Hydroelectric actuator for 3-dimensional analysis of electrophoretic and dielectrophoretic behavior of cancer cells; suitable in diagnosis and invasion studies.

Cancer is a cellular-based disease, so cytological diagnosis is one of the main challenges for its early detection. An extensive number of diagnostic methods have been developed to separate cancerous cells from normal ones, in electrical methods attract progressive attention. Identifying and specifying different cells requires understanding their dielectric and electric properties. This study evaluated MDA-MB-231, HUVEC, and MCF-10A cell lines, WBCs isolated from blood, and patient-derived cell samples with a cylindrical body with two transparent FTO (fluorine-doped tin oxide) plate electrodes. Cell mobility rates were recorded in response to these stimuli. It was observed that cancer cells demonstrate drastic changes in their motility in the presence and absence of an electric field (DC/AC). Also, solution viscosity's effect on cancer cells' capturing efficacy was evaluated. This research's main distinguished specification uses a non-microfluidic platform to detect and pathologically evaluate cytological samples with a simple, cheap, and repeatable platform. The capturing procedure was carried out on a cytological slide without any complicated electrode patterning with the ability of cytological staining. Moreover, this platform successfully designed and experimented with the invasion assay (the ability of captured cancer cells to invade normal cells).

A comparison between 2D and 3D planning of high-dose-rate vaginal cuff brachytherapy in patients with stage I-II endometrial cancer using cobalt-60.

PURPOSE: Post-surgery radiation can reduce the risk of loco-regional relapse in high-intermediate-risk endometrial cancer. High-dose-rate vaginal cuff brachytherapy (HDR-BRT) is an acceptable method of radiation in majority of endometrial cancer cases. Although 2D planning is frequently used for treatment based on physical examination without any imaging, measurement of the dose received by organs-at-risk (OARs) is not possible. Therefore, the present study was the first to compare dose delivered to target and OARs in 2D vs. 3D planning in patients treated with cobalt-60 source. MATERIAL AND METHODS: In this study, organs including vagina wall, bladder, rectum, and sigmoid were contoured on computed tomography (CT) scan images of 37 endometrial cancer patients, and doses delivered to organs were recorded. Statistics, such as D90, D99, V100, V150, V200, D0.1cc, D1cc, and D2cc were determined. RESULTS: D90 and D99 were lower in 3D treatment planning in comparison with 2D. Although V100 was more in 3D planning, V150 and V200 were less. Analyzing D0.1cc, D1cc, and D2cc of OARs revealed that doses given to rectum, sigmoid, and bladder were less in 3D planning compared to 2D. CONCLUSIONS: Comparison of 2D and 3D planning results showed that 3D planning could deliver an appropriate dose to the target while sparing more OARs.

Evaluating human epidermal growth factor receptor 2 roles in the efficacy of Tamoxifen treatment in breast cancer, a systematic review.

PURPOSE: Hormone therapy with Tamoxifen is an effective treatment that can decrease recurrence rate and mortality. Numerous molecular mechanisms can modify the response to Tamoxifen. The objective of this study was to determine Tamoxifen efficacy on patients' recurrence and mortality rates, according to the human epidermal growth factor receptor 2 (HER2) status. METHODS: In this meta-analysis of published studies, relapse and death rates were measured in both HER2 negative and positive patients treated with Tamoxifen. Besides, the relative risk of treatment with Tamoxifen compared to no Tamoxifen treatment was evaluated in both HER2 positive and negative patients. RESULTS: There was an increased risk of recurrence in HER2 positive patients who received Tamoxifen compared with HER2 negative ones (RR = 1.63, p value < 0.001). Tamoxifen treatment is associated with decreased relapse rate (RR = 0.70, p value < 0.001); however, it did not effect on HER2 positive ones (RR = 1, p value = 0.99). CONCLUSION: According to the analysis result, the relapse rate in breast cancer patients who were treated with Tamoxifen depends on the HER2 situation. Despite the limited sample size, it is revealed that Tamoxifen can decrease the relapse rate only in HER2 negative patients.

Evaluating the Incidence Rate of an Accelerated Short Course High Dose Rate Intravaginal Brachytherapy Complications in Patients with Endometrial Cancer.

Background: Brachytherapy in treatment of endometrial cancer patients is growing and therefore, evaluation of more feasible schedule has become of great importance. The purpose of current study was to evaluate the complications of accelerated short course high dose rate intravaginal brachytherapy (HDR IVB), a new brachytherapy approach which is a more feasible treatment option in developing countries. Method: From 2017 to 2018, 54 patients diagnosed with endometrial cancer and FIGO stages IA to IIB who underwent total abdominal hysterectomy with a bilateral salpingo-oophorectomy were enrolled in present study. They were treated with a total dose of 25 Gy in 5 fractions which was prescribed daily. A dose of 5 Gy was prescribed at a depth of 0.5 cm in the upper third and middle third of vagina. Adverse effects related to organs at risk consist of bladder, vagina and rectum were documented based on the Common Terminology Criteria for Adverse Events v3.0 (CTCAE v3.0). Results: The accelerated short course HDR IVB was well tolerated and no grade 3 or higher toxicities was reported for patients during the follow up period. There were no chronic rectal toxicities and only one patient showed chronic urinary toxicities. However, the incidence rate of vaginal toxicities at the end of 4-month and 8-month follow up periods was higher than acute toxicities and significantly lower in elderly group compared to younger group. Conclusion: Overall, the accelerated HDR IVB was safe and was well tolerated in endometrial cancer patients and the incidence rate of undue complications were equal, if not less, in elderly patients compared to the younger ones.

The Prognostic Value of Circulating Tumor Cells in Primary Breast Cancer Prior to any Systematic Therapy: A Systematic Review.

BACKGROUND: Numerous studies have defined the outstanding role of circulating tumor cells (CTC) in the management of cancer, particularly the ones in association with primary tumor metastases. OBJECTIVE: The overall aim of the present study was to investigate whether CTCs may serve as a clinical prognostic marker for survival in primary breast cancer. METHODS: Articles Published from June 2011 to July 2017 in PubMed, EMBase, and Cochrane library databases were thoroughly screened for selecting the ones meeting the inclusion criteria. RESULT: Studies applying CellSearch® method demonstrated the risk ratios (RR) of 2.51 (95% CI: 1.78- 3.54), 3.98 (95% CI: 2.28- 6.95), 5.59 (95% CI: 3.29- 9.51), and 3.38 (95% CI: 1.88- 6.06) for death rate and relapse rates of 2.48 (95% CI: 1.89 - 3.26), 3.62 (95% CI: 2.37 - 5.51), 4.45 (95% CI: 2.94 - 6.73), and 2.88 (95 % CI: 1.99 - 4.17) at four CTC positive cut points (≥ 1, ≥ 2, ≥ 3, and ≥ 5 CTCs/7.5 ml). Two studies applying the AdnaTest® also documented increased death (RR: 1.38, 95 % CI: 0.42- 4.49) and relapse rates (RR: 2.97, 95 % CI: 1.23 - 7.18)). CONCLUSION: Results of this meta-analysis allude CTCs as potent prognostic markers in primary breast cancers prior to any systemic therapy especially when it is studied via CellSearch® administration, considering that the more the CTCs, the greater the death and relapse rates.

A Review on The Role of VEGF in Tamoxifen Resistance.

BACKGROUND: Certain molecular deviations can lead to the development of breast cancer. For instance, estrogen and estrogen receptors play a significant role in inducing tumor proliferation. However, the efficacy of endocrine therapy through the administration of anti-estrogen drugs, such as Tamoxifen, is challenged by acquired resistance. METHODS: Relevant articles were retrieved from Medline and google scholar. All were screened to select the ones discussing the molecular mechanisms of angiogenesis and Tamoxifen resistance. The molecular interactions contributing in the resistant network were studied from the eligible articles. RESULTS: Tamoxifen resistance occurs as a consequence of over-activated signal transduction pathways such as RTK s dependent cascades. It has been shown that microvessel count was greater in Tamoxifen resistant tissues than in responsive ones. CONCLUSION: In this review, the interaction between estrogen, Tamoxifen, VEGF, and VEGF receptors (VEGFRs) in Tamoxifen resistant cells has been discussed. VEGF and estrogen-independent growth cascades, especially MAPK have a positive feedback loop in Tamoxifen resistant cells. It has been proposed that over-activated pathways in Tamoxifen resistant cells induce pin1 mediated VEGF over-expression, which in turn result in enhanced activation of MAPK.

Stemness Phenotype in Tamoxifen Resistant Breast Cancer Cells May be Induced by Interactions Between Receptor Tyrosine Kinases and ERα-66.

BACKGROUND: Tamoxifen is widely administered for patients with estrogen receptor-positive breast cancer. Despite many patients benefiting from Tamoxifen as an effective anti-hormonal agent in adjuvant therapy, a noticeable number of patients tend to develop resistance. OBJECTIVE: The aim of this study was to shed light upon the molecular mechanisms associated with Tamoxifen resistance which can help improve current treatment strategies available for stimulating responsiveness and combating resistance. METHODS: Relevant articles were obtained from PubMed and google scholar, nearly all dated from 2010 to 2017. Articles were screened to select the ones meeting the objective. The molecular interactions in the resistant network were extracted from the appropriate articles. RESULTS: The mechanisms of developing Tamoxifen resistance were briefly outlined. Overactivation of Receptor Tyrosine Kinases (RTKs) pathways, commonly known as alternative growth cascades, is one of the main players in acquired cancer cell stemness, which can induce unrestricted proliferation in the presence of Tamoxifen. There are seven recent patents including 6291496B1 as an anti-HER2, 8143226B2 as an inhibitor of RTK phosphorylation, 9062308B2 as an anti-HOXB7, Lapatinib functioning as an anti-EGFR/HER2, Everolimus as an inhibitor of mTOR, Exemestane as an aromatase inhibitor and Perifosine as an AKT inhibitor. CONCLUSION: Altogether, it seems that tumor cells express a stemness phenotype which tends to override anti-hormonal adjuvant therapies. Since RTKs are overactivated and overexpressed in such cells, specialized targeted therapies suppressing RTKs would be a novel and effective way in restoring Tamoxifen sensitivity in resistant breast cancer tumor cells.

Clinical Evidence on the Magnitude of Change in Growth Pathway Activity in Relation to Tamoxifen Resistance is Required.

BACKGROUND: Despite prolonged disease-free survival and overall survival rates in Estrogen Receptor (ER)-positive patients undergoing adjuvant treatment, Tamoxifen therapy tends to fail due to eventual acquisition of resistance. OBJECTIVE: Although numerous studies have emphasized the Role of Receptor Tyrosine Kinases (RTKs) in the development of Tamoxifen resistance, inadequate clinical evidence is available regarding the alteration of biomarker expression during acquired resistance, thus undermining the validity of the findings. RESULTS: Results of two meta-analyses investigating the effect of HER2 status on the prognosis of Tamoxifen-receiving patients have demonstrated that despite HER2-negative patients having longer disease-free survival; there is no difference in overhaul survival between the two groups. Furthermore, due to the intricate molecular interactions among estrogen receptors including ERα36, ERα66, and also RTKs, it is not surprising that RTK suppression does not restore Tamoxifen sensitivity. In considering such a complex network, we speculate that by the time HER2/EGFR is suppressed via targeted therapies, activation of ERα66 and ERα36 initiate molecular signaling pathways downstream of RTKs, thereby enhancing cell proliferation even in the presence of both Tamoxifen and RTK inhibitors. CONCLUSION: Although clinical findings regarding the molecular pathways downstream of RTKs have been thoroughly discussed in this review, further clinical studies are required in determining a consistency between preclinical and clinical findings. Discovering the best targets in preventing tumor progression requires thorough comprehension of estrogen-dependent and estrogen-independent pathways during Tamoxifen resistance development. Indeed, exploring additional clinically-proven targets would allow for better characterized treatments being available for breast cancer patients.

Estrogen can restore Tamoxifen sensitivity in breast cancer cells amidst the complex network of resistance.

Breast cancer-related deaths have been on the decline ever since the application of systemic therapies. Chiefly, endocrine therapy, such as Tamoxifen, enhances the survival of estrogen receptor (ER)-positive patients. More than a decade has passed since the introduction of Tamoxifen, however, drug resistance, particularly to Tamoxifen, still remains a major challenge. It has been shown that not only does chronic Tamoxifen exposures induce resistance, but estrogen deprivation can as well. There are two Tamoxifen resistant cell lines, long term estrogen deprived (LTED) cells and cells that have acquired resistance due to long-term exposure to Tamoxifen (Tam-R). Despite having similar cytosolic pathways over-activated in Tam-R and LTED-R cells during the development of resistance, the administration of receptor tyrosine kinases (RTKs) inhibitors fail to restore Tamoxifen sensitivity in LTED-Rs. This alludes to existing differences in the underlying molecular mechanisms of resistance. Surprisingly, despite estrogen being recognized as a breast cancer stimulator; it has recently been introduced as an apoptotic inducer in unresponsive cells. Furthermore, the addition of estrogen to the media of LTED and Tam-R cells triggers cell death, perhaps is functioning as an anti-proliferative agent. In this review, we outline the molecular pathways potentially facilitating estrogen-induced apoptosis in resistant cells.

MUC1 induces tamoxifen resistance in estrogen receptor-positive breast cancer.

INTRODUCTION: Tamoxifen, as an essential therapeutic tool in the treatment of estrogen receptor-positive breast cancer, has been available for the past three decades and is currently being utilized as a chemo-preventive agent for patients at high risk for breast carcinoma. However, the induction of chemo-resistance during therapy has indicated a significant challenge with regards to this agent. Areas covered: This review enumerates the role of MUC1-C proto-oncogene in tamoxifen resistance and describes a number of signaling pathways by which MUC1-C would mediate the development of resistance. Finally, recent clinical studies conducted on the magnitude of MUC1 in inducing tamoxifen resistance are described. Expert commentary: Mucin 1, or MUC1, is aberrantly overexpressed on the entire tumor cell surface of most human cancers. Thus, it may result in the upregulation of several signaling pathways, such as growth cascades related to receptor tyrosine kinases (RTK), ß-catenin and E-cadherin, as well as promoting gene transcription of Ras-related protein Rab-31 in order to mediate tumor growth control in response to tamoxifen. On the contrary, MUC1 suppresses apoptotic events, which in turn impresses upon cell fate. Also, it has been demonstrated that silencing MUC1-C proto-oncogene is associated with increased sensitivity to tamoxifen-induced growth inhibitors.

ER-α36 Interactions With Cytosolic Molecular Network in Acquired Tamoxifen Resistance.

According to the World Health Organization (WHO) published data in 2015; breast cancer is the most prevalent and the second leading cause of cancer death among females. As approximately 70% of breast cancer tumor cells are estrogen receptor (ER) positive, primary therapeutic agents such as Anti-estrogens were produced mostly in a way to target this receptor. Anti-estrogen therapies mostly target Estrogen receptor and block its underlying signaling pathways. Nevertheless, resistance to these agents made the condition more complicated. Recently the role of one molecule in the resistance development has been studied in some cases: ER-α36 is a 36 kDa variant of estrogen receptor molecule which is mostly absent in normal breast cells. Its interactions with epidermal growth factor receptors and ER-α66 leads in over-activation and/or over-expression of estrogen-independent pathways and suppression of estrogen-dependent pathways; they all in turn, will maintain tumor cell's growth even in the presence of tamoxifen. In this mini-review, we mainly surveyed different pathways which ER-α36 could lead to tamoxifen resistance. We also briefly mentioned how ER-α36 could switch the growth cascades from estrogen dependent into independent and make this resistance network become even more complicated.

MED1 may explain the interaction between receptor tyrosine kinases and ERα66 in the complicated network of Tamoxifen resistance.

According to the American Society of Clinical Oncology or ASCO's clinical practice guidelines, administration of Tamoxifen for hormone receptor positive patients improved outcomes. However, many studies have been conducted in this issue, with the rise of Tamoxifen resistance in recent decades. There are many alternative growth cascades that are activated in Tamoxifen resistant cells. The most common and well characterized components of such a resistant network are receptor tyrosine kinases, or RTKs, which can influence many other cellular processes. The interactions between estrogen dependent and independent pathways further complicate the networking. MED1, as a member of a mediator complex, which is activated by RTK growth pathways, plays role in co-activating ERα66 to transcribe genes and enhance cellular proliferation. Herein, we will discuss MED1, a novel biomarker which can explain how RTKs interact with ERα66 which results in Tamoxifen resistance.

Impact of Melatonin on Motor, Cognitive and Neuroimaging Indices in Patients with Multiple Sclerosis.

A series of preclinical and clinical studies have shown the immunomodulatory effect of  melatonin, especially in the state of chronic inflammation. A double-blind, randomized, parallel-group, placebo-controlled clinical trial was designed to study the tolerability and efficacy of supplemental therapy with melatonin (3 mg/day) in comparison to placebo in relapsing-remitting MS (RRMS) patients receiving once weekly interferon beta. Patients were followed up for 12 months. Primary outcomes consisted of the number of relapses, change in Extended Disability Status Scale (EDSS), and the number and volume of new T2 and gadolinium-enhancing brain lesions. Secondary outcomes included change in performance on Multiple Sclerosis Functional Composite (MSFC) as well as change in fatigue and depression. The outcomes were evaluated every three months. Twenty-six patients (13 in each group) were recruited in the study. All participants, except for one patient in the placebo group, completed the study. No patient reported serious adverse events. There was no significant difference either in primary or secondary outcomes between melatonin and placebo arm. However, a trend for beneficial effect was observed for melatonin on change in MSFC performance and the cognitive subscore of the Modified Fatigue Impact Scale (p=0.05 and 0.006, respectively, not corrected for multiple comparisons). We found no significant effect for treatment with melatonin on measures of clinical and functional disability and development of brain lesions in our small sample-size study. Studies with higher statistical power and longer follow up are needed to further evaluate the potential immunomodulatory effect of melatonin in RRMS treatment.