Prescriptions of Traditional Chinese Medicine Are Specific to Cancer Types and Adjustable to Temperature Changes

Targeted cancer therapies, with specific molecular targets, ameliorate the side effect issue of radiation and chemotherapy and also point to the development of personalized medicine. Combination of drugs targeting multiple pathways of carcinogenesis is potentially more fruitful. Traditional Chinese medicine (TCM) has been tailoring herbal mixtures for individualized healthcare for two thousand years. A systematic study of the patterns of TCM formulas and herbs prescribed to cancers is valuable. We analysed a total of 187,230 TCM prescriptions to 30 types of cancer in Taiwan in 2007, a year's worth of collection from the National Health Insurance reimbursement database (Taiwan). We found that a TCM cancer prescription consists on average of two formulas and four herbs. We show that the percentage weights of TCM formulas and herbs in a TCM prescription follow Zipf's law with an exponent around 0.6. TCM prescriptions to benign neoplasms have a larger Zipf's exponent than those to malignant cancers. Furthermore, we show that TCM prescriptions, via weighted combination of formulas and herbs, are specific to not only the malignancy of neoplasms but also the sites of origins of malignant cancers. From the effects of formulas and natures of herbs that were heavily prescribed to cancers, that cancers are a ‘warm and stagnant’ syndrome in TCM can be proposed, suggesting anti-inflammatory regimens for better prevention and treatment of cancers. We show that TCM incorporated relevant formulas to the prescriptions to cancer patients with a secondary morbidity. We compared TCM prescriptions made in different seasons and identified temperatures as the environmental factor that correlates with changes in TCM prescriptions in Taiwan. Lung cancer patients were among the patients whose prescriptions were adjusted when temperatures drop. The findings of our study provide insight to TCM cancer treatment, helping dialogue between modern western medicine and TCM for better cancer care

Neuromagnetic Index of Hemispheric Asymmetry Prognosticating the Outcome of Sudden Hearing Loss

The longitudinal relationship between central plastic changes and clinical presentations of peripheral hearing impairment remains unknown. Previously, we reported a unique plastic pattern of “healthy-side dominance” in acute unilateral idiopathic sudden sensorineural hearing loss (ISSNHL). This study aimed to explore whether such hemispheric asymmetry bears any prognostic relevance to ISSNHL along the disease course. Using magnetoencephalography (MEG), inter-hemispheric differences in peak dipole amplitude and latency of N100m to monaural tones were evaluated in 21 controls and 21 ISSNHL patients at two stages: initial and fixed stage (1 month later). Dynamics/Prognostication of hemispheric asymmetry were assessed by the interplay between hearing level/hearing gain and ipsilateral/contralateral ratio (I/C) of N100m latency and amplitude. Healthy-side dominance of N100m amplitude was observed in ISSNHL initially. The pattern changed with disease process. There is a strong correlation between the hearing level at the fixed stage and initial I/Camplitude on affected-ear stimulation in ISSNHL. The optimal cut-off value with the best prognostication effect for the hearing improvement at the fixed stage was an initial I/Clatency on affected-ear stimulation of 1.34 (between subgroups of complete and partial recovery) and an initial I/Clatency on healthy-ear stimulation of 0.76 (between subgroups of partial and no recovery), respectively. This study suggested that a dynamic process of central auditory plasticity can be induced by peripheral lesions. The hemispheric asymmetry at the initial stage bears an excellent prognostic potential for the treatment outcomes and hearing level at the fixed stage in ISSNHL. Our study demonstrated that such brain signature of central auditory plasticity in terms of both N100m latency and amplitude at defined time can serve as a prognostication predictor for ISSNHL. Further studies are needed to explore the long-term temporal scenario of auditory hemispheric asymmetry and to get better psychoacoustic correlates of pathological hemispheric asymmetry in ISSNHL

MT1-MMP regulates urothelial cell invasion via transcriptional regulation of Dickkopf-3

Membrane type-1 matrix metalloproteinase (MT1-MMP) is a zinc-binding endopeptidase, which plays a crucial role in tumour growth, invasion and metastasis. We have shown previously that MT1-MMP has higher expression levels in the human urothelial cell carcinoma (UCC) tissue. We show here that siRNA against MT1-MMP blocks invasion in UCC cell lines. Invasion is also blocked by broad-spectrum protease and MMP inhibitors including tissue inhibitor of metalloproteinase-1 and -2. Membrane type-1-MMP can also regulate transcription. We have used expression arrays to identify genes that are differentially transcribed when siRNA is used to suppress MT1-MMP expression. Upon MT1-MMP knockdown, Dickkopf-3 (DKK3) expression was highly upregulated. The stability of DKK3 mRNA was unaffected under these conditions, suggesting transcriptional regulation of DKK3 by MT1-MMP. Dickkopf-3 has been previously shown to inhibit invasion. We confirm that the overexpression of DKK3 leads to decreased invasive potential as well as delayed wound healing. We show for the first time that the effects of MT1-MMP on cell invasion are mediated in part through changes in DKK3 gene transcription

Transphosphorylation of kinase-dead HER3 and breast cancer progression: a new standpoint or an old concept revisited?

Although neither kinase-dead human epidermal growth factor receptor (HER)3 nor orphan HER2 can be activated by HER-related ligands on their own, the formation of HER2/HER3 heterodimers creates the most mitogenic and transforming receptor complex within the HER (erbB) family of transmembrane receptor tyrosine kinases. The incorporation of markers such as HER3 transactivation, HER2/HER3 dimer, or others that may provide information regarding the level of HER pathway engagement has been demonstrated to allow identification of patients who respond to or escape HER-targeted therapies. Pioneering studies showed that high expression of kinase-dead HER3 can predict early escape from the anti-HER2 monoclonal antibody trastuzumab. Also, the growth-inhibitory effects of HER1/2 tyrosine kinase inhibitors (TKIs) were previously found to be attenuated in the presence of heregulin, which is a high-affinity combinatorial ligand for HER3. All of these concepts are being revisited with respect to the efficacy of HER family TKI therapies; in particular, HER3 signalling buffered against incomplete inhibition of HER2 kinase activity has been suggested to be the mechanism that allows HER2 over-expressing breast cancer cells to escape HER TKIs. It remains to be elucidated whether reactivation of HER3 signalling can also account for the poor efficacy of HER TKIs in treating breast carcinomas that contain low overall levels of HER2 receptors. However, it appears that regardless of the mechanism that triggers the formation of oncogenic HER2/HER3 heterodimers (HER2 over-expression or overall low HER2 but high levels of the HER3 ligand heregulin), HER3 transphosphorylation is a common response of breast cancer cells upon treatment with current inhibitors of the HER receptor tyrosine kinase network. Because kinase-inactive HER3 is not presently an amenable target for forthcoming HER TKIs, molecular approaches that can efficiently block heregulin-triggered HER3 transactivation or nucleocytoplasmic trafficking of heregulin might offer novel strategies with which to manage HER-driven breast cancer disease

Synergy between inhibitors of androgen receptor and MEK has therapeutic implications in estrogen receptor-negative breast cancer

Introduction: Estrogen receptor-negative (ER-) breast cancer is a heterogeneous disease with limited therapeutic options. The molecular apocrine subtype constitutes 50% of ER-tumors and is characterized by overexpression of steroid response genes including androgen receptor (AR). We have recently identified a positive feedback loop between the AR and extracellular signal-regulated kinase (ERK) signaling pathways in the molecular apocrine subtype. In this feedback loop, AR regulates ERK phosphorylation through the mediation of ErbB2 and, in turn, ERK-CREB1 signaling regulates the transcription of AR in molecular apocrine cells. In this study, we investigated the therapeutic implications of the AR-ERK feedback loop in molecular apocrine breast cancer.Methods: We examined a synergy between the AR inhibitor flutamide and the MEK inhibitor CI-1040 in the molecular apocrine cell lines MDA-MB-453, HCC-1954 and HCC-202 using MTT cell viability and annexin V apoptosis assays. Synergy was measured using the combination index (CI) method. Furthermore, we examined in vivo synergy between flutamide and the MEK inhibitor PD0325901 in a xenograft model of the molecular apocrine subtype. The effects of in vivo therapies on tumor growth, cell proliferation and angiogenesis were assessed.Results: We demonstrate synergistic CI values for combination therapy with flutamide and CI-1040 across three molecular apocrine cell lines at four dose combinations using both cell viability and apoptosis assays. Furthermore, we show in vivo that combination therapy with flutamide and MEK inhibitor PD0325901 has a significantly higher therapeutic efficacy in reducing tumor growth, cellular proliferation and angiogenesis than monotherapy with these agents. Moreover, our data suggested that flutamide and CI-1040 have synergy in trastuzumab resistance models of the molecular apocrine subtype. Notably, the therapeutic effect of combination therapy in trastuzumab-resistant cells was associated with the abrogation of an increased level of ERK phosphorylation that was developed in the process of trastuzumab resistance.Conclusions: In this study, we demonstrate in vitro and in vivo synergies between AR and MEK inhibitors in molecular apocrine breast cancer. Furthermore, we show that combination therapy with these inhibitors can overcome trastuzumab resistance in molecular apocrine cells. Therefore, a combination therapy strategy with AR and MEK inhibitors may provide an attractive therapeutic option for the ER-/AR+ subtype of breast cancer

Epidermal Stem Cells Are Defined by Global Histone Modifications that Are Altered by Myc-Induced Differentiation

Activation of Myc induces epidermal stem cells to exit their niche and differentiate into sebocytes and interfollicular epidermis, a process that is associated with widespread changes in gene transcription. We have identified chromatin modifications that are characteristic of epidermal stem cells and investigated the effects of Myc activation. Quiescent stem cells in the interfollicular epidermis and the hair follicle bulge had high levels of tri-methylated histone H3 at lysine 9 and H4 at lysine 20. Chromatin in both stem cell populations was hypoacteylated at histone H4 and lacked mono-methylation of histone H4 at lysine 20. Myc-induced exit from the stem cell niche correlated with increased acetylation at histone H4 and transiently increased mono-methylation at lysine 20. The latter was replaced by epigenetic modifications that are largely associated with chromatin silencing: di-methylation at histone H3 lysine 9 and histone H4 lysine 20. These modifications correlated with changes in the specific histone methyltransferases Set8 and Ash-1. The Myc-induced switch from mono- to di-methylated H4K20 required HDAC activity and was blocked by the HDAC inhibitor trichostatin A (TSA). TSA treatment induced a similar epidermal phenotype to activation of Myc, and activation of Myc in the presence of TSA resulted in massive stimulation of terminal differentiation. We conclude that Myc-induced chromatin modifications play a major role in Myc-induced exit from the stem cell compartment