Meridian study on the response current affected by acupuncture needling direction.

Acupuncture manipulation with needling direction is important for the therapeutic effect based on traditional Chinese medicine theory. However, there is controversy over directional manipulation and therapeutic effect, despite some research showing that acupuncture manipulations may have something to do with therapeutic effect. Moreover, research usually focuses on the therapeutic effects on the acupoints and acupuncture time rather than exploring the manipulation method. This study applies a semiconductor analyzer to investigate the effects of acupuncture manipulation. 10 healthy participants were recruited for the study. We used a cross-over design to compare the effect of different manipulation on individuals. This study employed an Agilent B1500A semiconductor analyzer to investigate the electric characteristics of meridians under directional supplementation and draining manipulation. We measured the electric current of meridians under different manipulation, and compared the difference between supplementation and draining manipulation in healthy individuals. The electric current was significantly larger in supplementation manipulation compared to draining manipulation in the meridians (P < .001). The measured electric current in the same manipulation methods did not show a statistical difference between meridians (P = .094). The different directional manipulation result in different electric currents in humans. Our finding implies that the supplementation and draining manipulation may result in different therapeutic effects clinically as the description of traditional Chinese medicine theory. Therefore, directional manipulation may need to be taken into consideration in future acupuncture studies and clinical management.

Analysis of Meridian Flow Direction by Electrical Stimulation Method.

Meridians constitute the theoretical foundation of acupuncture in traditional Chinese medicine (TCM), and they have been described for 2000 years. Classical TCM advocates for the directionality of meridians. Finding an accurate method to verify this directionality is an important goal of TCM doctors and researchers. In this study, we objectively explored the physical properties of meridians, such as response current from electrical stimulation, to explore their directionality. The Agilent B1500A semiconductor measurement analyzer was utilized to input the alternating current waveforms and detect the response current on the meridians. The results showed that the direction of the meridians influences the intensity of the response current. Therefore, the mechanisms behind the directions of ion transportation and the meridians were investigated using the response time and the intensity of the response current. Thereafter, we propose a model to explain this mechanism. Afterward, a comparison between the direction of the meridian in this experiment and ancient Chinese medicine classics was performed.

Stabilizing resistive random access memory by constructing an oxygen reservoir with analyzed state distribution.

In this paper, the instability mechanism of resistive random access memory (RRAM) was investigated, and a technique was developed to stabilize the distribution of high resistance states (HRS) and better concentrate the set voltage. Due to the accumulation of oxygen, an interface-type switching characteristic was observed on the I-V curves beneath the filament-type switching behavior. In this work, the interface-type switching characteristic is used to fit the natural distribution of HRS as an analysis of the instability mechanism. According to the results, the HRS distribution is attributed to the accumulation of excess oxygen ions left from the lower oxygen content and oxygen vacancy recombination during the reset process. The proposed solution with simple plasma treatment, can create an excess oxygen reservoir by changing the surface topography of the electrode to store the surplus oxygen ions from the reset process, eliminating the oxygen accumulation effect and further improving the device stability.

Adaptive Synaptic Memory via Lithium Ion Modulation in RRAM Devices.

Biologically plausible computing systems require fine-grain tuning of analog synaptic characteristics. In this study, lithium-doped silicate resistive random access memory with a titanium nitride (TiN) electrode mimicking biological synapses is demonstrated. Biological plausibility of this RRAM device is thought to occur due to the low ionization energy of lithium ions, which enables controllable forming and filamentary retraction spontaneously or under an applied voltage. The TiN electrode can effectively store lithium ions, a principle widely adopted from battery construction, and allows state-dependent decay to be reliably achieved. As a result, this device offers multi-bit functionality and synaptic plasticity for simulating various strengths in neuronal connections. Both short-term memory and long-term memory are emulated across dynamical timescales. Spike-timing-dependent plasticity and paired-pulse facilitation are also demonstrated. These mechanisms are capable of self-pruning to generate efficient neural networks. Time-dependent resistance decay is observed for different conductance values, which mimics both biological and artificial memory pruning and conforms to the trend of the biological brain that prunes weak synaptic connections. By faithfully emulating learning rules that exist in human's higher cortical areas from STDP to synaptic pruning, the device has the capacity to drive forward the development of highly efficient neuromorphic computing systems.

Meridian study on the response current affected by electrical pulse and acupuncture.

Acupuncture and its meridians are important components of traditional Chinese medicine, and numerous opinions have been previously expressed regarding these meridians. This study aims to explore the phenomenon of meridians from the perspective of electronic physics by studying these meridians for the response current affected by electrical pulse and acupuncture. In this study, acupuncture which applies an electrical pulse was used to research the physical properties of the meridians. Different kinds of pulses were applied to the human body to realize abnormal electrical signals. Comparing these electrical measurement results with the isothermal transient ionic current (ITIC) theory, we found that the transmission of meridian messages may be related to ion conduction. The movement of ions induced by acupuncture and electrical stimulation can lead to drift and diffusion currents through the meridians. The ionic conduction of meridian hypothesis is proved in that the substances delivered by meridians are in fact ions.

Role of class II P fimbriae and cytokine response in the pathogenesis of Escherichia coli kidney infection in diabetic mice.

BACKGROUND: The role of class II P fimbriae (P fimbriae II) in diabetic kidney infections is uncertain, although some genetic and epidemiological studies suggest a lower prevalence of P fimbriae II genes in Escherichia coli strains isolated from diabetic patients with complicated kidney infections. METHODS: We inoculated a P fimbriae II deficient E. coli (DH5αT) or an isogenic P fimbriae II expressing transformant (DH5αTP) into the bladders of diabetic and non-diabetic BALB/C mice, and sacrificed them after 3 days. The incidence of bladder or kidney infection (≥103 CFU of E. coli per bladder or kidney), bacteremia (≥102 CFU of E. coli on blood culture plate), kidney pathological score, immunoreactive Histo-score (H-score), and corrected H-score (H-score adjusted for Log10 CFU of bacteria in the kidney) were compared among groups. RESULTS: Diabetic mice were more susceptible to bladder infection than non-diabetic mice with both transformants. The geometric mean of bacteria counts in kidneys was significantly increased only when the diabetic mice were infected with DH5αTP. Among the 4 groups of mice, diabetic mice infected with DH5αTP had the highest incidence of kidney infection and bacteremia, and the highest renal pathology scores. The IL-8 H-score and the corrected IL-6 and IL-8 H-score were significantly lower in diabetic than non-diabetic mice. CONCLUSION: We concluded that P fimbriae II contribute to the pathogenesis and severity of E. coli kidney infections in diabetic mice. An impaired cytokine response may also contribute to the increased incidence and severity of kidney infections in diabetic hosts.

Conduction Mechanism and Improved Endurance in HfO2-Based RRAM with Nitridation Treatment.

A nitridation treatment technology with a urea/ammonia complex nitrogen source improved resistive switching property in HfO2-based resistive random access memory (RRAM). The nitridation treatment produced a high performance and reliable device which results in superior endurance (more than 109 cycles) and a self-compliance effect. Thus, the current conduction mechanism changed due to defect passivation by nitrogen atoms in the HfO2 thin film. At a high resistance state (HRS), it transferred to Schottky emission from Poole-Frenkel in HfO2-based RRAM. At low resistance state (LRS), the current conduction mechanism was space charge limited current (SCLC) after the nitridation treatment, which suggests that the nitrogen atoms form Hf-N-Ox vacancy clusters (Vo+) which limit electron movement through the switching layer.

HDAC2 and HDAC5 Up-Regulations Modulate Survivin and miR-125a-5p Expressions and Promote Hormone Therapy Resistance in Estrogen Receptor Positive Breast Cancer Cells.

Intrinsic or acquired resistance to hormone therapy is frequently reported in estrogen receptor positive (ER+) breast cancer patients. Even though dysregulations of histone deacetylases (HDACs) are known to promote cancer cells survival, the role of different HDACs in the induction of hormone therapy resistance in ER+ breast cancer remains unclear. Survivin is a well-known pro-tumor survival molecule and miR-125a-5p is a recently discovered tumor suppressor. In this study, we found that ER+, hormone-independent, tamoxifen-resistant MCF7-TamC3 cells exhibit increased expression of HDAC2, HDAC5, and survivin, but show decreased expression of miR-125a-5p, as compared to the parental tamoxifen-sensitive MCF7 breast cancer cells. Molecular down-regulations of HDAC2, HDAC5, and survivin, and ectopic over-expression of miR-125a-5p, increased the sensitivity of MCF7-TamC3 cells to estrogen deprivation and restored the sensitivity to tamoxifen. The same treatments also further increased the sensitivity to estrogen-deprivation in the ER+ hormone-dependent ZR-75-1 breast cancer cells in vitro. Kaplan-Meier analysis and receiver operating characteristic curve analysis of expression cohorts of breast tumor showed that high HDAC2 and survivin, and low miR-125a-5p, expression levels correlate with poor relapse-free survival in endocrine therapy and tamoxifen-treated ER+ breast cancer patients. Further molecular analysis revealed that HDAC2 and HDAC5 positively modulates the expression of survivin, and negatively regulates the expression miR-125a-5p, in ER+ MCF7, MCF7-TamC3, and ZR-75-1 breast cancer cells. These findings indicate that dysregulations of HDAC2 and HDAC5 promote the development of hormone independency and tamoxifen resistance in ERC breast cancer cells in part through expression regulation of survivin and miR-125a-5p.

Quantitative PPARγ expression affects the balance between tolerance and immunity.

PPARγ modulates energy metabolism and inflammation. However, its specific functions in the balance of immunity in vivo have been explored incompletely. In this study, by the age of 14 mo, Pparg(C/-) mice with PPARγ expression at 25% of the normal level exhibited high autoantibody levels and developed mesangial proliferative glomerulonephritis, which resembled systemic lupus erythematosus (SLE)-like autoimmune disease. These symptoms were preceded by splenomegaly at an early age, which was associated with increases in splenocyte accumulation and B-cell activation but not with relocation of hematopoiesis to the spleen. The mechanism of splenic lymphocyte accumulation involved reduced sphingosine-1-phosphate receptor 1 (S1P1) expression and diminished migration toward S1P in the Pparg(C/-) splenocytes, which impeded lymphocyte egression. Mechanistically, increased Th17 polarization and IL-17 signaling in the Pparg(C/-) CD4(+) T cells contributed to B-cell hyperactivation in the spleen. Finally, the activation of the remaining PPARγ in Pparg(C/-) mice by pioglitazone increased S1P1 levels, reduced the Th17 population in the spleen, and ameliorated splenomegaly. Taken together, our data demonstrated that reduction of Pparg expression in T-helper cells is critical for spontaneous SLE-like autoimmune disease development; we also revealed a novel function of PPARγ in lymphocyte trafficking and cross talk between Th17 and B cells.

Integrin-linked kinase as a novel molecular switch of the IL-6-NF-κB signaling loop in breast cancer.

Substantial evidence has clearly demonstrated the role of the IL-6-NF-κB signaling loop in promoting aggressive phenotypes in breast cancer. However, the exact mechanism by which this inflammatory loop is regulated remains to be defined. Here, we report that integrin-linked kinase (ILK) acts as a molecular switch for this feedback loop. Specifically, we show that IL-6 induces ILK expression via E2F1 upregulation, which, in turn, activates NF-κB signaling to facilitate IL-6 production. shRNA-mediated knockdown or pharmacological inhibition of ILK disrupted this IL-6-NF-κB signaling loop, and blocked IL-6-induced cancer stem cells in vitro and estrogen-independent tumor growth in vivo Together, these findings establish ILK as an intermediary effector of the IL-6-NF-κB feedback loop and a promising therapeutic target for breast cancer.

Albumin stimulates renal tubular inflammation through an HSP70-TLR4 axis in mice with early diabetic nephropathy.

Increased urinary albumin excretion is not simply an aftermath of glomerular injury, but is also involved in the progression of diabetic nephropathy (DN). Whereas Toll-like receptors (TLRs) are incriminated in the renal inflammation of DN, whether and how albumin is involved in the TLR-related renal inflammatory response remains to be clarified. Here, we showed that both TLR2 and TLR4, one of their putative endogenous ligands [heat shock protein 70 (HSP70)] and nuclear factor-κB promoter activity were markedly elevated in the kidneys of diabetic mice. A deficiency of TLR4 but not of TLR2 alleviated albuminuria, tubulointerstitial fibrosis and inflammation induced by diabetes. The protection against renal injury in diabetic Tlr4(-/-) mice was associated with reduced tubular injuries and preserved cubilin levels, rather than amelioration of glomerular lesions. In vitro studies revealed that albumin, a stronger inducer than high glucose (HG), induced the release of HSP70 from proximal tubular cells. HSP70 blockade ameliorated albumin-induced inflammatory mediators. HSP70 triggered the production of inflammatory mediators in a TLR4-dependent manner. Moreover, HSP70 inhibition in vivo ameliorated diabetes-induced albuminuria, inflammatory response and tubular injury. Finally, we found that individuals with DN had higher levels of TLR4 and HSP70 in the dilated tubules than non-diabetic controls. Thus, activation of the HSP70-TLR4 axis, stimulated at least in part by albumin, in the tubular cell is a newly identified mechanism associated with induction of tubulointerstitial inflammation and aggravation of pre-existing microalbuminuria in the progression of DN.

Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy.

INTRODUCTION: Platinum (Pt)-based antitumor agents remain important chemotherapeutic agents for treating many human malignancies. Elevated expression of the human high-affinity copper transporter 1 (hCtr1), resulting in enhanced Pt drug transport into cells, has been shown to be associated with improved treatment efficacy. Thus, targeting hCtr1 upregulation is an attractive strategy for improving the treatment efficacy of Pt-based cancer chemotherapy. AREA COVERED: Regulation of hCtr1 expression by cellular copper homeostasis is discussed. Association of elevated hCtr1 expression with intrinsic sensitivity of ovarian cancer to Pt drugs is presented. Mechanism of copper-lowering agents in enhancing hCtr1-mediated cis-diamminedichloroplatinum (II) (cisplatin, cDDP) transport is reviewed. Applications of copper chelation strategy in overcoming cDDP resistance through enhanced hCtr1 expression are evaluated. EXPERT OPINION: While both transcriptional and post-translational mechanisms of hCtr1 regulation by cellular copper bioavailability have been proposed, detailed molecular insights into hCtr1 regulation by copper homeostasis remain needed. Recent clinical study using a copper-lowering agent in enhancing hCtr1-mediated drug transport has achieved incremental improvement in overcoming Pt drug resistance. Further improvements in identifying predictive measures in the subpopulation of patients that can benefit from the treatment are needed.

Delayed uterine rupture occurred 4 weeks after cesarean section following sexual intercourse: a case report and literature review.

OBJECTIVE: Spontaneous delayed uterine rupture is life-threatening and extremely rare following sexual intercourse in postpartum. Here, we present a case of delayed uterine rupture that occurred 4 weeks after cesarean section following intercourse. CASE REPORT: A 31-year-old postpartum woman, gravida 4, para 1, abortion 3, underwent a cesarean section for prolonged labor. She was transferred to our hospital in shock status with brisk vaginal bleeding following intercourse 4 weeks after delivery. An emergency subtotal hysterectomy was performed to stop the bleeding. The pathology confirmed tissue necrosis and suture granuloma at the previous surgical wound. CONCLUSION: The presented case demonstrated that delayed uterine rupture may occur even 4 weeks after delivery following intercourse, without any obvious abdominal pain or infection signs, which deserved the attention of obstetricians.

Interleukin-17-producing cell infiltration in the breast cancer tumour microenvironment is a poor prognostic factor.

AIMS: Interleukin-17 (IL-17) is a proinflammatory cytokine that is most prominently produced by T-helper type 17 (Th17) cells, a distinct CD4+ T-helper cell subset. The aim of this study was to investigate the level of IL-17-producing cells in the breast cancer tumour microenvironment and its prognostic role. METHODS AND RESULTS: A total of 207 breast carcinoma specimens were assessed by IL-17 immunohistochemistry, and the findings were correlated with clinicopathological parameters. We found that increased numbers of IL-17-producing cells were correlated with high histological grade, negative ER/PR status, and triple-negative molecular subtypes segregated by immunoprofiles. However, they did not correlate with stage, tumour size, nodal status, HER2 status, or histological type. Patients with tumours with high numbers of IL-17-producing cells had shorter disease-free survival (DFS) than patients with tumours with low numbers of IL-17-producing cells (P < 0.01). In multivariate analysis, high IL-17 level [hazard ratio (HR) 2.24; 95% CI 1.06-4.75], advanced T stage (HR 2.73; 95% CI 1.30-5.73), positive HER2 status (HR 4.88; 95% CI 1.47-16.18) and triple-negative subtype (HR 7.46; 95% CI 1.38-40.36) were significant prognostic factors for DFS. CONCLUSIONS: Our results indicate that a high level of IL-17-producing cells in the breast cancer tumour microenvironment is a poor prognostic factor.

Diffuse sclerosing variant of thyroid papillary carcinoma: diagnostic challenges occur with Hashimoto's thyroiditis.

Diffuse sclerosing papillary thyroid carcinoma (DSPTC) is a relatively rare variant of papillary thyroid carcinoma with distinct histological features, radiological characteristics, and biological aggressiveness. Compared with conventional papillary thyroid carcinoma, DSPTC is characterized by scattered microscopic tumor islands, diffuse fibrosis, calcification, and abundant lymphocytic aggregation. A preoperative diagnosis is challenging in the absence of nodules and scanty fine needle aspiration cytology samples. We describe a unique DSPTC patient, an 18-year-old woman who presented with a neck mass that grew slowly for 2 years. The palpable neck mass was nontender, well defined, firm, and unmovable. Laboratory studies showed normal thyroid function and positive autoimmune markers: antithyroglobulin antibody = 1:1600 and antimicrosomal antibody = 1:1600. A neck ultrasound showed diffusely prominent microcalcifications with one small vague nodule. Hashimoto's thyroiditis with an accompanying malignancy was suspected. Based on the result of intraoperative pathology reports, the patient was given a total thyroidectomy. Lymph node dissection and histological analysis revealed bilateral DSPTC in addition to lymphocytic thyroiditis in nonmalignant areas of the thyroid. Clinical and histological diagnostic challenges usually occur when DSPTC presents with a diffuse thyroid enlargement, dispersed microscopic tumor islands (frequently without mass formation), extensive fibrosis, and abundant lymphocytic infiltration mimicking thyroiditis.

Validation of Memorial Sloan-Kettering Cancer Center nomogram for prediction of non-sentinel lymph node metastasis in sentinel lymph node positive breast cancer patients an international comparison.

BACKGROUND: Current guidelines for breast cancer treatment recommend completion axillary lymph node dissection (CALND) following in case of positive sentinel lymph node (SLN) metastasis, which only in 35%-70% shows additional nodal metastases. Several nomograms and scoring systems have been created to predict the risk of metastasis in non-SLNs. The aim of the study was to identify individual patient risk for non-sentinel lymph node metastasis by validating with MSKCC nomogram and to evaluate the variability within a group of SLN-positive breast cancer patients with the final goal of avoiding unnecessary CALND. PATIENTS AND METHODS: We retrospectively evaluated 1496 primary breast cancer patients. 324 women with a positive SLN who underwent CALND were identified. The predictive accuracy was measured and compared with the MSKCC nomogram by the area under the receiver operating characteristic curve. Receiver operating characteristic (ROC) curve was drawn on the basis of the sensitivity and specificity, and the area under the curve (AUC) was calculated. RESULTS: At least one metastatic non-SLN were identified in 88/324 (27.2%) patients. Tumor size, tumor type, tumor grade, number of positive SLNs and number of negative SLNs were significantly associated with non-SLN status in multivariate analyses. The MSKCC nomogram showed an AUC value of 0.738 (95% confidence interval = 0.682-0.793) after the validation for our collectives. CONCLUSIONS: The MSKCC nomogram showed a good prediction for the non-SLN metastasis and performed adequately in our patient collective. Therefore, for the use of nomogram, validation with other populations of patients is strongly suggested.

Coenzyme Q10 rescues ethanol-induced corneal fibroblast apoptosis through the inhibition of caspase-2 activation.

Recent studies indicate that caspase-2 is involved in the early stages of apoptosis, particularly before the occurrence of mitochondrial damage. Here we report the important role of the coenzyme Q10 (CoQ10) on the activity of caspase-2 upstream of mitochondria in ethanol (EtOH)-treated corneal fibroblasts. After EtOH exposure, cells produce excessive reactive oxygen species formation, p53 expression, and most importantly, caspase-2 activation. After the activation of the caspase-2, the cells exhibited hallmarks of apoptotic pathway, such as mitochondrial damage and translocation of Bax and cytochrome c, which were then followed by caspase-3 activation. By pretreating the cells with a cell-permeable, biotinylated pan-caspase inhibitor, we identified caspase-2 as an initiator caspase in EtOH-treated corneal fibroblasts. Loss of caspase-2 inhibited EtOH-induced apoptosis. We further found that caspase-2 acts upstream of mitochondria to mediate EtOH-induced apoptosis. The loss of caspase-2 significantly inhibited EtOH-induced mitochondrial dysfunction, Bax translocation, and cytochrome c release from mitochondria. The pretreatment of CoQ10 prevented EtOH-induced caspase-2 activation and mitochondria-mediated apoptosis. Our data demonstrated that by blocking caspase-2 activity, CoQ10 can protect the cells from mitochondrial membrane change, apoptotic protein translocation, and apoptosis. Taken together, EtOH-induced mitochondria-mediated apoptosis is initiated by caspase-2 activation, which is regulated by CoQ10.

Predictive and prognostic value of human copper transporter 1 (hCtr1) in patients with stage III non-small-cell lung cancer receiving first-line platinum-based doublet chemotherapy.

BACKGROUND: Recent studies have shown that human copper transporter 1 (hCtr1), the major copper influx transporter, is involved in the transport of platinum-based antitumor agents. We investigated the predictive and prognostic values of hCtr1, and copper efflux transporters ATP7A and ATP7B, in patients with locally advanced non-small cell lung cancer (NSCLC) receiving first-line platinum-based chemotherapy. METHODS: From 2004 to 2009, we identified 54 consecutive stage III NSCLC patients who underwent first-line platinum-based doublet chemotherapy. Immunohistochemical studies of hCtr1, ATP7A and ATP7B on the paraffin-embedded pre-treatment tumor samples were performed and correlated with chemotherapy response and survival. RESULTS: Overexpression of hCtr1, ATP7A and ATP7B were observed in 68%, 48% and 74% of the participants, respectively. hCtr1 overexpression was associated with better chemotherapy responses (P<0.01); whereas ATP7A and ATP7B were not. Patients with hCtr1 overexpressing tumors had better progression-free survival (PFS) and overall survival (OS) (P=0.01 and 0.047, respectively). In multivariate analyses for chemotherapy response and PFS, only hCtr1 overexpression emerged as a favorable independent predictive and prognostic factor (all P<0.01). CONCLUSION: This is the first report to state that hCtr1 is not only an independent predictor of platinum-based chemotherapy response but also a prognostic factor in stage III NSCLC.