Co-culture device for in vitro high throughput analysis of cancer associated fibroblast and cancer cell interactions.

Introduction Cancers in general, and specifically lung cancer, continue to have low patient survival rates when the patient is at an advanced stage when diagnosed. It appears that the local environment, especially fibroblasts and their signaling molecules, tends to induce metastasis, increase cancer cell resistance to treatment, and aid in tumor growth rates. Since 3-D models quickly become too complex and/or expensive, and therefore rarely leave the lab they are developed in, it is interesting to develop a 2-D model that more closely mimics the clustered tumor formation and bulk interaction with a surrounding fibroblast environment. Methods In the present study, we utilize an off-the-shelf stereolithography 3-D printer, standard use well plates, magnets, and metallic beads to create a customizable 2-D co-culture system capable of being analyzed quantitatively with staining and qualitatively with standard fluorescent/brightfield microscopy to determine cancer-fibroblast interactions while also being able to test chemotherapeutic drugs in a high-throughput manner with standard 96-well plates. Results Comparisons from monoculture and co-culture growth rates shows that the presence of fibroblasts allows for significantly increased growth rates for H460 cancer. Additionally, viability of cancer cells can be quantified with simple cell staining methods and morphology and cell-cell interactions can be observed and studied. Discussion The high throughput model demonstrates that boundary condition changes can be observed between cancer cells and fibroblasts based upon the different chemotherapeutics that have been administered.

Physical Forces in Glioblastoma Migration: A Systematic Review.

The invasive capabilities of glioblastoma (GBM) define the cancer's aggressiveness, treatment resistance, and overall mortality. The tumor microenvironment influences the molecular behavior of cells, both epigenetically and genetically. Current forces being studied include properties of the extracellular matrix (ECM), such as stiffness and "sensing" capabilities. There is currently limited data on the physical forces in GBM-both relating to how they influence their environment and how their environment influences them. This review outlines the advances that have been made in the field. It is our hope that further investigation of the physical forces involved in GBM will highlight new therapeutic options and increase patient survival. A search of the PubMed database was conducted through to 23 March 2022 with the following search terms: (glioblastoma) AND (physical forces OR pressure OR shear forces OR compression OR tension OR torsion) AND (migration OR invasion). Our review yielded 11 external/applied/mechanical forces and 2 tumor microenvironment (TME) forces that affect the ability of GBM to locally migrate and invade. Both external forces and forces within the tumor microenvironment have been implicated in GBM migration, invasion, and treatment resistance. We endorse further research in this area to target the physical forces affecting the migration and invasion of GBM.

Fabrication of junction-free Cu nanowire networks via Ru-catalyzed electroless deposition and their application to transparent conducting electrodes.

Over the past few years, metal nanowire networks have attracted attention as an alternative to transparent conducting oxide materials such as indium tin oxide for transparent conducting electrode applications. Recently, electrodeposition of metal on nanoscale template is widely used for formation of metal network. In the present work, junctionless Cu nanowire networks were simply fabricated on a substrate by forming a nanostructured Ru with 80 nm width as a seed layer, followed by direct electroless deposition of Cu. By controlling the density of Ru nanowires or the electroless deposition time, we readily achieve desired transmittance and sheet resistance values ranging from ∼1 kΩ sq-1at 99% to 9 Ω sq-1at 89%. After being transferred to flexible substrates, the nanowire networks exhibited no obvious increase in resistance during 8000 cycles of a bending test to a radius of 2.5 mm. The durability was verified by evaluation of its heating performance. The maximum temperature was greater than 180 °C at 3 V and remained constant after three repeated cycles and for 10 min. Transmission electron microscopy and x-ray diffraction studies revealed that the adhesion between the electrolessly deposited Cu and the seed Ru nanowires strongly influenced the durability of the core-shell structured nanowire-based heaters.

Use of bevacizumab before or after radiotherapy increases the risk of fistula formation in patients with cervical cancer.

OBJECTIVE: Several reports have documented the risk of fistula formation after bevacizumab in patients previously treated with radiation therapy. The aim of this study was to investigate the risk of fistula formation with bevacizumab and radiotherapy compared with radiotherapy alone. METHODS: We retrospectively analyzed patients with stage I-IV cervical cancer between January 2013 and December 2018. Patients who had a history of pelvic radiotherapy, who were treated with intracavitary brachytherapy alone, received radiotherapy at another hospital, received concurrent bevacizumab and radiotherapy, or had missing follow-up data or a short follow-up period (<6 months) were excluded. The fistula rates were compared between the groups using the Cox proportional hazards model and propensity score analyses. RESULTS: A total of 302 patients were included in the study: 249 patients were treated with definitive or adjuvant radiotherapy, and 53 patients were treated with radiotherapy before or after bevacizumab. With a median follow-up of 35.9 (IQR 22.8-53.5) months, the 3 year cumulative fistula incidence rate was significantly higher in the radiotherapy + bevacizumab group than in the radiotherapy group (27.0% vs 3.0%, p<0.001). Bevacizumab administration was significantly associated with fistula formation in the multivariable adjusted model (HR 4.76, 95% CI 1.71 to 13.23) and three propensity score adjusted model (all p<0.05). Biologically equivalent dose in 2 Gy fractions for 2 cc of the rectum more than 76 Gy was also associated with fistula formation (HR 4.30, 95% CI 1.52 to 12.18). Additionally, a 10 month interval between radiotherapy and bevacizumab reduced the incidence of fistula formation in the radiotherapy + bevacizumab group (p=0.032). CONCLUSIONS: In patients with cervical cancer treated with pelvic radiotherapy, the addition of bevacizumab substantially increased the risk of fistula formation. Physicians should perform pelvic radiotherapy in combination with bevacizumab with caution; moreover, close monitoring for fistula formation is warranted in these patients.

Comparison of outcomes between the one-step and two-step sentinel lymph node mapping techniques in endometrial cancer.

INTRODUCTION: Fluorescence image-guided sentinel lymph node (SLN) biopsy using a two-step mapping technique incorporates sequential injection of indocyanine green into the bilateral uterine cornus, followed by cervical injection. Outcomes were compared with the conventional cervical (one-step) method . METHODS: Patients with FIGO stage I-III endometrial cancer who underwent laparoscopic or robotic staging, including SLN biopsy, from May 2014 to December 2018, were retrospectively reviewed. Patient characteristics, pre-operative imaging, SLN detection pattern, pathologic result, adjuvant, and recurrence locations were analyzed. RESULTS: A total of 199 patients received one-step (n=123) and two-step (n=76) SLN biopsy. Para-aortic SLN were more frequently identified in the two-step group. Lower and upper para-aortic SLN were identified in 67.1% and 38.2%, respectively, in the two-step group and in 18.7% and 5.7% in the one-step group (p<0.001). The number of para-aortic SLN harvested was superior in the two-step group (p<0.001). Metastatic para-aortic SLN were found in 7.9% of the two-step group and 2.4% of the one-step group (p=0.070). In detecting nodal metastasis, the sensitivities of the one- and two-step methods were 91.7% and 100.0%, negative predictive values were 99.0% and 100.0%, false-negative rates were 8.3% and 0%, and accuracy rates were 99.1% and 100.0%, respectively. The one-step method identified only three out of eight para-aortic lymph node metastases and missed five para-aortic lymph node metastases. There was no missed para-aortic lymph node metastasis in the two-step group. Recurrence was observed in two patients (2.6%; vaginal vault and adrenal gland) in the two-step group and seven patients (5.7%) including three nodal recurrences in the one-step group (p=0.307). DISCUSSION: Two-step SLN mapping improved the para-aortic SLN detection rate, a known pitfall of conventional cervical injection. Proper evaluation of aortic nodal status will assist in the tailoring of adjuvant and prevent undertreatment of patients with isolated para-aortic metastasis.

Glioblastoma Multiforme heterogeneity profiling with solid-state micropores.

Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. It is characterized by widespread heterogeneity at the cellular and molecular levels. The detection of this heterogeneity is valuable for accurate diagnosis. Herein, solid-state 20 µm diameter micropore made in thin suspended silicon dioxide membrane is used as cell sensor device. The device relies on a cell's mechano-physical properties as an indicator to differentiate between the subtypes of GBM. A library of GBM cell lines (U251, U87, D54 EGFRviii, and G55) was created by measuring the differences in cell's micropore translocation properties from their distinct electrical profiles. Each GBM subtype has distinct phenotype and this was delineated in their cell translocation behaviors. The library was used to distinguish cells from samples of brain tumor patients. The micropore device accurately profiled GBM patient samples for cell subtypes by comparing data with the GBM library. The micropore approach is simple, can be implemented at low cost and can be used in the clinical setups and operation theaters to detect and identify GBM subtypes from patient samples.

Risk factors for recurrent lumbar disc herniation after discectomy.

PURPOSE: There are many reports about the risk factors for recurrence after lumbar disc surgery. However, there are none about whether lumbosacral transitional vertebrae (LSTV) are associated with recurrent lumbar disc herniation (LDH). We investigated various risk factors for recurrent LDH after discectomy including LSTV. METHODS: A total of 119 patients who had undergone a discectomy for L4-5 disc herniation were evaluated with a minimum follow-up of two years. Clinical parameters including age, gender, body mass index (BMI), and smoking status, and radiological parameters including type of herniated disc, degree of disc degeneration, LSTV, and sagittal range of motion (SROM) in flexion-extension radiography were evaluated. SROM was measured by the difference of the lordotic angle between the flexion and extension view. RESULTS: Recurrent disc herniation at L4-5 developed in 21 (17.6%) of the 119 patients. The mean period between primary surgery and recurrence was 17.6 ± 21.1 months. LSTV was found in 11 (52.4%) of the 21 patients who had recurrence and seven (7.1%) of the 98 patients in the non-recurrent group. SROM at L4-5 was 11.68 ± 4.24° in the recurrent group and 9.04 ± 3.65° in the non-recurrent group with a significant difference (p = 0.004). Multiple logistic regression analyses confirmed that LSTV and a larger SROM were significant risk factors for recurrent disc herniation at L4-5. CONCLUSIONS: Lumbosacral transitional vertebrae and a hypermobile disc in flexion-extension radiography were found to be risk factors for recurrent lumbar disc herniation.

Correlation of Controllable Aggregation with Light-Emitting Property in Polymer Blend Optoelectronic Devices.

The control of solution-processed emitting layers in organic-based optoelectronic devices enables cost-effective processing and highly efficient properties. However, a solution-based protocol for emitter fabrication is highly complex, and the link between the device performance and internal nanoscale features as well as three associated fabricating parameters (e.g., the employed solvents, annealing temperatures, and molecular concentration) needs to be understood. Here, this study investigates the influence of the solution-processing parameters on the nanostructure-property relationship in light emitters that consist of iridium complexes doped in polymer. The boiling points and evaporation rates of the selected solvents govern the nanomorphology of molecular aggregation in the as-processed state, and the aggregation is either needle-like, spherical, or even a mixture of needles and spheres. Furthermore, a direct observation via in situ heating microscopy indicates that annealing of emitters containing a needle-type aggregation promotes the associated molecular transport, leading to a substantial reduction in the surface roughness. Consequently, a nearly threefold increase in the current efficiency of the device is induced. These findings have important implications for the tuning of the aggregation of iridium complexes for emitters used in the new evolution of high-performance organic-based optoelectronic devices.

Role of key genetic mutations on increasing migration of brain cancer cells through confinement.

Uncontrolled invasive cancer cell migration is among the major challenges for the treatment and management of brain cancer. Although the genetic profiles of brain cancer cells have been well characterized, the relationship between the genetic mutations and the cells' mobility has not been clearly understood. In this study, using microfluidic devices that provide a wide range of physical confinements from 20 × 5 µm2 to 3 × 5 µm2 in cross sections, we studied the effect of physical confinement on the migratory capacity of cell lines with different types of mutations. Human glioblastoma and genetically modified mouse astrocytes were used. Human glioblastoma cells with EGFRvIII mutation were found to exhibit high degree of migratory capacity in narrow confinement. From mouse astrocytes, cells with triple mutations (p53-/- PTEN-/- BRAF) were found to exhibit the highest level of migratory capacity in narrow confinement compared to both double (p53-/- PTEN-/-) and single (p53-/-) mutant cells. Furthermore, when treating the triple mutant astrocytes with AZD-6244, an inhibitor of the RAF/MEK/ERK pathway, we found significant reduction in migration through the confined channels when compared to that of controls (83% decrease in 5 × 5 µm2 and 86% in 3 × 5 µm2 channels). Our data correlate genetic mutations from different cell lines to their motility in different degrees of confinement. Our results also suggest a potential therapeutic target such as BRAF oncogene for inhibition of brain cancer invasion.

Functionalization of nanotextured substrates for enhanced identification of metastatic breast cancer cells.

Metastasis is the major cause of low survival rates among cancer patients. Once cancer cells metastasize, it is extremely difficult to contain the disease. We report on a nanotextured platform for enhanced detection of metastatic cells. We captured metastatic (MDA-MDB-231) and non-metastatic (MCF-7) breast cancer cells on anti-EGFR aptamer modified plane and nanotextured substrates. Metastatic cells were seen to change their morphology at higher rates when captured on nanotextured substrates than on plane substrates. Analysis showed statistically different morphological behaviors of metastatic cells that were very pronounced on the nanotextured substrates. Several distance matrices were calculated to quantify the dissimilarity of cell shape change. Nanotexturing increased the dissimilarity of the metastatic cells and as a result the contrast between metastatic and non-metastatic cells increased. Jaccard distance measurements found that the shape change ratio of the non-metastatic and metastatic cells was enhanced from 1:1.01 to 1:1.81, going from plane to nanotextured substrates. The shape change ratio of the non-metastatic to metastatic cells improved from 1:1.48 to 1:2.19 for the Hausdorff distance and from 1:1.87 to 1:4.69 for the Mahalanobis distance after introducing nanotexture. Distance matrix analysis showed that nanotexture increased the shape change ratios of non-metastatic and metastatic cells. Hence, the detectability of metastatic cells increased. These calculated matrices provided clear and explicit measures to discriminate single cells for their metastatic state on functional nanotextured substrates.

Understanding of Capping Effects on the Tip Shape Evolution and on the Atom Probe Data of Bulk LaAlO3 Using Transmission Electron Microscopy.

Two challenges exist in laser-assisted atom probe tomography (APT). First, a drastic decline in mass-resolving power is caused, not only by laser-induced thermal effects on the APT tips of bulk oxide materials, but also the associated asymmetric evaporation behavior; second, the field evaporation mechanisms of bulk oxide tips under laser illumination are still unclear due to the complex relations between laser pulse and oxide materials. In this study, both phenomena were investigated by depositing Ni- and Co-capping layers onto the bulk LaAlO3 tips, and using stepwise APT analysis with transmission electron microscopy (TEM) observation of the tip shapes. By employing the metallic capping, the heating at the surface of the oxide tips during APT analysis became more symmetrical, thereby enabling a high mass-resolving power in the mass spectrum. In addition, the stepwise microscopy technique visualized tip shape evolution during APT analysis, thereby accounting for evaporation sequences at the tip surface. The combination of "capping" and "stepwise APT with TEM," is applicable to any nonconductors; it provides a direct observation of tip shape evolution, allows determination of the field evaporation strength of oxides, and facilitates understanding of the effects of ultrafast laser illumination on an oxide tip.

Differentiating Metastatic and Non-metastatic Tumor Cells from Their Translocation Profile through Solid-State Micropores.

Cancer treatment, care, and outcomes are much more effective if started at early stages of the disease. The presence of malignant cancer cells in human samples such as blood or biopsied tissue can be used to reduce overtreatment and underdiagnosis as well as for prognosis monitoring. Reliable quantification of metastatic tumor cells (MTCs) and non-metastatic tumor cells (NMTCs) from human samples can help in cancer staging as well. We report a simple, fast, and reliable approach to identify and quantify metastatic and non-metastatic cancer cells from whole biological samples in a point-of-care manner. The metastatic (MDA MB-231) and non-metastatic (MCF7) breast cancer cells were pushed through a solid-state micropore made in a 200 nm thin SiO2 membrane while measuring current across the micropore. The cells generated very distinctive translocation profiles. The translocation differences stemmed from their peculiar mechanophysical properties. The detection efficiency of the device for each type of tumor cells was ∼75%. MTCs showed faster translocation (36%) and 34% less pore blockage than NMTCs. The micropore approach is simple, exact, and quantitative for metastatic cell detection in a lab-on-a chip setting, without the need for any preprocessing of the sample.

Electromechanical transducer for rapid detection, discrimination and quantification of lung cancer cells.

Tumor cells are malignant derivatives of normal cells. There are characteristic differences in the mechanophysical properties of normal and tumor cells, and these differences stem from the changes that occur in the cell cytoskeleton during cancer progression. There is a need for viable whole blood processing techniques for rapid and reliable tumor cell detection that do not require tagging. Micropore biosensors have previously been used to differentiate tumor cells from normal cells and we have used a micropore-based electromechanical transducer to differentiate one type of tumor cells from the other types. This device generated electrical signals that were characteristic of the cell properties. Three non-small cell lung cancer (NSCLC) cell lines, NCl-H1155, A549 and NCI-H460, were successfully differentiated. NCI-H1155, due to their comparatively smaller size, were found to be the quickest in translocating through the micropore. Their translocation through a 15 µm micropore caused electrical pulses with an average translocation time of 101 ± 9.4 µs and an average peak amplitude of 3.71 ± 0.42 µA, whereas translocation of A549 and NCI-H460 caused pulses with average translocation times of 126 ± 17.9 µs and 148 ± 13.7 µs and average peak amplitudes of 4.58 ± 0.61 µA and 5.27 ± 0.66 µA, respectively. This transformation of the differences in cell properties into differences in the electrical profiles (i.e. the differences in peak amplitudes and translocation times) with this electromechanical transducer is a quantitative way to differentiate these lung cancer cells. The solid-state micropore device processed whole biological samples without any pre-processing requirements and is thus ideal for point-of-care applications.

Broad spectral excitation of opsin for enhanced stimulation of cells.

Optical stimulation of cells expressing light-sensitive proteins (opsins) has allowed targeted activation with cellular specificity. However, since narrow-band light has been used for excitation of these optogenetic probes, only active stimulation strategies are being attempted for clinical applications such as restoration of vision. Here, we report use of broad spectral excitation (white light) for optogenetic stimulation of opsin-sensitized cells. We found that ReaChR is optimally excited with white light offering significantly higher photocurrents compared to spectrally filtered narrow-band light stimulation. Our findings open up the possibility of passive stimulation strategy by use of natural sunlight for retinal stimulation, which could have benefits for ambient light stimulated vision restoration.

Nanotextured polymer substrates show enhanced cancer cell isolation and cell culture.

Detection of circulating tumor cells (CTCs) in the early stages of cancer is a great challenge because of their exceedingly small concentration. There are only a few approaches sensitive enough to differentiate tumor cells from the plethora of other cells in a sample like blood. In order to detect CTCs, several antibodies and aptamers have already shown high affinity. Nanotexture can be used to mimic basement membrane to further enhance this affinity. This article reports an approach to fabricate nanotextured polydimethylsiloxane (PDMS) substrates using micro reactive ion etching (micro-RIE). Three recipes were used to prepare nanotextured PDMS using oxygen and carbon tetrafluoride. Micro-RIE provided better control on surface properties. Nanotexturing improved the affinity of PDMS surfaces to capture cancer cells using surface immobilized aptamers against cell membrane overexpressed with epidermal growth factor receptors. In all cases, nanotexture of PDMS increased the effective surface area by creating nanoscale roughness on the surface. Nanotexture also enhanced the growth rate of cultured cells compared to plain surfaces. A comparison among the three nanotextured surfaces demonstrated an almost linear relationship between the surface roughness and density of captured tumor cells. The nanotextured PDMS mimicked biophysical environments for cells to grow faster. This can have many implications in microfluidic platforms used for cell handling.

Temperature-dependent nanomorphology-performance relations in binary iridium complex blend films for organic light emitting diodes.

Understanding the mechanism responsible for the temperature-dependent performances of emitting layers is essential for developing advanced phosphorescent organic light emitting diodes. We described the morphological evolution occurring in PVK:Ir(ppy)3 binary blend films, with respect to thermal annealing up to 300 °C, by coupling atomic force microscopy and transmission electron microscopy. In particular, in situ temperature-dependent experimental characterization was performed to directly determine the overall sequence of morphological evolution occurring in the films. The device thermally annealed at 200 °C exhibits a noticeable enhancement in the performances, compared to the devices in the as-processed state and to the devices annealed at 300 °C. Our approaches reveal that the Ir(ppy)3 molecules, with a needle-like structure in the as-processed state, were aggregated, and thus diffused into PVK without a morphological change at the temperature regime between 150 °C and 200 °C. Moreover, both network-like and droplet patterns existed in the devices annealed at 300 °C, which was beyond the glass temperature of PVK, leading to a profound increase in the surface roughness. The observed pattern formation is discussed in terms of viscoelastic phase separation. Based on our experimental findings, we propose that the performances of the devices are significantly controlled by the diffusion of dopant molecules and the morphological evolution of the host materials in binary blend systems.

Design of endoscopic micro-robotic end effectors: safety and performance evaluation based on physical intestinal tissue damage characteristics.

During the last several years, legged locomotive mechanism has been considered as one of the main self-propelling mechanisms for future endoscopic microrobots due to its superior propulsion efficiency of an endoscopic microrobot inside the intestinal track. Nevertheless, its clinical application has been largely limited since the legged locomotive mechanism utilizes an end effector which has a sharp tip to generate sufficient traction by physically penetrating and interlocking with the intestinal tissue. This can cause excessive physical tissue damage or even complete perforation of the intestinal wall that can lead to abdominal inflammation. Hence, in this work two types of new end effectors, penetration-limited end effector (PLEE) and bi-material structured end effector (BMEE) were specially designed to acquire high medical safety as well as effective traction generation performance. The microscopic end effector specimens were fabricated with micro-wire electric discharge machining process. Traction generation performance of the end effectors was evaluated by direct measurement of resistance forces during contact-sliding tests using a custom-built contact-sliding tester. The safety of the end effector design was evaluated by examination of microscopic intestinal tissue damage using a scanning electron microscope (SEM). Physical damage characteristics of the intestinal tissue and related contact physics of the end effectors were discussed. From the results, the end effectors were evaluated with respect to their prospects in future medical applications as safe end effectors as well as micro-surgical tools.

Micro+nanotexturing of substrates to enhance ligand-assisted cancer cell isolation.

This paper presents a simple approach to create a two-tiered surface for superior cancer cell isolation. The idea is inspired by the interactions of cells with a nanotextured basement membrane. The texture mimicked the extracellular matrix and basement membrane for superior target cell adhesion. Prepared micro+nanotextured surfaces showed enhanced cell capture. Preparation of the two-tiered surface was done using micro- and nanotexturing and was easily reproducible. It has been shown before that the larger surface area of a nanotextured surface assists the cell's attachment through surface-anchored ligands. Taking it a step further, ligand functionalized two-level micro+nanotextured surfaces improved the sensitivity of the cancer cell isolation over simple flat nanotexturing. The isolation efficiency increased by 208% compared to the surface with a single-level nanotexture. The two-tiered surface was compatible with previously reported nanotextured devices used for cancer cell isolation. Micro-texture on the glass surface was created using simple sand gritting, followed by reactive ion etching (RIE) of the entire surface. The approach could create large surface areas within a short time while maintaining superior cell isolation efficiency.

SleepMI: An AI-based screening algorithm for myocardial infarction using nocturnal electrocardiography.

Myocardial infarction (MI) is a common cardiovascular disease, the early diagnosis of which is essential for effective treatment and reduced mortality. Therefore, novel methods are required for automatic screening or early diagnosis of MI, and many studies have proposed diverse conventional methods for its detection. In this study, we aimed to develop a sleep-myocardial infarction (sleepMI) algorithm for automatic screening of MI based on nocturnal electrocardiography (ECG) findings from diagnostic polysomnography (PSG) data using artificial intelligence (AI) models. The proposed sleepMI algorithm was designed using representation and ensemble learning methods and optimized via dropout and batch normalization. In the sleepMI algorithm, a deep convolutional neural network and light gradient boost machine (LightGBM) models were mixed to obtain robust and stable performance for screening MI from nocturnal ECG findings. The nocturnal ECG signal was extracted from 2,691 participants (2,331 healthy individuals and 360 patients with MI) from the PSG data of the second follow-up stage of the Sleep Heart Health Study. The nocturnal ECG signal was extracted 3 h after sleep onset and segmented at 30-s intervals for each participant. All ECG datasets were divided into training, validation, and test sets consisting of 574,729, 143,683, and 718,412 segments, respectively. The proposed sleepMI model exhibited very high performance with precision, recall, and F1-score of 99.38%, 99.38%, and 99.38%, respectively. The total mean accuracy for automatic screening of MI using a nocturnal single-lead ECG was 99.387%. MI events can be detected using conventional 12-lead ECG signals and polysomnographic ECG recordings using our model.

Efficacy and safety of BVAC-C in HPV type 16- or 18-positive cervical carcinoma who failed 1st platinum-based chemotherapy: a phase I/IIa study.

Background: BVAC-C, a B cell- and monocyte-based immunotherapeutic vaccine transfected with recombinant HPV E6/E7, was well tolerated in HPV-positive recurrent cervical carcinoma patients in a phase I study. This phase IIa study investigates the antitumor activity of BVAC-C in patients with HPV 16- or 18-positive cervical cancer who had experienced recurrence after a platinum-based combination chemotherapy. Patients and methods: Patients were allocated to 3 arms; Arm 1, BVAC-C injection at 0, 4, 8 weeks; Arm 2, BVAC-C injection at 0, 4, 8, 12 weeks; Arm 3, BVAC-C injection at 0, 4, 8, 12 weeks with topotecan at 2, 6, 10, 14 weeks. Primary endpoints were safety and objective response rate (ORR) as assessed by an independent radiologist according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included the disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: Of the 30 patients available for analysis, the ORR was 19.2% (Arm 1: 20.0% (3/15), Arm 2: 33.3% (2/6), Arm3: 0%) and the DCR was 53.8% (Arm 1: 57.1%, Arm 2: 28.6%, Arm3: 14.3%). The median DOR was 7.5 months (95% CI 7.1-not reported), the median PFS was 5.8 months (95% CI 4.2-10.3), and the median OS was 17.7 months (95% CI 12.0-not reported). All evaluated patients showed not only inflammatory cytokine responses (IFN-γ or TNF-α) but also potent E6/E7-specific T cell responses upon vaccinations. Immune responses of patients after vaccination were correlated with their clinical responses. Conclusion: BVAC-C represents a promising treatment option and a manageable safety profile in the second-line setting for this patient population. Further studies are needed to identify potential biomarkers of response. Clinical trial registration: ClinicalTrials.gov, identifier NCT02866006.