Targeting undruggable phosphatase overcomes trastuzumab resistance by inhibiting multi-oncogenic kinases.

AIMS: Resistance to targeted therapy is one of the critical obstacles in cancer management. Resistance to trastuzumab frequently develops in the treatment for HER2+ cancers. The role of protein tyrosine phosphatases (PTPs) in trastuzumab resistance is not well understood. In this study, we aim to identify pivotal PTPs affecting trastuzumab resistance and devise a novel counteracting strategy. METHODS: Four public datasets were used to screen PTP candidates in relation to trastuzumab responsiveness in HER2+ breast cancer. Tyrosine kinase (TK) arrays were used to identify kinases that linked to protein tyrosine phosphate receptor type O (PTPRO)-enhanced trastuzumab sensitivity. The efficacy of small activating RNA (saRNA) in trastuzumab-conjugated silica nanoparticles was tested for PTPRO upregulation and resistance mitigation in cell models, a transgenic mouse model, and human cancer cell line-derived xenograft models. RESULTS: PTPRO was identified as the key PTP which influences trastuzumab responsiveness and patient survival. PTPRO de-phosphorated several TKs, including the previously overlooked substrate ERBB3, thereby inhibiting multiple oncogenic pathways associated with drug resistance. Notably, PTPRO, previously deemed "undruggable," was effectively upregulated by saRNA-loaded nanoparticles. The upregulated PTPRO simultaneously inhibited ERBB3, ERBB2, and downstream SRC signaling pathways, thereby counteracting trastuzumab resistance. CONCLUSIONS: Antibody-conjugated saRNA represents an innovative approach for targeting "undruggable" PTPs.

Tissue-resident memory CD103+CD8+ T cells in colorectal cancer: its implication as a prognostic and predictive liver metastasis biomarker.

BACKGROUND: Tissue-resident memory CD103+CD8+ T cells (CD103+CD8+ TRMs) are important components of anti-tumor immunity. However, the significance of CD103+CD8+ TRMs in colorectal cancer (CRC) and their advantages remain unclear. METHODS: Clinical data and specimens were used to evaluate the significance of CD103+CD8+ TRMs in CRC. A mouse subcutaneous tumorigenesis model and colony-formation assay were conducted to evaluate the anti-tumor effects of CD103+CD8+ TRMs. Finally, the infiltration density and function of CD103+CD8+ TRMs in the tumors were evaluated using flow cytometry. RESULTS: In this study, we showed that highly infiltrated CD103+CD8+ TRMs were associated with earlier clinical stage and negative VEGF expression in CRC patients and predicted a favorable prognosis for CRC/CRC liver metastases patients. Interestingly, we also found that CD103+CD8+ TRMs may have predictive potential for whether CRC develops liver metastasis in CRC. In addition, we found a positive correlation between the ratio of the number of α-SMA+ vessels to the sum of the number of α-SMA+ and CD31+ vessels in CRC, and the infiltration level of CD103+CD8+ TRMs. In addition, anti-angiogenic therapy promoted infiltration of CD103+CD8+ TRMs and enhanced their ability to secrete interferon (IFN)-γ, thus further improving the anti-tumor effect. Moreover, in vivo experiments showed that compared with peripheral blood CD8+ T cells, CD103+CD8+ TRMs infused back into the body could also further promote CD8+ T cells to infiltrate the tumor, and they had a stronger ability to secrete IFN-γ, which resulted in better anti-tumor effects. CONCLUSION: We demonstrated that CD103+CD8+ TRMs have the potential for clinical applications and provide new ideas for combined anti-tumor therapeutic strategies, such as anti-tumor angiogenesis therapy and CAR-T combined immunotherapy.

Direct Synthesis of α-Ketothioamide Derivatives through a One-Pot Reaction of Sulfur Ylides, Nitrosobenzenes, and Thioacetic Acid.

A one-pot approach has been developed for the synthesis of α-ketothioamide derivatives from sulfur ylides, nitrosobenzenes, and thioacetic acid. This protocol is carried out under mild reaction conditions in generally moderate to excellent yields without any precious catalysts, affording the derivatives with structural diversity. Additionally, a possible mechanism for this chemical transformation is proposed.

USP12 promotes nonsmall cell lung cancer progression through deubiquitinating and stabilizing RRM2.

RRM2 is the catalytic subunit of ribonucleotide reductase (RNR), which catalyzes de novo synthesis of deoxyribonucleotide triphosphates (dNTPs) and plays critical roles in cancer cell proliferation. RRM2 protein level is controlled by ubiquitination mediated protein degradation system; however, its deubiquitinase has not been identified yet. Here we showed that ubiquitin-specific peptidase 12 (USP12) directly interacts with and deubiquitinates RRM2 in non-small cell lung cancer (NSCLC) cells. Knockdown of USP12 causes DNA replication stress and retards tumor growth in vivo and in vitro. Meanwhile, USP12 protein levels were positively correlated to RRM2 protein levels in human NSCLC tissues. In addition, high expression of USP12 was associated with poor prognosis in NSCLC patients. Therefore, our study reveals that USP12 is a RRM2 regulator and targeting USP12 could be considered as a potential therapeutical strategy for NSCLC treatment.

Thrombospondin-2 holds prognostic value and is associated with metastasis and the mismatch repair process in gastric cancer.

BACKGROUND: This study aims to investigate thrombospondin 2 (TSP2) expression levels in gastric cancer (GC) and determine the relationship between TSP2 and clinical characteristics and prognosis. METHODS: The online database Gene Expression Profile Interactive Analysis (GEPIA) was used to analyse TSP2 mRNA expression levels in GC. The Kaplan-Meier plotter prognostic analysis tool was used to evaluate the influence of TSP2 expression on clinical prognosis in GC patients. TSP2 expression levels were analysed in paraffin-embedded GC samples and adjacent normal tissues by immunohistochemistry. The relationship between the clinicopathological characteristics and prognosis of GC patients was assessed. Transwell experiments were used to evaluate the effect of TSP2 on HGC27 and AGS cell invasion and migration. The EdU experiment was used to detect the effect of transfection of TSP2 on cell proliferation, and the flow cytometry experiment was used to detect the effect of TSP2 on cell apoptosis and the cell growth cycle. Western blotting (Wb) technology was used to detect MMP, E-cadherin, N-cadherin, Vimentin, Snail, AKT, PI3K, and VEGF protein expression in HGC27 cells. RESULTS: Compared with normal tissues, TSP2 mRNA expression in GC was significantly upregulated and was closely related to the clinical stage of GC. High TSP2 expression significantly affected the OS, FP and PPS of patients with GC. Among these patients, TSP2 expression levels did not affect the prognosis of patients with GC in the N0 subgroup but significantly affected the prognosis of patients with GC in the N (1 + 2 + 3) subgroup. TSP2 protein expression levels were significantly higher in GC tissue compared with normal tissues (P < 0.01). The overall survival (OS) and relapse-free survival (RFS) of patients with high TSP2 expression were lower than those of patients with low TSP2 expression. Cells transfected with the TSP2-silencing sequence exhibited increased apoptosis and inhibition of proliferation, migration and invasion. AKT and PI3K expression in cells was significantly downregulated (P < 0.01). AKT, PI3K and VEGF expression in cells transfected with the TSP2 silencing sequence was significantly reduced. Proliferation, migration, invasion ability, and TSP2 expression levels significantly correlated with mismatch repair genes, such as PMS2, MSH6, MSH2, and MLH1 (P < 0.05). CONCLUSION: TSP2 expression is significantly increased in GC. TSP2 expression is closely related to metastasis and the mismatch repair process in GC patients and affects GC patient prognosis. The mechanism may involve regulating gastric cancer cell proliferation and migration by modulating the VEGF/PI3K/AKT signalling pathway. TSP2 is a potential marker and therapeutic target for the prognosis of GC patients.

Multiple accounting and driving factors of water resources use: A case study of Shanghai.

Previous research papers on urban water resources accounting were confined to the perspectives of production and consumption, ignoring the perspective of income. This paper proposes a systems framework to analyze the income, production, and consumption-based water uses and underlying driving forces of a city based on the methods of multi-scale input-output analysis and structural decomposition analysis. A case study is performed for Shanghai as a megacity. The results show that the income, production and consumption-based water uses of Shanghai had decreased from 5.70 billion m3, 10.85 billion m3 and 28.45 billion m3 in 2007 to 2.80 billion m3, 6.20 billion m3 and 24.10 billion m3 in 2017, respectively. Domestic imported primary inputs had emerged as an important virtual water supplier of Shanghai and its share of total supply-side water use had increased from 23.92% in 2007 to 42.95% in 2017. Meanwhile, about 46% and 40% of Shanghai's total consumption-based water use had been imported from other Chinese regions and foreign countries in 2017, respectively. It is revealed that trade played an important role in relieving water use pressure in Shanghai. The factors that had increased the uses of water resources in Shanghai include population, per capita value-added, per capita output, final consumption structure, and per capita final consumption. The factors that had reduced the water uses in Shanghai include technology, value added mix, output structure, value added structure, domestic import, commodity mix, and foreign import. It is suggested that in addition to curbing urban water use from the production side, more targeted water-saving measures should be devised from the supply (e.g., restricting loan to heavy water-consuming enterprises) and consumption sides (e.g., encouraging residents to buy low-water products).

Overexpression of microRNA-29b inhibits epithelial-mesenchymal transition and angiogenesis of colorectal cancer through the ETV4/ERK/EGFR axis.

BACKGROUND: Recent studies have reported the involvement of microRNA-29 (miR-29) family members in human cancers through their ability to regulate cellular functions. The present study investigated biological function of miR-29b in colorectal cancer (CRC). METHODS: CRC tissues and adjacent normal tissues were collected and the expression of ETV4 and miR-29b in the tissues were identified. The relationship between ETV4 and miR-29b or ETV4 expression and the EGFR promoter was identified using dual-luciferase reporter gene and CHIP assays. The proliferation, invasion, migration, and apoptosis of CRC HCT116 cells were assayed using MTT assay, Scratch test, Transwell assay, and flow cytometry, respectively. Also, expression of epithelial-mesenchymal transition (EMT) markers, angiogenic factors, and vasculogenic mimicry formation were evaluated using RT-qPCR and Western blot. RESULTS: ETV4 was upregulated, while miR-29b expression was decreased in CRC tissues. ETV4 was identified as a target gene of miR-29b, which in turn inactivated the ERK signaling pathway by targeting ETV4 and inhibiting EGFR transcription. Transfection with miR-29b mimic, siRNA-ETV4, or ERK signaling pathway inhibitor U0126 increased expression of E-cadherin and TSP-1, and CRC cell apoptosis, yet reduced expression of ERK1/2, MMP-2, MMP-9, Vimentin, and VEGF, as well as inhibiting EMT, angiogenesis, and CRC cell migration and invasion. The EMT, angiogenesis and cancer progression induced by miR-29b inhibitor were reversed by siRNA-mediated ETV4 silencing. CONCLUSIONS: miR-29b suppresses angiogenesis and EMT in CRC via the ETV4/ERK/EGFR axis.

Relationship between Tertiary Lymphoid Structure and the Prognosis and Clinicopathologic Characteristics in Solid Tumors.

Background: An increasing number of studies had shown that tertiary lymphoid structure (TLS) plays an important role in tumor progression. However, the prognostic role of TLS in various tumors remains controversial. This meta-analysis aims to investigate the clinicopathological and prognostic values of TLS in solid tumors. Methods: A systematic search was conducted in PubMed, EMBASE and Cochrane Library undated to November 2, 2020. Odds ratios of clinical parameters, hazard ratio (HR) of overall survival (OS), relapse-free survival (RFS), disease-free survival (DFS) and relapse rate were calculated in order to evaluate the relationship between TLS expression and clinicopathological or prognostic values in different tumors. Result: 27 eligible studies including 6647 patients with different types of tumors were analyzed. High TLS expression was associated with a longer OS (HR = 0.66, 95% CI: 0.50 - 0.86, P = 0.002) and RFS (HR = 0.61, 95% CI: 0.47 - 0.79, P = 0.0001). Moreover, high TLS levels in tumor were associated with a low risk of recurrence (HR = 0.43, 95% CI: 0.32 - 0.57, P < 0.0001). However, there was no relationship between TLS expression and DFS. Meanwhile, high TLS expression was associated with smaller tumor size (P < 0.00001) and higher tumor infiltrating lymphocytes (TILs). Furthermore, the subgroup analysis showed high TLS expression that may be associated with a lower clinical grading and N stage in breast cancer and colorectal cancer. Conclusion: High TLS expression is associated with the longer OS and RFS in solid tumors, and a lower risk of cancer relapse. Meanwhile, high TLS expression is also associated with a smaller tumor size, higher infiltration of TILs, lower clinical grading and N stage in the tumor. Therefore, high TLS expression in the tumor is a favorable prognostic biomarker for solid tumor patients.

Nicotinamide phosphoribosyl transferase regulates cell growth via the Sirt1/P53 signaling pathway and is a prognosis marker in colorectal cancer.

Colorectal cancer (CRC) is the third most common malignancy, and the metabolic properties of CRC cells include enhanced aerobic glycolysis (the Warburg effect). Nicotinamide phosphoribosyl transferase (NAMPT) is one of the crucial enzymes that regulate the activity of nicotinamide adenine dinucleodinucleotide dependent enzymes. Targeting NAMPT is a potential method of CRC therapy. Nevertheless, the underlying clinical implications and regulatory mechanisms of NAMPT in CRC remain unclear. In this study, we showed that NAMPT protein expression was increased in subjects with rectal localization compared with those with colon localization, and NAMPT was a poor prognostic marker for the overall survival rate in patients with CRC. In addition, the NAMPT inhibitor FK866 or lentivirus-mediated silencing induced CRC cell growth inhibition. Mechanistically, NAMPT regulated Sirt1 and P53 expression and induced G0/G1 cell cycle arrest, along with the upregulation of downstream p21 and downregulation of cyclin D1, cyclin E1, and cyclin E2 expression. FK866 administration or knockdown of NAMPT induced CRC cell apoptosis via upregulation of caspase-3. In conclusion, NAMPT regulated Sirt1/P53 signaling during CRC cell growth and warrants further investigation for clinical administration in CRC.

α/ß-Hydrolase domain-containing 6 (ABHD6) negatively regulates the surface delivery and synaptic function of AMPA receptors.

In the brain, AMPA-type glutamate receptors are major postsynaptic receptors at excitatory synapses that mediate fast neurotransmission and synaptic plasticity. α/ß-Hydrolase domain-containing 6 (ABHD6), a monoacylglycerol lipase, was previously found to be a component of AMPA receptor macromolecular complexes, but its physiological significance in the function of AMPA receptors (AMPARs) has remained unclear. The present study shows that overexpression of ABHD6 in neurons drastically reduced excitatory neurotransmission mediated by AMPA but not by NMDA receptors at excitatory synapses. Inactivation of ABHD6 expression in neurons by either CRISPR/Cas9 or shRNA knockdown methods significantly increased excitatory neurotransmission at excitatory synapses. Interestingly, overexpression of ABHD6 reduced glutamate-induced currents and the surface expression of GluA1 in HEK293T cells expressing GluA1 and stargazin, suggesting a direct functional interaction between these two proteins. The C-terminal tail of GluA1 was required for the binding between of ABHD6 and GluA1. Mutagenesis analysis revealed a GFCLIPQ sequence in the GluA1 C terminus that was essential for the inhibitory effect of ABHD6. The hydrolase activity of ABHD6 was not required for the effects of ABHD6 on AMPAR function in either neurons or transfected HEK293T cells. Thus, these findings reveal a novel and unexpected mechanism governing AMPAR trafficking at synapses through ABHD6.

Identification of Protein Tyrosine Phosphatase Receptor Type O (PTPRO) as a Synaptic Adhesion Molecule that Promotes Synapse Formation.

The proper formation of synapses-specialized unitary structures formed between two neurons-is critical to mediating information flow in the brain. Synaptic cell adhesion molecules (CAMs) are thought to participate in the initiation of the synapse formation process. However, in vivo functional analysis demonstrates that most well known synaptic CAMs regulate synaptic maturation and plasticity rather than synapse formation, suggesting that either CAMs work synergistically in the process of forming synapses or more CAMs remain to be found. By screening for unknown CAMs using a co-culture system, we revealed that protein tyrosine phosphatase receptor type O (PTPRO) is a potent CAM that induces the formation of artificial synapse clusters in co-cultures of human embryonic kidney 293 cells and hippocampal neurons cultured from newborn mice regardless of gender. PTPRO was enriched in the mouse brain and localized to postsynaptic sites at excitatory synapses. The overexpression of PTPRO in cultured hippocampal neurons increased the number of synapses and the frequency of miniature EPSCs (mEPSCs). The knock-down (KD) of PTPRO expression in cultured neurons by short hairpin RNA (shRNA) reduced the number of synapses and the frequencies of the mEPSCs. The effects of shRNA KD were rescued by expressing either full-length PTPRO or a truncated PTPRO lacking the cytoplasmic domain. Consistent with these results, the N-terminal extracellular domain of PTPRO was required for its synaptogenic activity in the co-culture assay. Our data show that PTPRO is a synaptic CAM that serves as a potent initiator of the formation of excitatory synapses.SIGNIFICANCE STATEMENT The formation of synapses is critical for the brain to execute its function and synaptic cell adhesion molecules (CAMs) play essential roles in initiating the formation of synapses. By screening for unknown CAMs using a co-culture system, we revealed that protein tyrosine phosphatase receptor type O (PTPRO) is a potent CAM that induces the formation of artificial synapse clusters. Using loss-of-function and gain-of-function approaches, we show that PTPRO promotes the formation of excitatory synapses. The N-terminal extracellular domain of PTPRO was required for its synaptogenic activity in cultured hippocampal neurons and the co-culture assay. Together, our data show that PTPRO is a synaptic CAM that serves as a potent initiator of synapse formation.

Conjugation of gold nanoparticles and recombinant human endostatin modulates vascular normalization via interruption of anterior gradient 2-mediated angiogenesis.

Several studies have revealed the potential of normalizing tumor vessels in anti-angiogenic treatment. Recombinant human endostatin is an anti-angiogenic agent which has been applied in clinical tumor treatment. Our previous research indicated that gold nanoparticles could be a nanoparticle carrier for recombinant human endostatin delivery. The recombinant human endostatin-gold nanoparticle conjugates normalized vessels, which improved chemotherapy. However, the mechanism of recombinant human endostatin-gold nanoparticle-induced vascular normalization has not been explored. Anterior gradient 2 has been reported to be over-expressed in many malignant tumors and involved in tumor angiogenesis. To date, the precise efficacy of recombinant human endostatin-gold nanoparticles on anterior gradient 2-mediated angiogenesis or anterior gradient 2-related signaling cohort remained unknown. In this study, we aimed to explore whether recombinant human endostatin-gold nanoparticles could normalize vessels in metastatic colorectal cancer xenografts, and we further elucidated whether recombinant human endostatin-gold nanoparticles could interrupt anterior gradient 2-induced angiogenesis. In vivo, it was indicated that recombinant human endostatin-gold nanoparticles increased pericyte expression while inhibit vascular endothelial growth factor receptor 2 and anterior gradient 2 expression in metastatic colorectal cancer xenografts. In vitro, we uncovered that recombinant human endostatin-gold nanoparticles reduced cell migration and tube formation induced by anterior gradient 2 in human umbilical vein endothelial cells. Treatment with recombinant human endostatin-gold nanoparticles attenuated anterior gradient 2-mediated activation of MMP2, cMyc, VE-cadherin, phosphorylation of p38, and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in human umbilical vein endothelial cells. Our findings demonstrated recombinant human endostatin-gold nanoparticles might normalize vessels by interfering anterior gradient 2-mediated angiogenesis in metastatic colorectal cancer.

Robotic thyroidectomy versus conventional open thyroidectomy for thyroid cancer: a systematic review and meta-analysis.

BACKGROUND: Despite the new technical alternative offered by the robotic surgery for minimally invasive thyroid surgery, the role of the robotic thyroidectomy (RT) in thyroid cancer has been highly disputed. This paper gives a systematic review and meta-analysis aiming to compare RT and open thyroidectomy (OT) based on the surgical outcomes and oncologic results. METHODS: Relevant literature was searched from various databases up to July 2016, including PubMed, MEDLINE, EMBASE, Cochrane Library, Web of science and Clinical Trials. gov. Outcomes of interest included patient characteristics, surgical outcomes, adverse events and complications, recurrence rate, and surgical completeness. RESULTS: The systematic review and meta-analysis were based on the 5200 cases selected from the twenty-three publications. RT was associated with an equivalent adverse event and complication rate including transient hypocalcemia, permanent hypocalcemia, transient hoarseness, permanent recurrent laryngeal nerve (RLN) palsy, transient hypoparathyroidism, permanent hypoparathyroidism, hematoma, postoperative bleeding, seroma, chyle leakage, the Voice Handicap Index-10 (VHI-10) score, as well as equivalent surgical completeness including postoperative radioactive iodine (RAI) ablation rate, number of RAI ablation sessions, mean total RAI ablation dose, mean stimulated Tg of postoperation RAI, and proportion of stimulated Tg < 1.0 ng/ml on first ablation. Moreover, RT had lesser blood loss (WMD - 1.47, p = 0.04), smaller number of retrieved lymph nodes (WMD - 1.21, p = 0.0002), a low level of swallowing impairment (WMD - 4.17, p < 0.00001), and better cosmetic satisfaction (OR 4.05, p < 0.00001). However, OT was associated with shorter operation time (WMD 69.80, p < 0.00001), less total drain amount (WMD 66.53, p < 0.0001), and lower postoperative serum Tg level (WMD 0.21, p < 0.00001). CONCLUSIONS: RT is as safe as OT for the treatment of thyroid cancer. Based on the long-time follow-up and surgical completeness, the adverse events and complications, and recurrence rate of RT were comparable with OT. RT was associated with a significantly lesser blood loss, smaller number of retrieved lymph nodes, a lower level of swallowing impairment, and better cosmetic satisfaction. In contrast, OT was associated with shorter operation time, smaller total drain amount, and lower postoperative serum Tg level. Overall, randomized clinical trials and larger patient cohort with long-term follow-up are still essential to further demonstrate the value of the robotic approach.

Long-term oncological outcomes in robotic gastrectomy versus laparoscopic gastrectomy for gastric cancer: a meta-analysis.

BACKGROUND: Robotic gastrectomy (RG) has been a new technical alternative for gastric cancer. However, the long-term oncological outcomes of RG still should be further evaluated. In this meta-analysis, the long-term oncological outcomes of RG and laparoscopic gastrectomy (LG) are compared. METHODS: Comprehensive searches from various databases are compared in February 2017 to identify that the oncological outcomes of RG and LG are evaluated in gastric cancer patients. The pooled oncological outcomes of the overall survival (OS), disease-free survival (DFS), and the recurrence rate were performed by adopting the meta-analysis to calculate the hazard ratio (HR) or the odds ratio with 95% confidence intervals (CIs). RESULTS: Five studies that concern retrospective design and prospective data collection and involve 1614 patients were included. All the five studies evaluated OS. Two studies evaluated DFS, while four studies reported the recurrence rate or recurrence cases in RG and LG groups with the long-term follow-up. The pooled analysis showed no significant difference in OS and DFS between RG and LG, without significant between-study heterogeneity. Besides, the recurrence rate between RG and LG had no significant difference without heterogeneity. CONCLUSIONS: RG could provide comparable long-term oncological outcomes as well as LG for the treatment of gastric cancer. OS, DFS, and the recurrence rate by the long-time follow-up of RG were comparable with LG. Generally speaking, more randomized clinical trials and a larger patient cohort with longer follow-up are still essential to further demonstrate the value of the robotic surgery for gastric cancer.

Endoscopic thyroidectomy via areola approach: summary of 1,250 cases in a single institution.

BACKGROUND: The aim of this study was to evaluate the effect and cosmetic results of endoscopic thyroidectomy (ETE) via the areola approach for patients with thyroid diseases. METHODS: A total of 1,250 patients with thyroid diseases underwent ETE via the areola approach between April 2005 and January 2011. Of these, 898 were benign goiters, 260 were Graves' disease, 28 were secondary hyperthyroidism, and 64 were papillary carcinomas. RESULTS: The surgery was successfully completed in 1,249 cases, and 1 case was converted to open surgery. The mean operation time, estimated blood loss, and hospital stay after surgery for patients with a goiter, hyperthyroidism, and papillary carcinoma were 94.4 min, 15.2 ml, 5.0 days, 97.9 min, 16.1 ml, 5.5 days, and 134.3 min, 18.6 ml, 6.4 days, respectively. Complications included 4 cases of postoperative bleeding, 1 case of transection of the recurrent laryngeal nerve (RLN) on one side, 7 cases of temporary RLN injury, 34 cases of transient hypocalcemia, 5 cases of skin bruising on the chest wall, and 1 case of subcutaneous infection in the neck. At 4.6-year (2.5-8 years) follow-up of 1,185 (94.8 %) patients, 3 patients with Graves' disease had recurrence of hyperthyroidism, and 4 patients with nodular goiter had recurrence of small nodules. Four patients had discomfort on swallowing, 4 patients had an abnormal sensation of skin traction on the neck and the chest, and 1 patient with scar diathesis had mild scar hyperplasia. A total of 876 patients were satisfied, 4 equivocal, and 0 unsatisfied with the cosmetic results. CONCLUSION: ETE via the areola approach for patients with benign goiters, Graves' disease, secondary hyperthyroidism, and papillary carcinomas without metastasis to lateral cervical lymph nodes is an effective and safe procedure with excellent cosmetic results.

Long-term effects of laparoscopic sleeve gastrectomy versus roux-en-Y gastric bypass for the treatment of Chinese type 2 diabetes mellitus patients with body mass index 28-35 kg/m(2).

BACKGROUND: To compare long term effects of two bariatric procedures for Chinese type 2 diabetes mellitus (T2DM) patients with a body mass index (BMI) of 28-35 kg/m(2). METHODS: Sixty four T2DM patients with Glycated hemoglobin A1c (HbA1c) ≧ 7.0 % were randomly assigned to receive laparoscopic sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) procedure. Weight, percentage of excess weight loss (%EWL), BMI, waist circumference, HbA1c, fasting blood glucose (FBG), and C-peptide were measured. Serum lipid levels were also measured during three-year postoperative follow-up visits. RESULTS: Fifty five patients completed the 36-month follow-up. Both groups had similar baseline anthropometric and biochemical measures. At the end point, 22 patients (78.6 %) in SG group and 23 patients (85.2 %) in RYGB group achieved complete remission of diabetes mellitus with HbA1c < 6.0 % (P = 0.525) and without taking diabetic medications, and 25 patients in each group (89.3 % vs. 92.6 %) gained successful treatment of diabetes with HbA1c≦6.5 % (P = 0.100). Change in HbA1c, FBG and C peptide were comparable in the two groups. The RYGB group had significantly greater weight loss than the SG group [percentage of total weight loss (%TWL) of 31.0 % vs. 27.1 % (P = 0.049), %EWL of 92.3 % vs. 81.9 % (P = 0.003), and change in BMI of 11.0 vs. 9.1 kg/m(2)(P = 0.017), respectively]. Serum lipids in each group were also greatly improved. CONCLUSION: In this three-year study, SG had similar positive effects on diabetes and dyslipidemia compared to RYGB in Chinese T2DM patients with BMI of 28-35 kg/m(2). Longer term follow-ups and larger sample studies are needed to confirm these outcomes, however.

Inhibition effects of gold nanoparticles on proliferation and migration in hepatic carcinoma-conditioned HUVECs.

Tumor angiogenesis is a complicated process based upon a sequence of interactions between tumor and vessel endothelial cells. Tumor conditioned medium has been widely used to stimulate endothelial cells in vitro angiogenesis. This work was aimed to investigate the effects of gold nanoparticles (GNPs) on angiogenesis in hepatic carcinoma-conditioned endothelial cells. Human umbilical vein endothelial cells (HUVECs) were cultured with conditioned medium (CM) from the human hepatocarcinoma cell line HepG2 (HepG2-CM), and then treated with different concentrations of GNPs. The effects of GNPs on the viability, migration and active VEGF level of HUVECs were investigated by MTT assay, wound healing assay and transwell chamber assay, and ELISA assay, respectively. The data showed that GNPs significantly inhibited HUVECs proliferation and migration induced by HepG2-CM, and also reduced the levels of active VEGF in the co-culture system. Then, the alterations in morphology and ultrastructure of HUVECs detected by atomic force microscopy (AFM) showed that there appeared obvious pseudopodia, larger membrane particle sizes and much rougher surface in HUVECs after HepG2-CM treatment, which were all reversed after GNPs treatment. Changes in cytoskeleton of HUVECs determined by immunocytochemistry demonstrated that GNPs treatment remarkably inhibited the activation effect of HepG2-CM on HUVECs, which was associated with the disruption of actin filaments induced by GNPs. This study indicates that GNPs can significantly inhibit HepG2-CM activated endothelial cell proliferation and migration through down-regulation of VEGF activity and disruption of cell morphology, revealing the potential applications of GNPs as antiangiogenic agent for the treatment of hepatic carcinoma.

New findings in prognostic factor assessment for adenocarcinoma of transverse colon: a comparison study between competing-risk and COX regression analysis.

Purpose: Competing-risk analysis was used to accurately assess prognostic factors for cancer-specific death in patients with adenocarcinoma of transverse colon (ATC), and the results were compared with those from a conventional Cox regression analysis. Materials and Methods: Patients diagnosed with ATC between 2000 and 2019 were selected from the Surveillance, Epidemiology, and End Results database. The crude mortality rates of patients with ATC were calculated and their differences were tested using the Gray's test, respectively. In performing multivariate analysis, the Cox regression model and the subdistribution hazard function (SD) in competing risk analysis were utilized, respectively. Results: This study included 21,477 eligible patients. The SD model indicated that age, etc. are actual independent prognostic factors. In contrast to previous recognition, the results of the Cox regression showed false-positives for sex and Carcinoembryonic antigen, and underestimated point-estimates in the stage and American Joint Committee on Cancer stage due to competing events. A detailed comparison of treatment revealed that the larger surgical scopes were prognostic risk factors compared with the smaller scope of local tumor excision, partial colectomy, or segmental resection. Patients treated with external proton beam radiotherapy had an increased risk compared with those with no radiotherapy and internal radiotherapy. Conclusions: After comparing the results of the two methods and mitigating the significant bias introduced by Cox regression, we found independent factors that really affect the prognosis of ATC. On the other hand, in terms of ATC, a larger surgical scope and external proton beam radiotherapy may not improve the long-term survival of patients. Therefore, when faced with ATC patients, these differences should be noted and treated differently from common colorectal cancer patients. Thus, clinicians are able to give more targeted treatment plans and prognostic assessments.

maxPIE: An innovative high throughput approach to enhance pathogen inactivation practices.

Effective pathogen inactivation is highly desired in public health but limited by existing methods each capable of assessing pathogen inactivation effectiveness (PIE) only in a specific condition. We therefore developed a novel method maxPIE designed to identify maximal PIEs across inactivation conditions by leveraging the power of massive array technologies. maxPIE implements a three-step algorithm to quickly identify maximal PIEs of inactivation treatments: (1) dilute pathogens into different initial titers each stored in an array well, (2) submit one sorted array to one treatment, (3) scan the treated array to find the maximum. maxPIE outperformed the conventional methods in (a) inactivating S. aureus using ultraviolet light of different wavelengths with different durations; (b) antibiotic treatment of S. aureus, E. coli, and multidrug-resistant E. coli; (c) inactivating S. aureus in plasma using ultraviolet light in different wavelengths with and without riboflavin. maxPIE was easy to understand and interpret and was robust in situations where conventional PIE methods would suffer. Hence, maxPIE can serve as an innovative and high throughput approach that can be widely used to enhance pathogen inactivation practices.