The presence of cancer-associated fibroblast in breast cavity side margins is in correlation with the expression of oncoproteins by adjacent epithelial cells: a new era in cancerous potential.

PURPOSE: Cancer-associated fibroblasts (CAFs) are one of the most critical cells in the tumor environment, with crucial roles in cancer progression and metastasis. Due to Field-Effect phenomena (also called field cancerization), the adjacent cavity side area of the margin is histologically normal, but it has been entered into neoplastic transformation due to MCT4 and MCT1 pathways activated by H2O2/ROS oxidative stress agents secreted by CAF in adjacent tumor bed microenvironment. This paper specifically focused on the role of cancer-associated fibroblast in breast tumor beds and its correlation with the presence of scattered cancer cells or onco-protein-activated cells (may be high risk but not completely transformed cancer cells) in the cavity side margins. METHODS: In this study, the glycolytic behavior of non-tumoral cavity side margins was examined using carbon nanotube-based electrochemical biosensors integrated into a cancer diagnostic probe. This method enabled the detection of CAF accumulation sites in non-cancerous neighboring tissues of tumors, with a correlation to CAF concentration. Subsequently, RT-PCR, fluorescent, histopathological, and invasion assays were conducted on hyperglycolytic lesions to explore any correlation between the abundance of CAFs and the electrochemical responses of the non-cancerous tissues surrounding the tumor, as well as their neoplastic potential. RESULTS: We observed overexpression of cancer-associated transcriptomes as well as the presence and hyperactivation of CAFs in cavity-side regions in which glycolytic metabolism was recorded, independent of the histopathological state of the lesion. At mean 70.4%, 66.7%, 70.4%, and 44.5% increments were observed in GLUT-1, MMP-2, N-cadherin, and MMP-9 transcriptomes by highly glycolytic but histologically cancer-free expression samples in comparison with negative controls (histologically non-cancer lesions with low glycolytic behavior). CONCLUSION: The presence of CAFs is correlated with the presence of high glycolytic metabolism in the cavity margin lesion, high ROS level in the lesion, and finally aggressive cancer-associated proteins (such as MMP2, …) in the margin while these metabolomes, molecules, and proteins are absent in the margins with negatively scored CDP response and low ROS level. So, it seems that when we observe CAFs in glycolytic lesions with high ROS levels, some high-risk epithelial breast cells may exist while no histological trace of cancer cells was observed. Further research on CAFs could provide valuable insights into the local recurrence of malignant breast diseases. Hence, real-time sensors can be used to detect and investigate CAFs in the non-tumoral regions surrounding tumors in cancer patients, potentially aiding in the prevention of cancer recurrence.

Innovative technique for managing extreme relapsing bilateral pseudoangiomatous stromal hyperplasia (PASH) in a young woman: A case report highlighting a novel intervention in reconstruction.

INTRODUCTION: Pseudoangiomatous stromal hyperplasia (PASH) is a rare breast stromal lesion that typically manifests clinically as a palpable unilateral, painless lump that is freely movable and has a rubbery or firm consistency. The diagnosis can be confirmed by a core needle biopsy (CNB) or surgical excision. Treatment options include medical treatment with hormonal management for asymptomatic patients or local excision and breast reduction in rare cases. CASE PRESENTATION: We reported the case of a 24-year-old woman with a history of taking contraceptive pills for about a year. Examination revealed extremely enlarged, sore, and swollen breasts, particularly the right side, marking her third PASH relapse. The patient underwent a surgical skin-reducing mastectomy (SRM) using a novel technique with an immediate prepectoral implant covered by a dermal flap to reconstruct the breast shape due to the large PASH lesions and aiming for optimal cosmetic outcomes. The procedure was complication-free with no recurrence after 18 months of follow-up. DISCUSSION: Mastectomy followed by immediate implantation offers benefits such as prompt restoration of breast shape with fewer surgeries. CONCLUSION: This case report highlights the successful use of immediate implantation in reconstructing large recurrent benign breast diseases. The outcomes indicate that immediate implantation shows promise as a suitable choice for carefully selected patients managing large, relapsing bilateral benign breast diseases. However, due to common complications such as infection and implant loss, it is not generally recommended for benign lesions. The decision should be made on a case-by-case basis, considering the size, recurrence, and individual suitability.

Electrical lymph node scanning (ELS) system for real-time intra-operative detection of involved axillary lymph nodes in adjuvant breast cancer patients.

Lymph node (LN) status is an essential prognostic factor in breast cancer (BC) patients, with an important role in the surgical and therapeutic plan. Recently, we have been developed a novel system for real-time intra-operative electrical LN scanning in BC patients. The ELS scores were calibrated by pathological evaluation of the LNs. Herein, we evaluated the efficacy of ELS in a prospective study for non-chemo-treated breast cancer patients. This is a prospective study in which ELS scores are blind for pathologists who declare the clearance or involvement of LNs based on permanent pathology as the gold standard. ELS and frozen-section (FS) pathology results were achieved intra-operatively, and samples were sent for the permanent pathology. The score of ELS did not affect the surgeons' decision, and the treatment approach was carried out based on FS pathology and pre-surgical data, such as imaging and probable biopsies. Patients were recruited from October 2021 through November 2022, and 381 lymph nodes of 97 patients were included in the study. In this study we recruited 38 patients (39.2%) with sentinel lymph node biopsy (SLNB) and 59 patients (60.8%) with ALND. Of the 381 LNs scored by ELS, 329 sentinel LNs underwent routine pathology, while others (n = 52) underwent both FS and permanent pathology. ELS showed a sensitivity of 91.4% for node-positive patients, decreasing to 84.8% when considering all LNs. Using ROC analysis, ELS diagnosis showed a significant AUC of 0.878 in relation to the permanent pathology gold standard. Comparison of ELS diagnosis for different tumor types and LN sizes demonstrated no significant differences, while increasing LN size correlated with enhanced ELS sensitivity. This study confirmed ELS's efficacy in real-time lymph node detection among non-chemo-treated breast cancer patients. The use of ELS's pathological scoring for intra-operative LN diagnosis, especially in the absence of FS pathology or for non-sentinel LN involvement, could improve prognosis and reduce complications by minimizing unnecessary dissection.

A human pilot study on positive electrostatic charge effects in solid tumors of the late-stage metastatic patients.

Background: Correlative interactions between electrical charges and cancer cells involve important unknown factors in cancer diagnosis and treatment. We previously reported the intrinsic suppressive effects of pure positive electrostatic charges (PEC) on the proliferation and metabolism of invasive cancer cells without any effect on normal cells in cell lines and animal models. The proposed mechanism was the suppression of pro-caspases 3 and 9 with an increase in Bax/Bcl2 ratio in exposed malignant cells and perturbation induced in the KRAS pathway of malignant cells by electrostatic charges due to the phosphate molecule electrostatic charge as the trigger of the pathway. This study aimed to examine PECs as a complementary treatment for patients with different types of solid metastatic tumors, who showed resistance to chemotherapy and radiotherapy. Methods: In this study, solid metastatic tumors of the end-stage patients (n = 41) with various types of cancers were locally exposed to PEC for at least one course of 12 days. The patient's signs and symptoms, the changes in their tumor size, and serum markers were followed up from 30 days before positive electrostatic charge treating (PECT) until 6 months after the study. Results: Entirely, 36 patients completed the related follow-ups. Significant reduction in tumor sizes and cancer-associated enzymes as well as improvement in cancer-related signs and symptoms and patients' lifestyles, without any side effects on other tissues or metabolisms of the body, were observed in more than 80% of the candidates. Conclusion: PECT induced significant cancer remission in combination with other therapies. Therefore, this non-ionizing radiation would be a beneficial complementary therapy, with no observable side effects of ionizing radiotherapy, such as post-radiation inflammation.

Electrochemical therapy (EChT) of cancer tumor with an external anode, a way to achieve pathological complete response.

There is a critical need for re-evaluation of electrochemical therapy (EChT) approaches of solid tumors to address the challenges of the currently used method: incomplete pathological response. The coexistence of anode and cathode in the tumor region resulted in acid-alkaline mixation (buffered pH) when the electrodes are so near each other (d < 1 cm), and in the non-affected lesions when the electrodes are far from each other (d > 1 cm), both have resulted in intact tumoral lesions in EChT field. Here, we presented a designation model study of EChT with an external anode out of the tumor and filled the tumor with dense distribution of cathode electrodes to completely destroy the tumoral lesions without any remaining vital tumoral residues. Anode was located in a biological ionic gel chamber (located on top of the skin) which mediates the ionic interface between the external anode and intratumoral cathode. Our newly reported method can solve the lack of a comprehensive therapeutic guideline for any solid tumors. A remarkable increase in the efficiency of EChT without any over-treating was achieved by alkaline therapy of the tumor (without any limitation in locating cathodic needles all over the tumor) and an external acidic region on top of the skin in a cylindrical gel chamber. We found that the destructive volumes and treating ability of mice tumors by this newly represented method were more significant than the conventional EChT method in fewer therapy sessions and no damage to the skin (both anode and cathode electrodes inside the tumor) (P < 0.05). Results of this study applied to mouse model tumors shed new light on returning attraction to EChT as a valuable complementary method for treating different types of solid breast tumors.

High-Frequency (30 MHz-6 GHz) Breast Tissue Characterization Stabilized by Suction Force for Intraoperative Tumor Margin Assessment.

A gigahertz (GHz) range antenna formed by a coaxial probe has been applied for sensing cancerous breast lesions in the scanning platform with the assistance of a suction tube. The sensor structure was a planar central layer and a metallic sheath of size of 3 cm2 connected to a network analyzer (keySight FieldFox N9918A) with operational bandwidth up to 26.5 GHz. Cancer tumor cells have significantly higher water content (as a dipolar molecule) than normal breast cells, changing their polarization responses and dielectric losses to incoming GHz-based stimulation. Principal component analysis named S11, related to the dispersion ratio of the input signal, is used as a parameter to identify malignant tumor cells in a mouse model (in vivo) and tumor specimens of breast cancer patients (in vitro) (both central and marginal parts). The results showed that S11 values in the frequency range from 5 to 6 GHz were significantly higher in cancer-involved breast lesions. Histopathological analysis was the gold standard for achieving the S11 calibration to distinguish normal from cancerous lesions. Our calibration on tumor specimens presented 82% positive predictive value (PPV), 100% negative predictive value (NPV), and 86% accuracy. Our goal is to apply this system as an in vivo non-invasive tumor margin scanner after further investigations in the future.

Intraoperative Assessment of High-Risk Thyroid Nodules Based on Electrical Impedance Measurements: A Feasibility Study.

Precise diagnosis of thyroid nodules is challenging due to non-diagnostic/inconclusive results and uncertainties about the malignancy of follicular neoplasms (FNs), even in frozen-section pathology. Therefore, surgical management, especially in Bethesda III and IV categories, may be complicated, and sometimes a second surgery may be required. The Thyroid Nodule Impedance Measurement System (TN-IMS) consists of a metallic patch attached to submental skin and a G20 I.V. cannula inserted into the targeted nodules. Two impedance-based parameters named Z1kHz and impedance phase slope (IPS) in 100 kHz to 500 kHz of the thyroid nodules are recorded and compared with their histopathological results as the gold standard. TN-IMS was intra-surgically applied to 103 human thyroid nodules and normal thyroid tissues. A remarkable consistency between defined co-ranges of Z1kHz/IPS and the histopathological status of specimens was achieved (p < 0.001). Based on these measurements, it was concluded that intraoperative bioelectrical impedance scanning of thyroid nodules would be a helpful complementary approach to detecting high-risk excision-required thyroid nodules.

Intraradiological pathology-calibrated electrical impedance spectroscopy in the evaluation of excision-required breast lesions.

PURPOSE: Evaluating a real-time complementary bioelectrical diagnostic device based on electrical impedance spectroscopy (EIS) for improving breast imaging-reporting and data system (BI-RADS) scoring accuracy, especially in high-risk or borderline breast diseases. The primary purpose is to characterize breast tumors based on their dielectric properties. Early detection of high-risk lesions and increasing the accuracy of tumor sampling and pathological diagnosis are secondary objectives of the study. METHODS: The tumor detection probe (TDP) was first applied to the mouse model for electrical safety evaluations by electrical current measurement. Then it was utilized for characterization of 138 human palpable breast lesions that were to undergo core needle biopsy (CNB), vacuum-assisted biopsy (VAB), or fine needle aspiration (FNA) on the surgeon's requests. Impedance phase slope (IPS) in frequency ranges of 100- 500 kHz and impedance magnitude in f = 1 kHz were extracted as the classification parameters. Consistency of radiological and pathological declarations for the excisional recommendation was then compared with the IPS values. RESULTS: Considering pathological results as the gold standard, meaningful correlations between IPS and pathophysiological status of lesions recommended for excision (such as atypical ductal hyperplasia, papillary lesions, complex sclerosing adenosis, and fibroadenoma) were observed (p < 0.0001). These pathophysiological properties may include cell size, membrane permeability, packing density, adenosis, cytoplasm structure, etc. Benign breast lesions showed IPS values greater than 0, while high-risk proliferative, precancerous, or cancerous lesions had negative IPS values. Statistical analysis showed 95% sensitivity with area under the curve (AUC) equal to 0.92. CONCLUSION: Borderline breast diseases and high-risk lesions that should be excised according to standard guidelines can be diagnosed with TDP before any sampling process. It is an important outcome for high-risk lesions that are radiologically underestimated to BI-RADS3, specifically in younger patients with dense breast masses that present challenges in mammographic and sonographic evaluations. Also, the lowest IPS value detects the most pathologic portions of the tumor for increasing sampling accuracy in large tumors. SIGNIFICANCE: Precise detection of high-risk breast masses, which may be declared BI-RADS3 instead of BI-RADS4a.

Human study on cancer diagnostic probe (CDP) for real-time excising of breast positive cavity side margins based on tracing hypoxia glycolysis; checking diagnostic accuracy in non-neoadjuvant cases.

BACKGROUND: Cancer diagnostic probe (CDP) had been developed to detect involved breast cavity side margins in real-time (Miripour et al. Bioeng Transl Med. e10236.). Here, we presented the results of the in vivo human model CDP studies on non-neoadjuvant cases. METHODS: This study is a prospective, blind comparison to a gold standard, and the medical group recruited patients. CDP and frozen data were achieved before the permanent pathology experiment. The main outcome of the study is surgical margin status. From November 2018 to April 2020, 202 patients were registered, and 188 were assigned for the study. Breast-conserving surgery at any age or gender, re-surgery due to re-currency, or involved margins are acceptable. Patients must be non-neoadjuvant. The reliability of CDP scoring had been evaluated by the pathology of the scored IMs. Then, three models of the study were designed to compare CDP with the frozen sections. Receiver operating characteristic (ROC) curves and AUC were measured based on the permanent postoperative pathology gold standard. RESULTS: A matched clinical diagnostic categorization between the pathological results of the tested IMs and response peaks of CDP on 113 cases, was reported (sensitivity = 97%, specificity = 89.3%, accuracy = 92%, positive predictive value (PPV) = 84.2%, and negative predictive value (NPV) = 98%). Study A showed the independent ability of CDP for IM scoring (sensitivity = 80%, specificity = 90%, accuracy = 90%, PPV = 22.2%, and NPV = 99.2%). Study B showed the complementary role of CDP to cover the missed lesions of frozen sections (sensitivity = 93.8%, specificity = 91%, accuracy = 91%, PPV = 55.6%, and NPV = 99.2%). Study C showed the ability of CDP in helping the pathologist to reduce his/her frozen miss judgment (specificity = 92%, accuracy = 93%, PPV = 42.1%, and NPV = 100%). Results were reported based on the post-surgical permanent pathology gold standard. CONCLUSION: CDP scoring ability in intra-operative margin detection was verified on non-neoadjuvant breast cancer patients. Non-invasive real-time diagnosis of IMs with pathological values may make CDP a distinct tool with handheld equipment to increase the prognosis of breast cancer patients.

Electrochemical tracing of hypoxia glycolysis by carbon nanotube sensors, a new hallmark for intraoperative detection of suspicious margins to breast neoplasia.

For most people, the first step in treatment is to take out the tumor (surgery), so precise and fast diagnosis of any sign of high-risk and neoplastic cells, especially in surgical cavity margins, is significant. The frozen pathology method is the conventional standard of intraoperative diagnosis, but the low number of slides prepared from non-fixed tissues prevents us from achieving a perfect diagnosis. Although many improvements in intraoperative margin detection were achieved, still real-time detection of neoplastic lesions is crucial to improving diagnostic quality. Functionalized carbon nanotubes grown on the electrode needles lively and selectively determine the H2O2 released from cancer/atypical cells through reverse Warburg effect and hypoxia assisted glycolysis pathways in a quantitative electrochemical manner. The study was carried out on cell lines, 57 in vivo mice models with breast cancer, and 258 fresh in vitro samples of breast cancer tumors. A real-time electrotechnical system, named cancer diagnostic probe (CDP) (US Patent Pub. No.: US 2018/02991 A1, US 2021/0007638 A1, and US 2021/0022650 A1 [publications], and US 10,786,188 B1 [granted]), has been developed to find pre-neoplastic/neoplastic cells in vivo in a quantitative electrochemical manner by tracing hypoxia glycolysis byproducts. Matched pathological evaluations with response peaks of CDP were found based on the presence of neoplasia (from atypia to invasive carcinoma) in live breast tissues. The ability of CDP to find neoplastic lesions in mice models in vivo and fresh breast tumors in vitro was verified with sensitivity and specificity of 95% and 97%, respectively. The system may help a surgeon assistant system for usage in the operating room after passing many trials and standard examinations in the future.

Electrochemical measuring of reactive oxygen species levels in the blood to detect ratio of high-density neutrophils, suitable to alarm presence of cancer in suspicious cases.

Here for the first time, a real-time electrochemical assay on unprocessed blood was designed to detect the presence of cancer in patients. The system has been based on the recently approved pathway, which indicates that the abundance of immature and mature low-density neutrophils (LDNs) with reduced ROS production in peripheral blood is increased with the presence of active cancer tumors. Reduced ROS/H2O2 released from LDNs play the main role in determining the ROS/H2O2 levels of peripheral blood. In contrast, HDNs with increased levels of released ROS/H2O2 have higher concentrations than LDNs in normal cases. Hence, the reduced level of ROS species in peripheral blood recorded by our carbon nanostructure decorated sensor in less than 30 seconds showed a great pre-warning about the presence of non-treated cancer in patients with suspicious mass who have been sent for further evaluations.

Accuracy of cancer diagnostic probe for intra-surgical checking of cavity side margins in neoadjuvant breast cancer cases: A human model study.

BACKGROUND: Background Recently, a real-time system, named cancer diagnostic probe (CDP), has been developed to diagnose the presence of pre-neoplastic/neoplastic cells in breast cavity side margins. Detecting mechanism is real-time determination of the ROS/H2 O2 released from cancer or atypical cells, through reverse Warburg effect and hypoxia glycolysis pathways. AIMS: Here, we designed a human model study based on real-time checking of 387 internal margins (IM) from 39 neoadjuvant breast cancer cases by CDP. MATERIALS & METHODS: Each lesion was checked by entered needle sensor and electrical scores were recorded. The permanent pathology result of each tested lesion was our gold standard to evaluate CDP scoring. CDP results were compared with permanent pathology of tumour side margins (as a conventional margin evaluation procedure). RESULTS: Results showed that the sensitivity of CDP in scoring the cavity side margins of those cases is 91%. A total of 18 involved IM which had been detected by CDP were declared as free margins in pathology section of tumour side samples. Just five involved IM were missed by CDP. DISCUSSIONS: Such sensitivity revealed that metabolism based (here: hypoxia glycolysis) tracing of cancer cells show distinct electrochemical responses between clear and involved cavity side margin evaluation. CONCLUSION: This human study showed the promising role of CDP to achieve clear margins after BCS of neoadjuvant cases.

Intraoperative pathologically-calibrated diagnosis of lymph nodes involved by breast cancer cells based on electrical impedance spectroscopy; a prospective diagnostic human model study.

BACKGROUND: Nodal status evaluation is a crucial step in determining prognostic factors and managing treatment strategies for breast cancer patients. Preoperative (CNB), intraoperative (SLNB), and even postoperative techniques (Formalin-Fixed Paraffin-Embedded sectioning, FFPE) have definite limitations of precision or sometimes are time-consuming for the result declaration. The primary purpose of this prospective study is to provide a precise complementary system for distinguishing lymph nodes (LNs) involved by cancerous cells in breast cancer patients intraoperatively. METHODS: The proposed system, Electrical Lymph Scoring(ELS), is designed based on the dielectric properties of the under-test LNs. The system has a needle-shaped 2-electrode probe entered into SLNs or ALNs dissected from patients through standard surgical guidelines. Impedance magnitude in f = 1 kH (Z1kHz) and Impedance Phase Slope in frequency ranges of 100 kHz-500 kHz (IPS) were then extracted from the impedance spectroscopy data in a cohort study of 77 breast cancer patients(totally 282 dissected LNs) who had been undergone surgery before (n = 55) or after (n = 22) chemical therapies (non-neoadjuvant or neoadjuvant chemotherapy). A new admittance parameter(Yn') also proposed for LN detection in neoadjuvant chemotherapy patients. RESULTS: Considering the permanent pathology result as the gold standard checked by two independent expert pathologists, a significant correlation was observed between the presence of cancerous cells in LNs and individual ranges of the ELS electrical responses. Compared with normal LNs containing fatty ambient and immune cells, LNs involved by cancerous clusters would reduce the Z1kHz and increase the IPS. These changes correlate with fat metabolism by cancer cells due to their Fatty Acid Oxidation (FAO) in LN, which results in different dielectric properties between high and low-fat content of normal and cancerous LNs, respectively. CONCLUSIONS: By finding the best correlation between our defined impedimetric parameters and pathological states of tested LNs, a real-time intraoperative detection approach was developed for highly-sensitive (92%, P<0.001) diagnosis of involved sentinel or axillary LNs. The impact of real-time intraoperative scoring of SLNs would make a pre-estimation about the necessity of excising further LNs to help the surgeon for less invasive surgery, especially in the absence of frozen-section equipment.

Positive electrostatic therapy of metastatic tumors: selective induction of apoptosis in cancer cells by pure charges.

BACKGROUND: We discovered that pure positive electrostatic charges (PECs) have an intrinsic suppressive effect on the proliferation and metabolism of invasive cancer cells (cell lines and animal models) without affecting normal tissues. METHODS: We interacted normal and cancer cell lines and animal tumors with PECs by connecting a charged patch to cancer cells and animal tumors. many biochemical, molecular and radiological assays were carried out on PEC treated and control samples. RESULTS: Correlative interactions between electrostatic charges and cancer cells contain critical unknown factors that influence cancer diagnosis and treatment. Different types of cell analyses prove PEC-based apoptosis induction in malignant cell lines. Flowcytometry and viability assay depict selective destructive effects of PEC on malignant breast cancer cells. Additionally, strong patterns of pyknotic apoptosis, as well as downregulation of proliferative-associated proteins (Ki67, CD31, and HIF-1α), were observed in histopathological and immunohistochemical patterns of treated mouse malignant tumors, respectively. Quantitative real-time polymerase chain reaction results demonstrate up/down-regulated apoptotic/proliferative transcriptomes (P21, P27, P53/CD34, integrin α5, vascular endothelial growth factor, and vascular endothelial growth factor receptor) in treated animal tumors. Expression of propidium iodide in confocal microscopy images of treated malignant tissues was another indication of the destructive effects of PECs on such cells. Significant tumor size reduction and prognosis improvement were seen in over 95% of treated mouse models with no adverse effects on normal tissues. CONCLUSION: We discovered that pure positive electrostatic charges (PECs) have an intrinsic suppressive effect on the proliferation and metabolism of invasive cancer cells (cell lines and animal models) without affecting normal tissues. The findings were statistically and observationally significant when compared to radio/chemotherapy-treated mouse models. As a result, this nonionizing radiation may be used as a practical complementary approach with no discernible side effects after passing future human model studies.

Capture-free deactivation of CTCs in the bloodstream; a metastasis suppression method by electrostatic stimulation of the peripheral blood.

While limited investigations have been reported on CTC elimination and its profits, recently, some new works were reported on detection followed by the destruction of CTCs. Limitations and complications of CTC capturing procedures have highly reduced the chance of selective destruction of CTCs in the bloodstream in the therapeutic guidelines of the patients. Here, we selectively deactivated the invasive function of CTCs during their circulation in the bloodstream by exposing the whole blood to pure positive electrostatic charge stimulation (PPECS). Our treatment suppressed pulmonary metastasis and extended the survival of the mice had been intravenously injected by electrostatically deactivated 4T1 breast cancer CTCs. Moreover, the number of cancerous lung nodules was drastically reduced in the mice injected by treated CTCs in comparison with the non-treated cohort. Evaluating the side effect of the PPECS on the blood components revealed no major effect on the functional properties of the white blood cells, and just a negligible fraction (∼10%) was damaged during this process. This approach does not need any capturing or targeting of CTCs from the blood as it is focused on perturbing the electrical function of negatively-charged tumor cells after being exposed to positive electrostatic charges. Taken together, continuous in-vivo deactivation of CTCs by PPECS with no requirement to complicated capturing protocols may improve the survival of cancer patients.

Cell specific tumor suppressor effect of Hsa-miR-1226-3p through downregulation of HER2, PIK3R2, and AKT1 genes.

PI3K/AKT signaling has a crucial role in breast cancer incidence and finding the miRNAs that regulate this pathway enhances our understanding of breast cancer regulation. Firstly, our bioinformatics analysis suggested miR-1226-3p as a bona fide regulator of HER2, PIK3R2, and AKT1 putative target genes. Secondly, RT-qPCR, ELISA test and western blotting showed that overexpression of miR-1226 was followed by reduced expression of HER2, PIK3R2, and AKT1 putative targets genes in SKBR3 cells. Third, dual luciferase assay verified direct interaction of miR-1226-3p with 3'UTR sequences of these target genes. Then, overexpression of miR-1226 in SKBR3 cells brought about increased population of sub-G1 and decreased populations of G1 cells, measured by flow cytometry. This was consistent to the reduction of p-AKT protein and increased BAX protein levels, detected by western analysis and consistent to decreased CCND1 genes expression, detected by RT-qPCR. The reduced survival and increased apoptosis rate of these cells was also verified through MTT, Annexin V-FITC and Live-Dead cell staining assays. Our results suggest that miR-1226-3p is a tumor suppressor in SKBR3 cells. However, following the overexpression of miR-1226 in MDA-MB-231 cells, Bax/Bcl2 ratio and CCND1 genes expression levels were not significantly changed, sub-G1 and G1 cell cycle population were reduced while, S and G2/M cell populations were increased, consistent to the results acquired from the apoptosis and staining assays. Finally, TCGA data analysis and RT-qPCR against 20 pairs of Normal/Tumor breast tissues indicated that miR-1226-3p has been downregulated in breast cancer. Overall, the present study gathered shreds of evidence that suggest miR-1226-3p as a tumor suppressor that exerts its inhibitory effect on SKBR3 cells through targeting of HER2, PIK3R2, and AKT1 genes and downregulates PI3K/AKT pathway.

Mesenchymal Stem Cells Pretreatment With Stromal-Derived Factor-1 Alpha Augments Cardiac Function and Angiogenesis in Infarcted Myocardium.

BACKGROUND: Stem cell therapy is among the novel approaches for the treatment of post-myocardial infarction cardiomyopathy. This study aims to compare the effect of stromal-derived factor 1 α (SDF1α), mesenchymal stem cells (MSCs) in combination with the lentiviral production of vascular endothelial growth factor (VEGF) on infarct area, vascularization and eventually cardiac function in a rat model of myocardial infarction (MI). METHODS: The influence of SDf1α on MSCs survival was investigated. MSCs were transduced via a lentiviral vector containing VEGF. After that, the effect of mesenchymal stem cell transfection of VEGF-A165 and SDf1α preconditioning on cardiac function and scar size was investigated in five groups of MI rat models. The MSC survival, cardiac function, scar size, angiogenesis, and lymphocyte count were assessed 72 hours and 6 weeks after cell transplantation. RESULTS: SDF1α decreased the lactate dehydrogenase release in MSCs significantly. Also, the number of viable cells in the SDF1α-pretreated group was meaningfully more than the control. The left ventricular systolic function significantly enhanced in groups with p240MSC, SDF1αMSC, and VEGF-A165MSC in comparison to the control group. CONCLUSIONS: These findings suggest that SDF1α pretreatment and overexpressing VEGF in MSCs could augment the MSCs' survival in the infarcted myocardium, reduce the scar size, and improve the cardiac systolic function.

A label-free graphene-based impedimetric biosensor for real-time tracing of the cytokine storm in blood serum; suitable for screening COVID-19 patients.

Concurrent with the pandemic announcement of SARS-CoV-2 infection by the WHO, a variety of reports were published confirming the cytokine storm as the most mortal effect of the virus on the infected patients. Hence, cytokine storm as an evidenced consequence in most of the COVID-19 patients could offer a promising opportunity to use blood as a disease progression marker. Here, we have developed a rapid electrochemical impedance spectroscopy (EIS) sensor for quantifying the overall immune activity of the patients. Since during the cytokine storm many types of cytokines are elevated in the blood, there is no need for specific detection of a single type of cytokine and the collective behavior is just measured without any electrode functionalization. The sensor includes a monolayer graphene on a copper substrate as the working electrode (WE) which is able to distinguish between the early and severe stage of the infected patients. The charge transfer resistance (R CT) in the moderate and severe cases varies about 65% and 138% compared to the normal groups, respectively and a specificity of 77% and sensitivity of 100% based on ELISA results were achieved. The outcomes demonstrate a significant correlation between the total mass of the three main hypercytokinemia associated cytokines including IL-6, TNF-α and IFN-γ in patients and the R CT values. As an extra application, the biosensor's capability for diagnosis of COVID-19 patients was tested and a sensitivity of 92% and specificity of 50% were obtained compared to the RT-PCR results.

Nanoporous platinum needle for cancer tumor destruction by EChT and impedance-based intra-therapeutic monitoring.

Herein, we present a new design on the Single Needle Electrochemical Therapy (SNEChT) method by introducing some major improvements, including a nanoporous platinum electrode, tunable in situ anode size that depends on the width and location of the tumor, and the capability of measuring the efficacy of therapy based in intra-therapeutic impedance recording by the same EChT needle. It could have significant implications in optimizing EChT operative conditions. The nanoporous Pt electrode increased the interactive surface with a tumor, and produced a higher amount of current with lower stimulating DC voltage. The tunable anode size prevents the over-acidification of treated or non-desired lesions. Hence, this feature reduced the over distribution of tissue. Monitoring the impedance during the therapy clearly informs us about the local destruction of the tumor in each location. Thus, we can be informed about the threshold of tissue acidosis with the lowest electrical stimulation. The insertion of one needle with a tunable anode length for both precise therapy and impedance-based intra-therapeutic monitoring will shed new light on the applications of EChT.

Electrically guided interventional radiology, in-vivo electrochemical tracing of suspicious lesions to breast cancer prior to core needle biopsy.

An electrochemical biopsy probe was designed and fabricated to detect cancer tumors under the sonography guide without the need for any sample dissection (biopsy). The system was based on recording the hypoxic function of cancer tumors by Multi-wall carbon nanotubes (MWCNTs) sensing agents had been decorated on the tip of the needle electrodes by an electrostatic deposition method. This system named BGP successfully distinct 4T1 and MC4L2 breast tumors from normal lesions. It also diagnosed the treated tumors from vital ones. BGP as a clinically useful biosensor would detect the cancerous probability of any suspicious breast mass without any sample excision. Also, it can present a profile from neoplastic states of different regions of a tumor. This ability would make ensure for the radiologist to do biopsy or not, especially in the cases which are suspicious between BIRADS III and IVa. This would not only shed new light in detecting breast cancer tumors without biopsy (applied in radiological BIRADS classifications) but also evaluate the therapeutic effects on cancer tumors after chemotherapy/radiotherapy therapies without complicated and expensive scanning.