Pathology confirmation of the efficacy and safety of microwave ablation in papillary thyroid carcinoma.

Background: The incidence of papillary thyroid carcinoma (PTC) has rapidly increased in recent years. Microwave ablation (MWA) was proposed as an alternative treatment for PTC. This study aimed to investigate the efficacy and safety of MWA by exploring the postoperative pathology results of post-ablation lesions in patients with PTC. Methods: This study retrospectively analyzed data from 12 patients who underwent thyroid surgery after MWA treatment for primary PTC between January 2015 and November 2021 in six hospitals. Results: The average age of the 12 patients (8 female) was 45.3 ± 9.7 years. There was one patient with PTC (size > 1 cm) and 11 patients with micro-PTC (size ≤ 1 cm), of which eight patients had unifocal micro-PTC and three patients had multifocal micro-PTC. A total of 17 tumor foci with mean size of 6.2 ± 2.6 mm were treated by MWA. The median interval time between MWA and surgery was 6.6 months (range: 0.4-21.9 months). Intraoperatively, adherence to the anterior cervical muscle group was observed in three cases (3/12). Upon postoperative pathologic examination, all the post-ablation lesions of the eight unifocal micro-PTC and two multifocal micro-PTC showed no residual carcinomas. Outside the ablation zone, PTCs were detected in three cases, including two of the eight patients with unifocal micro-PTC and one of the three patients with multifocal micro-PTC. Cervical lymph node metastases were detected in seven patients (7/12). Conclusion: MWA was feasible for the treatment of primary unifocal low-risk micro-PTC (T1aN0M0) with good efficacy and safety. However, the use of MWA for treating PTC (size > 1 cm) and multifocal micro-PTC remains controversial.

Papillary thyroid microcarcinoma with contralateral lymphatic skip metastasis and breast cancer: A case report.

BACKGROUND: The recognized pattern of cervical lymph node metastasis (CLNM) of papillary thyroid carcinoma involves a stepwise route. Contralateral lymph node skip metastasis is very rare. In addition, the patient in our case report also suffered from a breast carcinoma accompanied by left supraclavicular lymphadenopathy, which made it difficult to distinguish the origin of the CLNM. Based on this case, we recommended that more detailed physical and imaging examinations are needed for patients with uncommon cervical lymphatic metastasis of primary cancer. CASE SUMMARY: A 53-year-old women was admitted to the hospital for a neck mass in the left cervical region that had existed for 2 mo. The neck mass was suspected to be an enlarged lateral LN originating from papillary thyroid microcarcinoma of the contralateral thyroid lobe, according to ultrasound and ultrasound-guided fine needle aspiration biopsy. The patient underwent total thyroidectomy and radical cervical LN dissection. Postoperative pathology confirmed the diagnosis of papillary thyroid microcarcinoma with contralateral lymphatic skip metastasis. Unfortunately, a breast cancer was discovered 4 mo later, which was accompanied by ipsilateral supraclavicular LN metastasis. She accepted neoadjuvant chemotherapy and subsequent left modified radical mastectomy for treatment. The patient is currently receiving postoperative radiotherapy, and no local recurrence was observed in the 6-mo follow-up after surgery. CONCLUSION: We present a rare case of papillary thyroid microcarcinoma with contralateral lymphatic skip metastasis and breast cancer with supraclavicular lymphatic metastasis.

The Local Anesthetic Bupivacaine Inhibits the Progression of Non-Small Cell Lung Cancer by Inducing Autophagy Through Akt/mTOR Signaling.

Non-small cell lung cancer (NSCLC) is a prevalent malignancy with high mortality and poor prognosis. Bupivacaine serves as a widely used local anesthetic and presents potential anti-tumor activity. Nevertheless, the function of bupivacaine in the NSCLC development remains elusive. Here, we tried to investigate the impact of bupivacaine on the NSCLC progression. Significantly, we revealed that bupivacaine was able to reduce the proliferation and induce the apoptosis of NSCLC cells. Bupivacaine could attenuate the invasion and migration in the cells. Mechanically, the treatment of bupivacaine increased the expression ratio of light chain 3B-II (LC3B-II)/LC3B-I and the expression of Beclin-1 in the NSCLC cells. Meanwhile, the expression of the autophagic adaptor protein p62 was decreased by bupivacaine treatment in the cells. The treatment of bupivacaine attenuated the phosphorylation of AKT and mTOR in the NSCLC cells. The AKT activator SC79 and autophagy inhibitor 3-methyladenine (3-MA) reversed the bupivacaine-inhibited phosphorylation of AKT and mTOR and bupivacaine-induced autophagy, as well as the bupivacaine-attenuated NSCLC progression in the cells. Bupivacaine could inhibit the tumor growth in vivo. In conclusion, we discovered that the local anesthetic bupivacaine inhibited the progression of NSCLC by inducing autophagy through Akt/mTOR signaling. Our finding provides new insights into the mechanism by which bupivacaine attenuates the development of NSCLC. Bupivacaine may serve as a potential anti-tumor candidate for the therapeutic strategy of NSCLC.

Analysis of risk factors for cervical lymph node metastasis of papillary thyroid microcarcinoma: a study of 268 patients.

BACKGROUND: To investigate the risk factors of cervical lymph node (LN) metastasis in papillary thyroid microcarcinoma (PTMC) patients. METHODS: We retrospectively analyzed the clinicopathologic data of all patients who received standard lobectomy for PTMC at our institution between October 2017 and January 2019. Central LNs were dissected in all patients. Lateral LNs were dissected if metastasis to the lateral LNs was suggested based on pre-op fine-needle aspiration biopsy. The relationship between variables available prior to surgery and cervical LN metastasis was examined using multivariate regression. RESULTS: Post-op pathologic examination revealed cervical LN metastasis in 79 (29.5%) patients. Seventy subjects had metastasis only to central LNs, and 4 (1.5%) patients had metastasis only to lateral LNs. Five patients had metastasis to both central and lateral LNs. In comparison to patients without cervical LN metastasis, those with LN metastasis were significantly younger (40.63 ± 13.07 vs. 44.52 ± 12.23 years; P = 0.021) and had significantly larger tumor diameter on pathology (6.7 ± 2.2 vs. 5.9 ± 2.4 mm; P = 0.010). Multivariate regression analysis identified the following independent risks for cervical LN metastasis: male sex (OR 2.362, 95%CI 1.261~4.425; P = 0.007), age (OR 0.977, 95%CI 0.956~0.999; P = 0.042) and ultrasound tumor diameter at > 5 mm (OR 3.172, 95%CI 1.389~7.240; P = 0.006). CONCLUSION: Cervical LN metastasis occurs in a non-insignificant proportion of PTMC patients. Independent risks included male sex, younger age and larger tumor diameter on ultrasound.

Neural Respiratory Drive Measured Using Surface Electromyography of Diaphragm as a Physiological Biomarker to Predict Hospitalization of Acute Exacerbation of Chronic Obstructive Pulmonary Disease Patients.

BACKGROUND: Neural respiratory drive (NRD) using diaphragm electromyography through an invasive transesophageal multi-electrode catheter can be used as a feasible clinical physiological parameter in patients with chronic obstructive pulmonary disease (COPD) to provide useful information on the treatment response. However, it remains unknown whether the surface diaphragm electromyogram (EMGdi) could be used to identify the deterioration of clinical symptoms and to predict the necessity of hospitalization in acute exacerbation of COPD (AECOPD) patients. METHODS: COPD patients visiting the outpatient department due to acute exacerbation were enrolled in this study. All patients who were subjected to EMGdi and classical parameters such as spirometry parameters, arterial blood gas analysis, COPD assessment test (CAT) score, and the modified early warning score (MEWS) in outpatient department, would be treated effectively in the outpatient or inpatient settings according to the Global Initiative for Chronic Obstructive Lung Disease guideline. When the acute exacerbation of the patients was managed, all the examination above would be repeated. RESULTS: We compared the relationships of admission-to-discharge changes (Δ) in the normalized value of the EMGdi, including the change of the percentage of maximal EMGdi (ΔEMGdi%max) and the change of the ratio of minute ventilation to the percentage of maximal EMGdi (ΔVE/EMGdi%max) with the changes of classical parameters. There was a significant positive association between ΔEMGdi%max and ΔCAT, ΔPaCO2, and ΔpH. The change (Δ) of EMGdi%max was negatively correlated with ΔPaO2/FiO2in the course of the treatment of AECOPD. Compared with the classical parameters including forced expiratory volume in 1 s, MEWS, PaO2/FiO2, the EMGdi%max (odds ratio 1.143, 95% confidence interval 1.004-1.300) has a higher sensitivity when detecting the early exacerbation and enables to predict the admission of hospital in the whole cohort. CONCLUSIONS: The changes of surface EMGdi parameters had a direct correlation with classical measures in the whole cohort of AECOPD. The measurement of NRD by surface EMGdi represents a practical physiological biomarker, which may be helpful in detecting patients who should be hospitalized timely.

Rotational Rheology of Bovine Serum Albumin Solutions: Confounding Effects of Impurities, Mechanistic Considerations and Potential Implications on Protein Formulation Development.

PURPOSE: To show and rationalize the confounding effects on the rotational/oscillatory rheology of surface active impurities in commercial protein formulations such as bovine serum albumin, BSA. METHODS: Bulk and interfacial rotational/oscillatory rheology were used to study the viscosity, complex viscosity, storage/elastic modulus, G' and loss/viscous modulus, G", as a function of time of aqueous formulations of BSA and their purified components. RESULTS: Viscosity/time profiles at steady shear for different commercial BSA products and lots showed viscosity increase, decrease and time-independent profiles at low shear rates. All lots showed shear thinning. BSA monomer and dimers/aggregates, in general, showed similar profiles. Addition of low levels of surfactant or high shear rates rendered all solutions to be Newtonian-like. Interfacial viscosity studies paralleled those on the rotational rheometer. G' > G" with viscosity increase and G' < G" with viscosity decrease over time. CONCLUSIONS: We provide a rational explanation for the time-dependent and source-dependent rheological behavior of aqueous formulations of commercially available BSA proteins based on the migration of protein and surface active impurities to the air/water interface within the rheometer plates leading to the formation and breakdown of protein networks. Highly purified proteins is warranted in rheological studies of protein drug product candidates.

Regulation of type II collagen, matrix metalloproteinase-13 and cell proliferation by interleukin-1ß is mediated by curcumin via inhibition of NF-κB signaling in rat chondrocytes.

Curcumin possesses strong anti-inflammatory, anti-rheumatoid and anti-oxidative activities, and has the potential to inhibit nuclear factor­κB (NF­κB) signaling. Cartilage damage in osteoarthritis (OA) is largely mediated by interleukin-1ß (IL-1ß) via activation of various transcription factors, including NF­κB and activator protein­1. The aim of the present study was to determine whether IL­1ß induces matrix metalloproteinase-13 (MMP-13) expression and inhibits type II collagen expression, as well as to examine whether cell proliferation may be inhibited by curcumin through the inhibition of NF­κB signaling. The effects of curcumin were investigated in rat articular chondrocyte cell cultures treated with IL­1ß in the presence or absence of curcumin or the NF­κB inhibitor pyrrolidine dithiocarbamate. Western blotting and reverse transcription­quantitative polymerase chain reaction were conducted to evaluate protein and mRNA expression levels of type II collagen, MMP­13, NF­κB inhibitor α (IκBα), phosphorylated­IκBα and NF­κB subunit p65/RelA. Western blotting and immunofluorescence were performed to examine the effects of curcumin on the expression, phosphorylation and nuclear translocation of NF­κB­associated proteins. The effects of curcumin on cell proliferation were evaluated by Cell Counting Kit­8 (CCK­8). Curcumin was demonstrated to inhibit the IL­1ß­induced activation of NF­κB by suppressing IκBα phosphorylation and p65/RelA nuclear translocation. These events were associated with the downregulation of MMP­13 expression and the upregulation of type II collagen expression, both of which are considered to be NF­κB targets. CCK­8 assays revealed that co­treatment with curcumin resulted in increased proliferation in IL­1ß­treated chondrocytes. These findings implicated curcumin as a naturally occurring anti­inflammatory agent for the treatment of OA via inhibition of NF­κB signaling.

CXC Chemokine Receptor Type 4 Antagonism Ameliorated Allograft Fibrosis in Rat Kidney Transplant Model.

OBJECTIVES: In this study, we evaluated the effects of CXC chemokine receptor type 4 and stromal cell-derived factor 1 signaling in the progression of chronic allograft nephropathy in a rat model. MATERIALS AND METHODS: Experimental rats were divided into 3 groups: Lewis-to-Lewis isograft transplant (group A), Fisher 344 rat-to-Lewis allograft transplant with immunosuppressant cyclosporine (group B), and Fisher 344 rat-to-Lewis allograft transplant treated with cyclosporine and the CXC chemokine receptor type 4 antagonist AMD3100 (1 mg/kg/d) (group C). On day 90 after the operation, renal graft function, proteinuria, and histologic Banff score were measured. The expression levels of transforming growth factor ß1 and collagen IV were determined by quantitative real-time polymerase chain reaction. RESULTS: Renal function and urinary protein were increased in allografts of groups B and C compared with isografts of group A. The Banff score was significantly decreased in the AMD3100-treated animals (group C), with renal fibrosis being reduced. In addition, overexpressed levels of transforming growth factor ß1 and collagen IV in group B allografts were significantly reduced versus that shown with treatment with the CXC chemokine receptor type 4 antagonist in group C. CONCLUSIONS: Together, these data strongly implicate that CXC chemokine receptor type 4 antagonism alleviated renal interstitial fibrosis in long-term surviving allografts by down-regulating expression of transforming growth factor ß1.

Association between the -1438G/A and T102C polymorphisms of 5-HT2A receptor gene and obstructive sleep apnea: a meta-analysis.

The serotonin 2A (5-HT2A) receptor has been implicated in obstructive sleep apnea (OSA). Single nucleotide polymorphisms (SNPs) in the 5-HT2A gene have been found in OSA, the most common being -1438G/A and T102C; however, studies of the association between 5-HT2A SNPs and OSA risk have reported inconsistent findings. A meta-analysis was performed to quantitatively review the association between -1438G/A and T102C SNPs and OSA. Five studies, including 791 subjects for -1438G/A genotype and 1,068 subjects for T102C genotype, were selected. Pooled data analysis of the -1438G/A genotype indicated a significantly increased OSA risk was associated with two variant genotypes (AA vs. AG+GG: OR 3.023, 95 % CI 2.169-4.213, P = 0.506 for heterogeneity; A allele carriers vs. GG: OR 1.938, 95 % CI 0.879-4.274, P = 0.012 for heterogeneity). Stratification analysis by gender supported the association in males, but not females. For the T102C genotype, no significantly increased OSA risk was associated with the two variant genotypes (CC vs. CT+TT: OR 1.065, 95 % CI 0.787-1.442, P = 0.361 for heterogeneity; C allele carriers vs. TT: OR 0.979, 95 % CI 0.737-1.3, P = 0.9 for heterogeneity).In conclusions, meta-analysis indicated that the -1438G/A, and not T102C, polymorphism of 5-HT2A is a positive risk factor of OSA, especially in males.

Rational design of lyophilized high concentration protein formulations-mitigating the challenge of slow reconstitution with multidisciplinary strategies.

An increasing number of protein therapies require chronic administration at high doses (>200 mg) by subcutaneous (sc) injection. Due to the injection volume limitation (<1.5 mL) associated with sc administration, high protein concentration formulations at or exceeding 100 mg/mL are required to achieve the dose. Development of a high concentration protein formulation can be challenging due to increased aggregation at higher concentration and/or chemical instability, which necessitates the development of lyophilized formulation for high protein concentration drug products. Unique challenges, such as long reconstitution time for a lyophilized high protein concentration drug product, can limit practical usage and commercial marketability of the product. In this paper, a systematic approach is presented to develop a lyophilized high concentration protein formulation. The focus is on achieving reasonable reconstitution times with multidisciplinary strategies. Many strategies have been shown to provide nominal improvement in reconstitution times, such as adding wetting agents in the diluents, incorporating high annealing steps in the lyophilization cycle and reconstituting under vacuum. The reconstitution strategy of reduced diluent volume, however, has enabled significant decrease in reconstitution time (4-7-fold) of lyophilized high protein concentration formulations.

Beyond glass transitions: studying the highly viscous and elastic behavior of frozen protein formulations using low temperature rheology and its potential implications on protein stability.

PURPOSE: A novel application of oscillatory shear rheology was used to directly monitor global phase behavior of protein formulations in the frozen state and study its correlation with physical instability of frozen protein formulations. METHODS: Oscillatory rheology was used to measure changes in rheological parameters and to identify mechanical softening temperature (Ts*) and related properties of an IgG2 mAb formulation. Rheological measurements were compared to DSC/MDSC. Physical stability of IgG2 formulations was monitored by SE-HPLC. RESULTS: Rheological parameters and Ts* of an IgG2 formulation were sensitive to physical/morphological phase changes during freezing and thawing. Ts* of the frozen formulation was a function of concentration of protein and excipient. Complex modulus, G*, and phase angle, δ, for IgG2 at 70 mg/mL in a sucrose-containing formulation showed the system was not completely frozen at -10°C, which correlated to stability data consistent with ice-induced protein aggregation. CONCLUSIONS: We report the first application of oscillatory shear rheology to study phase behavior of IgG2 in a sucrose-containing formulation and its correspondence with physical stability not explained by glass transition (Tg'). We provide a mechanism and data suggesting that protein instability occurs at the ice/water interface.

Anti-cancer effect of iNOS inhibitor and its correlation with angiogenesis in gastric cancer.

AIM: To observe the anti-cancer effect of iNOS selective inhibitor (aminoguanidine, AG) and investigate the relationship between iNOS inhibitor and angiogenesis, infiltration or metastasis in MFC gastric cancer xenografts. METHODS: Fifty athymic mice xenograft models were established by inoculating gastric cancer cell MFC subcutaneously. Twenty-four hours later, 0.9% sodium chloride solution, mitomycin, low dosage AG, high dosage AG, mitomycin and AG were administered by intraperitoneal injection respectively. Thus these mice were divided into five groups of 10 each randomly: control group, MMC group, AG(L) group, AG(H) group, MMC+AG(H) group. Two weeks later the mice were killed, and the tumor weight, inhibitory rate were evaluated. Greiss assay was used to detect the nitric oxide levels in plasma. HE and immunohistochemistry staining were used to examine microvessel density (MVD) and the expression of iNOS, VEGF, and PCNA. Apoptosis was detected by using TUNEL assay. RESULTS: The inhibitory rates in MMC+AG(H) group and AG(H) group were 52.9% and 47.1% respectively, which is significant statistically compared with that of control group (0). In treatment groups, the cell proliferation index (PI) was lower and apoptosis index was higher than those of control group. Microvessel density, iNOS, and VEGF in MMC+ AG(H) group were 8.8+/-2.6, 2.4+/-1.1, and 2.1+/-1.4 respectively, which is significant statistically compared with those of control group (68.3+/-10.6, 11.3+/-1.3, and 10.3+/-1.6). The NO level in plasma of MMC+ AGH and AG(H) group were 12.7+/-2.1 and 12.9+/-2.0 mumol/L. Compared with that of control group (46.6+/-2.3 mumol/L), the difference is statistically significant. CONCLUSION: AG has anticancer effect on gastric cancer, and it has positive synergistic effect with chemotherapeutic drugs. It may play important inhibitory roles in angiogenesis of gastric cancer. The anticancer effect of iNOS inhibitors may include inducing cell apoptosis, suppressing cell proliferation and reducing angiogenesis.

Preparation of Unilamellar Immunoliposomes by Passing Reversed Micelles through Oil-water Interface.

A novel method for the preparation of unilamellar immunoliposomes is introduced. In this method, the aqueous phase is first encapsulated into reverse micelles passing through the oil-water interface, where the monolayer of lecithin embedded with antibody has been formed to self-assemble into immunoliposomes. The main advantages of this method are that the procedure of preparation is simple with high encapsulation yield and it is favorable for large scale production. As shown by negative staining electronic micrograph, the immunoliposomes are unilamellar and 100-500 nm in size. The UV spectra of immunoliposomes solution and lysis assay show that sheep anti-human IgG has been coated on liposomes.