsurgical circulating tumor DNA (ctDNA) analysis of resectable NSCLC may identify patients at high risk of recurrence after adjuvant chemotherapy and facilitate personalized therapy. METHODS: This analysis included 38 patients who underwent curative-intent resection and received adjuvant chemotherapy for NSCLC. ctDNA analyses of tumor tissue, and pre- and post-operative plasma samples were performed with next-generation sequencing targeting 425 cancer-relevant genes. We define a ctDNA positive event as at least one shared mutation identified simultaneously in the plasma and tumor specimens. The primary endpoint was recurrence-free survival (RFS). RESULTS: At least one somatic mutation was identified in the tumor tissue of all 38 patients. Tumor tissue-specific mutated ctDNA was detected in the preoperative plasma samples of 19 (50%) patients. ctDNA in preoperative plasma was in good accordance with that in tissue. ctDNA was detectable in the first post-operative pre-chemotherapy samples of 8 of 35 (22.9%) patients and was associated with inferior RFS (HR, 3.69; P = 0.033). ctDNA was detected in the first post-chemotherapy samples of 8 of 36 (22.2%) patients and was also associated with inferior RFS (HR, 8.76; P < 0.001). CONCLUSIONS: Postoperative and post-chemotherapy ctDNA is a promising prognostic marker for resected NSCLC. ctDNA analyses may define a subgroup that remains at high risk of relapse despite standard adjuvant chemotherapy, and may help to inform intensified therapeutic strategies.