An LQT2-related mutation in the voltage-sensing domain is involved in switching the gating polarity of hERG.

BACKGROUND: Cyclic Nucleotide-Binding Domain (CNBD)-family channels display distinct voltage-sensing properties despite sharing sequence and structural similarity. For example, the human Ether-a-go-go Related Gene (hERG) channel and the Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channel share high amino acid sequence similarity and identical domain structures. hERG conducts outward current and is activated by positive membrane potentials (depolarization), whereas HCN conducts inward current and is activated by negative membrane potentials (hyperpolarization). The structural basis for the "opposite" voltage-sensing properties of hERG and HCN remains unknown. RESULTS: We found the voltage-sensing domain (VSD) involves in modulating the gating polarity of hERG. We identified that a long-QT syndrome type 2-related mutation within the VSD, K525N, mediated an inwardly rectifying non-deactivating current, perturbing the channel closure, but sparing the open state and inactivated state. K525N rescued the current of a non-functional mutation in the pore helix region (F627Y) of hERG. K525N&F627Y switched hERG into a hyperpolarization-activated channel. The reactivated inward current induced by hyperpolarization mediated by K525N&F627Y can be inhibited by E-4031 and dofetilide quite well. Moreover, we report an extracellular interaction between the S1 helix and the S5-P region is crucial for modulating the gating polarity. The alanine substitution of several residues in this region (F431A, C566A, I607A, and Y611A) impaired the inward current of K525N&F627Y. CONCLUSIONS: Our data provide evidence that a potential cooperation mechanism in the extracellular vestibule of the VSD and the PD would determine the gating polarity in hERG.

Inhibition of hsa_circ_0003489 shifts balance from autophagy to apoptosis and sensitizes multiple myeloma cells to bortezomib via miR-874-3p/HDAC1 axis.

BACKGROUND: Circular RNAs (circRNAs) crucially regulate tumor progression. In this study, we examined the functional roles and mechanisms of hsa_circ_0003489 in multiple myeloma (MM). METHODS: Upon altering the expressions of hsa_circ_0003489, miR-874-3p, and/or histone deacetylase 1 (HDAC1) in MM1.R cells and treating them with bortezomib (BTZ), cell viability was examined by CCK-8 assay; cell proliferation by Ki-67 immunofluorescence; apoptosis by TUNEL staining, flow cytometry, and western blot; and autophagy by electron microscopy and western blot. The interaction between hsa_circ_0003489 and miR-874-3p as well as that between miR-874-3p and HDAC1 was examined by expressional analysis, dual luciferase reporter assay, and RNA immunoprecipitation. The in vivo impacts of hsa_circ_0003489 on MM growth and sensitivity to BTZ were examined using an MM xenograft mouse model. RESULTS: Knocking down hsa_circ_0003489 significantly inhibited the viability, cell proliferation, and autophagy, while promoting the apoptosis of MM cells in vitro and MM xenograft in vivo. Suppressing hsa_circ_0003489 also further boosted the cytotoxic effects of BTZ in MM cells and reversed its promoting effect on autophagy. Mechanically, hsa_circ_0003489 acted as a sponge of miR-874-3p and positively regulated the expression of miR-874-3p target, HDAC1. MiR-874-3p and HDAC1 essentially mediated the effects of hsa_circ_0003489 on cell viability, proliferation, apoptosis, and autophagy. CONCLUSION: The hsa_circ_0003489/miR-874-3p/HDAC1 axis critically regulates the balance between apoptosis and autophagy. Silencing hsa_circ_0003489 sensitizes MM cells to BTZ by inhibiting autophagy and thus may boost the therapeutic effects of BTZ.

Insights into the theranostic value of precision medicine on advanced radiotherapy to breast cancer.

Breast cancer is the most common cancer in women worldwide. "Breast cancer" encompasses a broad spectrum of diseases (i.e., subtypes) with significant epidemiological, clinical, and biological heterogeneity. Each of these subtypes has a different natural history and prognostic profile. Although tumour staging (TNM classification) still provides valuable information in the overall management of breast cancer, the current reality is that clinicians must consider other biological and molecular factors that directly influence treatment decision-making, including extent of surgery, indication for chemotherapy, hormonal therapy, and even radiotherapy (and treatment volumes). The management of breast cancer has changed radically in the last 15 years due to significant advances in our understanding of these tumours. While these changes have been extremely positive in terms of surgical and systemic management, they have also created significant uncertainties concerning integration of local and locoregional radiotherapy into the therapeutic scheme. In parallel, radiotherapy itself has also experienced major advances. Beyond the evident technological advances, new radiobiological concepts have emerged, and genomic data and other patient-specific factors must now be integrated into individualized treatment approaches. In this context, "precision medicine" seeks to provide an answer to these open questions and uncertainties. Although precision medicine has been much discussed in the last five years or so, the concept remains somewhat ambiguous, and it often appear to be used as a "catch-all" term. The present review aims to clarify the meaning of this term and, more importantly, to critically evaluate the role and impact of precision medicine on breast cancer radiotherapy. Finally, we will discuss the current and future of precision medicine in radiotherapy.

Microbial antigens-loaded myeloma cells enhance Th2 cell proliferation and myeloma clonogenicity via Th2-myeloma cell interaction.

BACKGROUND: Myeloma cells retain B cell functions, considered to be potential antigen presenting cells, yet there is little information regarding promoting Th2 cell proliferation or the direct effects to myeloma on the Th2 cells stimulated by microbial antigens-loaded myeloma cells. METHODS: Mixed lymphocyte reaction was used colorimetric assays via CCK8-kit. Surface molecular expression was performed by flow cytometry, cells sorting using microbeads. The concentrations of cytokines in serum were assessed using an ELISA kit. Clonogenic assay were performed in a methylcellulose culture system. Statistical analysis was assessed using the Student's t-test or one-way analysis of variance for multiple comparisons test. RESULTS: The expression of HLA-DR, CD80 and CD40 on RPMI8266 cell membrane surface was upregulated by interaction with interferon-γ and/or Bacillus Calmette-Guerin Vaccine (BCGV). RPMI8266 cells were able to induce the mixed lymphocyte reaction in a dose-dependent fashion. The Th2 ratio induced by RPMI8266 treated by BCGV and interferon-γ (treated-RPMI8266) cells was only slightly greater than by untreated-tumor cells, but the serum IL-4 level secreted by Th2 cells was markedly higher in treated-RPMI8266 cells group. Th2 cells stimulated by treated-myeloma cells could directly promote treated-myeloma cell clonogenicity in a dose-dependent manner. Anti-HLADR IgG2b completely blocked increased of IL-4 secretion by Th2 cells stimulated by treated-myeloma cells, while also blocked enhancing the clonogenicity of treated tumor cells stimulated by MM-Th2 cells. CONCLUSIONS: These results indicate that a novel mechanism of myeloma pathogenesis in myeloma cells could act as an APC to present microbial Ags to Th2 cells, promoting Th2 cell proliferation, consequently facilitating tumor development by close interaction between Th2 myeloma cells. Taken together, the microbial Ag presenting course of MM-Th2-MM interactions-restricted by MHC class-II-may result in tumor development such that all factors involved in the system could have a potential for myeloma therapeutic intervention.

[Corrigendum] MicroRNA­497 inhibits multiple myeloma growth and increases susceptibility to bortezomib by targeting Bcl­2.

Subsequently to the publication of the article, the authors have realized that the second and third author affiliations were presented the wrong way around, and should have been reversed. Therefore, the author affiliations in this paper should have appeared as follows: Faqing Tian1, Yong Zhan2, Wei Zhu3, Juheng Li1, Meiqin Tang1, Xiaohui Chen1 and Jian Jiang1. Departments of 1Hematology and 2Radiology, Longgang District People's Hospital of Shenzhen, Shenzhen, Guangdong 518172; 3Department of Pathology, School of Basic Medicine, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China. The authors regret that these errors and omissions were not corrected prior to the publication of the paper, and apologize to the readership for the inconvenience caused. [the original article was published in International Journal of Molecular Medicine 43: 1058­1066, 2019; DOI: 10.3892/ijmm.2018.4019].

MicroRNA-497 inhibits multiple myeloma growth and increases susceptibility to bortezomib by targeting Bcl-2.

Multiple myeloma (MM) is a common severe hematopoietic malignancy occuring in aged population. MicroRNA (miR)­497 was previously reported to contribute to the apoptosis of other cell types, presumably through targeting B­cell lymphoma 2 (Bcl­2). In the present study, miRNA and protein expression levels were detected by reverse transcription­quantitative polymerase chain reaction and western blot analyses, respectively. The cell proliferation and viability was measured using 3­(4,5­dimethylthiazol­2­yl)­2, 5­diphenyltetrazolium bromide and plate clonality assays, and the cell growth cycle was measured with a flow cytometer. Terminal deoxynucleotidyl transferase (TdT)­mediated dUTP nick­end­labeling, Annexin V and caspase­3 activity assays were performed to examine the cell apoptotic rates. The results showed that miR­497 was markedly decreased, whereas Bcl­2 was enhanced in MM tissues and cell lines. miR­497 targeted Bcl­2 and affected its downstream apoptosis­related genes. The overexpression of miR­497 promoted MM cell apoptosis through cell cycle arrest, and decreased colony genesis ability and viability. In addition, miR­497 increased the sensitivity of MM cells to bortezomib. Taken together, miR­497 suppressed MM cell proliferation and promoted apoptosis by directly targeting Bcl­2 and altering the expression of downstream apoptosis­related proteins. The combination of miR­497 and bortezomib may enhance drug sensitivity, serving as a potentially available therapeutic method for MM.

[Dendritic Cells Promote the Proliferation of Peripheral Blood CRTH2 Cells (CD4(+)CD294(+)Th2) and Help B Cells to Secrete Immunoglobulin].

Objective：To investigate the promotive effect of dendritic cells(DCs) on proliferation of CRTH2 (CD4(+)CD294(+)Th2) cells and the influence of CRTH2 cells on secretion of immunoglobulin from B cells so as to provide a new approach for amplification and sorting of Th2 cells. Methods：DCs were induced from peripheral blood mononuclear cells, then the loaded-BCGV-Ag-DCs were cocultured with T cells, and the mixed lymphocyte reaction(MLR) was performed by CCK8 method. The phenotypes of DCs and CRTH2 cells were detected by flow cytometry. CRTH2 cells sorted by MACS were co-cultured with B cells for 5 days to detect the secretion of immunoglobulin. Results：The subsets and absolute number CRTH2 cells were significantly increased by loaded-BCGV-Ag-DCs. The levels of IgG, IgA and IgE were higher increased in supernatant of CRTH2 and B cell co-culture system than that in control group or that in transwell group(P<0.05). Conclusion：The proliferation of CRTH2 cells can be greatly promoted by loaded-BCGV-Ag-DCs, and the CRTH2 cells can help B cells to secrete IgG, IgA and IgE.

The antibiotic chloramphenicol may be an effective new agent for inhibiting the growth of multiple myeloma.

Chloramphenicol is an old antibiotic that also inhibits mammalian mitochondrial protein synthesis. Our studies demonstrated that chloramphenicol is highly cytotoxic to myeloma cells, acting in a dose- and time-dependent manner. Chloramphenicol sharply suppressed ATP levels in myeloma cells at concentrations ≥ 25 µg/mL. Colorimetric and clonogenic assays indicate that chloramphenicol inhibits growth of myeloma cell lines at concentrations ≥ 50 µg/mL, and inhibits primary myeloma cell growth at concentrations ≥ 25 µg/mL. Flow cytometry and Western blotting showed that chloramphenicol induces myeloma cell apoptosis at concentrations ≥ 50 µg/mL. Chloramphenicol increased levels of cytochrome c, cleaved caspase-9 and cleaved caspase-3, suggesting that myeloma cell apoptosis occurs through the mitochondria-mediated apoptosis pathway. It thus appears chloramphenicol is not only an old antibiotic, it is also a potential cytotoxic agent effective against myeloma cells. This suggests chloramphenicol may be an effective "new" drug for the treatment of myeloma.

Joint power and multiple access control for wireless mesh network with Rose projection method.

This paper investigates the utility maximization problem for the downlink of the multi-interface multichannel wireless mesh network with orthogonal frequency division multiple access. A cross-layer joint power and multiple access control algorithm are proposed. Rosen projection matrix is combined with Solodov projection techniques to build a three-memory gradient Rosen projection method, which is applied to solve this optimization problem. The convergence analysis is given and simulations show that the proposed solution achieves significant throughput compared with existing approaches.

Distributed optimal power and rate control in wireless sensor networks.

With the rapid development of wireless sensor networks, reducing energy consumption is becoming one of the important factors to extend node lifetime, and it is necessary to adjust the launching power of each node because of the limited energy available to the sensor nodes in the networks. This paper proposes a power and rate control model based on the network utility maximization (NUM) framework, where a weighting factor is used to reflect the influence degree of the sending power and transmission rate to the utility function. In real networks, nodes interfere with each other in the procedure of transmitting signal, which may lead to signal transmission failure and may negatively have impacts on networks throughput. Using dual decomposition techniques, the NUM problem is decomposed into two distributed subproblems, and then the conjugate gradient method is applied to solve the optimization problem with the calculation of the Hessian matrix and its inverse in order to guarantee fast convergence of the algorithm. The convergence proof is also provided in this paper. Numerical examples show that the proposed solution achieves significant throughput compared with exiting approaches.

Prunus pananensis (Rosaceae), a new species from Pan'an of central Zhejiang, China.

Prunus pananensis Z. L. Chen, W. J. Chen & X. F. Jin, a new species of Rosaceae from central Zhejiang, China is described and illustrated. Micromorphological characters of the indumentum on young shoots, leaves, petioles and peduncles, including scanning electron microscope [SEM] images, are provided. This new species is morphologically similar to P. schneiderianae Koehne in having its young shoots, petioles and pedicels all densely villose, but differs in having bracts persistent, styles glabrous, stipules 8-9 mm long, stamens 28-30 of per flower, and drupes glabrous. The new species is also similar to P. discoidea (Yü & C. L. Li) Yü & C. L. Li ex Z. Wei & Y. B. Chang in having 2 or 3 flowers in an umbellate inflorescence, and bracts persistent and marginally glandular, but it differs in having young shoots and petioles densely covered with yellowish-brown villose trichomes; leaves rounded or slightly cordate at base, the mid-ribs and lateral veins abaxially densely covered with yellowish-brown villose trichomes; and hypanthium ca. 3 mm long, shorter than sepals. The atpB-rbcL and trnL-F intergenic chloroplast spacers are selected for identification of the new and its similar species.

The prognosis of women with stage IB1-IIB node-positive cervical carcinoma after radical surgery.

BACKGROUND: Pelvic lymph nodes metastasis is an important prognostic factor for patients with cervical carcinoma. However, the relationships between the number of positive nodes, site of metastases nodes, adjuvant therapy and the prognosis is controversial. The purpose of this study was to investigate the influence of positive lymph nodes on the prognosis of Chinese women with stage IB1-IIB cervical carcinoma. PATIENTS AND METHODS: Between January 1992 and December 1997, 398 women with International Federation of Gynecology and Obstetrics (FIGO) stage IB1-IIB cervical carcinoma underwent radical surgery in Cancer Hospital, Fudan University. Of these sixty-six patients (16.6%) who were histologically confirmed to have positive pelvic lymph nodes were analyzed retrospectively. The survival was estimated using Kaplan-Meier method. The differences in survival were compared with Log-rank test. Multivariate analyses were performed with the Cox proportional hazard model. RESULTS: The 5-year survival of the patients with pelvic lymph nodes metastases was 40.7%. Cox proportional hazard model analysis showed that cellular differentiation, the number of positive nodes and adjuvant therapy to be the independent prognostic factors (P < 0.05). The 5-year survival of patients with one positive node was higher than that of those with two or more positive nodes (56.5% vs. 36.4%, P < 0.05). The distant metastasis rate in the former group (5.9%) was lower than the latter's (32.7%) (P = 0.05). However, there was no significant difference of pelvic recurrence between the two groups (P > 0.05). The number of positive nodes positively correlated with the level of positive nodes (P < 0.01). The 5-year survival of the patients who had no adjuvant therapy (12.6%) was much lower than that (53.7%) of those with adjuvant therapy (P < 0.05). However, there was no obvious difference between adjuvant radiotherapy, chemotherapy and chemo-radiotherapy (P > 0.05). CONCLUSIONS: The prognosis of patients with stage IB1-IIB node-positive cervical carcinoma who underwent radical surgery alone was very poor. Adjuvant therapy increases the survival rate, decreases the pelvic recurrence and distant metastasis.

[Prognosis of patients with stage Ib-IIb node-positive cervical carcinoma].

BACKGROUND & OBJECTIVE: Pelvic lymph node metastasis was the important prognostic factor for the patients with cervical carcinoma. However, the relationship among the number of positive nodes, site of metastatic nodes, adjuvant therapy, and the prognosis were unknown. The purpose of this study was to investigate the variables that could predict the prognosis of the patients with stage Ib-IIb node-positive cervical carcinoma. METHODS: Sixty-six patients with stage Ib-IIb cervical carcinoma who underwent radical hysterectomy and pelvic lymphadenectomy were analyzed retrospectively. Potential prognostic variables were studied by Cox proportional hazard model. RESULTS: The 5-year survival rate of the patients with pelvic lymph node metastasis was 40.7%. Cox proportional hazard model analysis showed cellular differentiation, number of positive nodes, and adjuvant therapy were the important prognostic factors (P< 0.05). The 5-year survival rate of patients with one positive node (56.5%) was higher than that (36.4%) of those with two or more positive nodes (P< 0.05). The former's distant metastatic rate (5.9%) was lower than the latter's (32.7%) (P=0.05). However, there was no difference of pelvic recurrence between them (P >0.05). The 5-year survival rate of the patients who had no adjuvant therapy (12.6%) was much lower than that (53.7%) of those with adjuvant therapy (P< 0.05). However, the differences of the effects among adjuvant radiotherapy, chemotherapy, and chemoradiotherapy were not obvious (P >0.05). CONCLUSION: The prognosis of patients with stage Ib-IIb node-positive cervical carcinoma who underwent radical surgery was poor. Adjuvant therapy can improve the survival rate, decrease the pelvic recurrence and distant metastasis.

[Significance of systematic retroperitoneal lymphadenectomy at second-look laparotomy for ovarian cancer].

OBJECTIVE: To investigate the timing and role of systemic retroperitoneal lymphadenectomy in patients with ovarian cancer. METHODS: From Jan. 1987 to Feb. 1994, 50 patients with ovarian cancer, who underwent retroperitoneal lymphadenectomy on second-look laparotomy (SLL), were retrospectively studied. RESULTS: The median age was 49 years. Overall survival at 3 and 5 years were 72% and 62%, respectively. Twenty of 50 (40%) women were found SLL(+), and the rates of positive SLL were related to International Federation of Gynecology Obstetrics (FIGO) stage, with 16% in stage I and II, 64% in stage III and IV (P < 0.01). Sixteen (32%) women were found to have retroperitoneal lymph nodes metastases at SLL, with 0% (0/15), 20% (2/10), 54% (13/24), 1/1 in stage I, II, III, IV respectively. In patients with SLL(+), 4 patients with sole disease in the pelvis, and 6 (12%) women only with micro-metastases of retroperitoneal lymph nodes. Fifteen patients with stage I ovarian cancer were all SLL(-), and SLL(-) were in 6 (60%) patients with stage II disease and 11 (38%) in stage III. There is no disease recurrence in patients with negative SLL till the data censored. CONCLUSION: Timing of systemic retroperitoneal lymphadenectomy at SLL is rational, and may aid in reducing disease recurrence of negative SLL and improving five-year survival rate in patients with ovarian cancer, especially in those with advanced epithelial ovarian cancer.