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In recent years, the repurposing of conventional and chemotherapeutic drugs is recognized as an alternative strategy for health care. The main purpose of this study is to strengthen the application of non‐oncological drug metformin on breast cancer treatment in the perspective of epigenetics. In the present study, metformin was found to inhibit cell proliferation, promote apoptosis and induce cell cycle arrest in breast cancer cells at a dose‐dependent manner. In addition, metformin treatment elevated acH3K9 abundance and decreased acH3K18 level. The expression of lncRNA MALAT1, HOTAIR, DICER1‐AS1, LINC01121 and TUG1 was up‐regulated by metformin treatment. In metformin‐treated cells, MALAT1 knock‐down increased the Bax/Bcl2 ratio and enhanced p21 but decreased cyclin B1 expression. The expression of Beclin1, VDAC1, LC3‐II, CHOP and Bip was promoted in the cells received combinatorial treatment of metformin and MALAT1 knock‐down. The reduced phosphorylation of c‐Myc was further decreased in the metformin‐treated cells in combination with MALAT1 knock‐down than metformin treatment alone. Taken together, these results provide a promising repurposed strategy for metformin on cancer treatment by modulating epigenetic modifiers.

Light sheet fluorescence microscopy provides optical sectioning and is widely used in volumetric imaging of large specimens. However, the axial resolution and the lateral Field of View (FoV) of the system, defined by the light sheet, typically limit each other due to the spatial band product of the excitation objective. Here, we develop a simple multi-focus scheme to extend the FoV, where a Gaussian light sheet can be focused at three or more consecutive positions. Axially overlapped multiple light sheets significantly enlarge the FoV with improved uniformity and negligible loss in axial resolution. By measuring the point spread function of fluorescent beads, we demonstrated that the obtained light sheet has a FoV of 450 um and a maximum axial FWHM of 7.5 um. Compared with the conventional single-focus one, the multi-focus Gaussian light sheet displays a significantly improved optical sectioning ability over the full FoV when imaging cells and zebrafish., Comment: 4 Pages, 4 Figures

This paper presents a novel self-bias CMOS rectifier for ultra-high frequency (UHF) RF energy harvester, which achieves a high power conversion efficiency (PCE) at an ultra-low input power. Compared to other state-of-the-art topologies, the proposed architecture combines static and dynamic compensated techniques to enhance the conduction capacity when the input power is lower than -27dBm. A six- stage rectifier is designed using this proposed topology in a 130nm CMOS process technology. Operating at 915MHz and driving a 1ΜΩ load resistor, the post-layout simulation PCE of this work is 27.6% at -30dBm input power. A sensitivity of - 30dBm is stimulated with 0.8V output voltage across a capacitive load.

Mitosis detection plays an import role in tumor grading of breast cancer. Automatic mitosis detection liberates pathologists from the time-consuming manual counting work. However, mitosis detection datasets are often provided only with centroid labels, limiting the performance of most deep learning methods. In this paper, we propose a novel method for mitosis detection to address this problem. First, we generate pixel-level labels directly from origin centroid labels with a gradient changing threshold approach. Then we apply a ResNet-based FCN to detect mitotic nuclei. Low confidence and tiny areas are removed from the prediction map to produce the final detections. By transforming the weak labels into strong labels, our method achieves $\mathrm{F}_{1} -$scores of 0.692, 0.608 and 0.805 on three public datasets, AMIDA 2013, ICPR 2014 and TUPAC 2016, respectively, outperforming all other state-of-the-art methods and showing great potential for clinical deployment.

Papillary Thyroid Carcinoma (PTC) is the most common type of thyroid cancer. BRAFV600E is a prominent oncogenic mutation and has been found to have strong associations with the mortality and recurrence of PTC. In this paper, we propose a workflow to show that BRAFV600E mutation status can be directly predicted from histopathological images with deep learning. Our method mainly consists of two steps, tumor detection and mutation classification; each of them contains a Convolutional Neural Network (CNN). The information derived from the two steps are combined to predict mutation. We propose three different strategies and build a PTC dataset of 6,541,586 512×512-pixel patches from 439 H&E stained Whole Slide Images (WSIs) to perform our experiments. In the PTC-V600E strategy, we use patches from 50 PTC WSIs and 202 WSIs of 200 cases to train the two networks, respectively, and get an AUC of 0.884 on the test of 187 WSIs of 186 cases. In PCam-V600E and PAIP-V600E strategies, we use public datasets, PCam and PAIP 2019, of other cancer types instead of 50 PTC WSIs and get AUCs of 0.884 and 0.860. All the three strategies separate mutation-positive and negative cases successfully in our experiments, demonstrating the availability and feasibility of our work and its potential in further research and applications.

Objective: This article discusses a treatment technique for ectopic earlobe in microtia reconstruction using a delayed postauricular skin flap. Methods: From January 2015 to September 2018, microtia reconstruction using a delayed postauricular skin flap was performed on 10 patients with microtia. During the operation, the position of the affected-side earlobe was designed according to the position of the opposite side. The ectopic earlobe was corrected by performing asymmetric Z-plasty or using an irregular “Y-V” advancement skin flap. This allowed full use of the remnant tissue of the microtia-affected ear to form a soft, plump, and realistic earlobe. Results: After the earlobe displacement surgery, the blood supply of the earlobe was good, and the reconstructed earlobe survived well without ulceration in all 10 patients. All patients were followed up for 2 months to 2 years. During this time, the positions of the reconstructed ear and the healthy side were basically symmetrical, and the shape of the earlobe formed by the remnant ear was natural. Conclusion: The use of asymmetric Z-plasty or an irregular “Y-V” advancement skin flap for the treatment of ectopic earlobe in microtia reconstruction using a delayed postauricular skin flap is a safe and effective method.

Double-side or 3-D integration of high-precision and high-performance bandpass and lowpass filters that are interconnected with through-vias were designed and demonstrated on 100-micron thin glass substrates for ultra-miniaturized diplexer components. A novel process for achieving high precision with large-area fabrication was developed to achieve much improved tolerance in electrical performance. High-precision, high quality factor, and high component densities with thin-film layers on glass were used to realize innovative topologies on glass for high out-of-band rejection and low insertion loss. Low-loss 100-μm thick glass cores and multiple layers of 15-μm thin polymer films were used to build the filters on substrates. The demonstrated diplexers have dimensions of 2.3 ×2.8 ×.2 mm. Aided by the dimensional stability of glass and process control with semiadditive patterning, the performance of the fabricated filters showed excellent correlation with the simulation. The impact of process-sensitivity analysis on diplexer performance was also analyzed. Finally, a unique and innovative process solution was demonstrated to control the process deviation and achieve good diplexer tolerance. The performance deviation was controlled by ~3.5X with the new process.

This paper presents the modeling, design, fabrication, and characterization of an innovative and miniaturized thin-film bandpass filter with coupled spiral structures in ultrathin glass substrates (30– $100~\mu \text{m}$ ). This filter is demonstrated for two applications: 3-D integrated passive devices and embedded thinfilm filters in RF modules. A compact filter design was achieved through an integrated resonant structure that effectively utilizes the inductive and capacitive coupling between metal layers on either side of an ultrathin glass substrate or organic build-up layer. The designed filters (layout area $150~\mu \text{m}$ device thickness) were fabricated on a 30- $\mu \text{m}$ -thin glass substrate using a panel-based low-cost approach with double-side thin-film wiring processes. The effect of process variations on the performance of the proposed structures was also studied. Furthermore, an improved WLAN filter is designed and demonstrated by employing specific structural modifications. The measured frequency response of the filters shows good model-to-hardware correlation, with very low insertion loss (0.6 dB) in the passband, and high adjacent-band rejection (>25 dB).

This article analyzes redistribution layer (RDL) technologies needed for 2.5-dimensional (2.5-D) die integration on thin glass interposers and developed using low-cost processes. The design, fabrication, and characterization of a four-metal layer RDL buildup required for wide input/output (I/O) routing at 40-μm bump pitch and a two-metal layer RDL buildup fabricated directly on glass for high-speed, off-package signaling are described. Such RDL technologies are targeted at 2.5-D glass interposer packages to achieve up to 1 Tb/s die-to-die bandwidth and off-interposer data rates > 400 Gb/s, driven by consumer demand of online services for mobile devices. Advanced packaging architectures including 2.5-D and 3-D interposers require fine-line lithography beyond the capabilities of current organic package substrates. High electrical loss and high cost are characteristic of silicon interposers fabricated using back-end-of-line (BEOL) processes that can achieve RDL wiring densities required for 2.5-D die integration. Organic interposers with high wiring densities have also been demonstrated using a single-sided, thin-film process. This article goes beyond silicon and organic interposers in demonstrating fine-pitch RDL on glass interposers fabricated by low-cost, double-side, and panel-scalable processes. The high modulus and smooth surface of glass help to achieve lithographic pitch close to that of silicon. Furthermore, the low permittivity and low loss tangent of glass reduce dielectric losses, thus improving high-speed signal propagation. A semiadditive process flow and projection excimer laser ablation were used to fabricate four-metal layer (2 + 0 + 2) fine-pitch RDL and two-metal layer RDL directly on glass. A minimum of 3 μm lithography and 20 μm microvia pitch was achieved. High-frequency characterization of these RDL structures demonstrated single-ended insertion losses of −0.097 dB/mm at f = 1 GHz and differential insertion losses of −0.05 dB/mm at f = 14 GHz.

Generalized nucleus segmentation techniques can contribute greatly to reducing the time to develop and validate visual biomarkers for new digital pathology datasets. We summarize the results of MoNuSeg 2018 Challenge whose objective was to develop generalizable nuclei segmentation techniques in digital pathology. The challenge was an official satellite event of the MICCAI 2018 conference in which 32 teams with more than 80 participants from geographically diverse institutes participated. Contestants were given a training set with 30 images from seven organs with annotations of 21,623 individual nuclei. A test dataset with 14 images taken from seven organs, including two organs that did not appear in the training set was released without annotations. Entries were evaluated based on average aggregated Jaccard index (AJI) on the test set to prioritize accurate instance segmentation as opposed to mere semantic segmentation. More than half the teams that completed the challenge outperformed a previous baseline. Among the trends observed that contributed to increased accuracy were the use of color normalization as well as heavy data augmentation. Additionally, fully convolutional networks inspired by variants of U-Net, FCN, and Mask-RCNN were popularly used, typically based on ResNet or VGG base architectures. Watershed segmentation on predicted semantic segmentation maps was a popular post-processing strategy. Several of the top techniques compared favorably to an individual human annotator and can be used with confidence for nuclear morphometrics.

A quantum dot (QD) is a semiconductor nanocrystal with a radius that is less than or equal to the exciton Bohr radius. As a new type of fluorescent marker, it shows great potential in biological and medical fields due to its unique tunable optical properties, such as a broad excitation spectrum, narrow emission spectra, tunable emission wavelength, and negligible photo-bleaching. Detection technology based upon this marker is simple, quick to use, sensitive, stable, and exhibits high throughput. The aim of this study was to examine the optical properties and surface modifications of QD in aquaculture pollution detection to assess potential applicability.

This paper describes the design, fabrication, and characterization of a two-metal layer RDL structure at 40 um pitch on thin glass interposers. Such an RDL structure is targeted at 2.5D glass interposer packages to achieve up to 1 TB/s die-to-die bandwidth and off-interposer data rates greater than 400 Gb/s, driven by consumer demand of online services for mobile devices. Advanced packaging architectures including 2.5D and 3D interposers require fine line lithography beyond the capabilities of current organic package substrates. Although silicon interposers fabricated using back-end-of-line processes can achieve these RDL wiring densities, they suffer from high electrical loss and high cost. Organic interposers with high wiring densities have also been demonstrated recently using a single sided thin film process. This paper goes beyond silicon and organic interposers in demonstrating fine pitch RDL on glass interposers fabricated by low cost, double sided, and panel-scalable processes. The high modulus and smooth surface of glass helps to achieve lithographic pitch close to that of silicon. Furthermore, the low loss tangent of glass helps in reducing dielectric losses, thus improving high-speed signal propagation. A semi-additive process flow and projection excimer laser ablation was used to fabricate two-metal layer RDL structures and bare glass RDL layers. A minimum of 3 um lithography and 20 um mico-via pitch was achieved. High-frequency characterization of these RDL structures demonstrated single-ended insertion losses of −0.097 dB/mm at f = 1 GHz and differential insertion losses of −0.05 dB/mm at f = 14 GHz.

This paper presents innovative compact three-dimensional integrated passive and active components (3D IPAC) packages with ultrathin glass substrates for radio frequency (RF) long-term evolution (LTE) front-end modules (FEMs). High component density was achieved through double-side integration of substrate-embedded passives for impedance matching networks and three-dimensional (3D) double-side assembly of filters onto glass substrates. Glass with 100 μm thickness formed the core of the package, while four build-up layers with 15 μm thickness each were used to embed passives and form redistribution layers (RDLs). Advanced panel-scale double-side assembly processes were developed with low-cost mass reflow. Board-level assembly was realized with paste-printed solder balls and reflow on printed circuit board (PCB) with no intermediate substrates. Electrical performance of filters with substrate-embedded impedance matching networks was characterized and compared to simulations.

In this paper, a flexible SIW wearable sensing platform is proposed with a novel 3D printing process which enables fast-prototyping customized wearable devices. The fabrication utilizes state-of-the-art SLA 3D printing that features fast prototyping of easy-to-reconfigure flexible 3D objects. Two different flexible metallization approaches are explored in this paper, which are complementary to each other and provide an excellent 3D metallization solution together. Two 3D shape SIW transmission lines are shown with a great flexibility and great potential for wearable devices. Moreover, based on a SIW slot waveguide antenna, this paper presents a proof-of-concept microfluidics sensor with sensitivity of 1.7 MHz/Er, which can be used as a wearable sensing device for real-time monitoring of body fluids. The proposed SIW-based flexible wearable devices along with the microfluidics sensors can be used in various Internet-of-Things applications, such as smart health and food quality monitoring.

Background This article presents a new microtia reconstruction method using a delayed postauricular skin flap. Methods The surgery is scheduled in three stages, the first of which delays the postauricular skin flap and deals with the remnant auricle. Three weeks later, the second stage is carried out. An erect, three-dimensional ear framework fabricated from autogenous rib cartilage is inserted between two flaps. The anterior auricular surface of the framework is draped with the delayed skin flap, and the postauricular surface is draped with postauricular fascia and overlying grafted skin. Six months later, the third stage reconstructs the tragus and shapes a hollow mimicking the external auditory meatus, and locally improves the reconstructed auricle. Results Ninety-six cases of microtia were reconstructed using the delayed skin flap. All ear reconstructions were successful, with good locations, sizes, and shapes, with few complications. Conclusions The authors' method enables an adequately large, thin skin flap with sufficient blood supply, and also appropriately manages the remnant auricle. A delayed postauricular skin flap with a three-dimensional autologous costal cartilage framework represents a promising approach to microtia reconstruction.

This paper introduces an innovative concept of electrical-thermal co-design for high-Q 3D inductors using through-package-via (TPV)-based copper networks in ultra-thin power amplifier-integrated glass modules. The copper networks are designed to provide high quality factor inductors, and also simultaneously enable heat transfer in ultra-miniaturized glass packages. Such TPV-based 3D inductors achieved the highest Q factor (>150 @ 1 GHz, >200 @ 2.4 GHz, SRF > 25 GHz), 7 times greater than that of the state-of-the-art package embedded inductors at LTE frequencies. The thermal structure, with power amplifier die assembled onto it, also reduces the package size by placing the embedded TPV-based inductor adjacent to it without affecting its Q.

This paper investigates the trade-offs in inductance density and quality factor of inductors with and without magnetic-cores through modeling, design, fabrication and model validation through characterization. Two type of inductors, one for power-supply and the other for EMI filters, are investigated. Parametric analysis was performed to study the enhancement in inductance density without compromising the current handling and efficiency. For EMI filter inductors, the inductance and quality factor (Q) were improved by 13X and 4X respectively with and without magnetic cores. For power inductors, the inductance and quality factor were improved by 5X and 1.6X respectively. The fabricated magnetic core inductors achieved 5X reduction in thickness, compared to the stage-of-the art air-core inductors which use multilayered and thick solenoid.

This paper presents a comprehensive study on the fundamental factors that impact the scalability of organic interposers to 40µm area array bump pitch, leading to the design and fabrication of ultra-thin and low CTE organic interposers at 40µm pitch. Silicon interposers were the first substrates used for 2.5D integration of logic and memory ICs at close proximity. However, the high cost and electrical loss of wafer back end of line (BEOL) silicon interposers has fueled the need for fine-pitch organic interposers. Organic substrates face two primary challenges in achieving finer I/O pitch: layer-to-layer mis-registration during copper-polymer re-distribution layer (RDL) fabrication due to the thermo-mechanical stability issue of organic laminate cores, and warpage during chip assembly on thin core substrates. This paper studies these two fundamental factors by finite element modeling (FEM) and experimental characterization, resulting in RDL design guidelines for low mis-registration and warpage. Reducing the copper thickness in each layer as well as the thickness of the polymer dielectric to below 10µm, resulted in significant reduction in CTE mismatch-induced stresses at different interfaces. The modeling-based design was verified by fabrication of a multi-layer RDL stack on 100µm thin low coefficient of thermal expansion (CTE) organic cores with ultra-thin build-up layers to achieve a bump pitch of 40µm. The assembly of chips on the thin organic interposer was optimized to minimize the warpage, leading to the demonstration of two-chip 2.5D organic interposers.

Background: Breast carcinoma (BC) and papillary thyroid carcinoma (PTC) occur predominantly in women. Many studies have shown that PTC is common among women with BC. Collision metastases in lymph nodes do occur but are not common. Case Report: Here we report 3 metachronous cases of BC with PTC. PTC developed after BC in each case. Histology and immunohistochemistry revealed that HER2 status was positive in each BC, and in 1, concurrent metastases of BC and PTC were shown in a lymph node of the left cervical region. Conclusion: From our results, we speculate that women with HER2-positive breast cancer may be at a higher risk for thyroid cancer than other cancers. Finding 2 distinct types of cancer metastasized to 1 lymph node in a patient may, therefore, warrant a high index of suspicion and the use of immunohistochemical stains to differentiate the types of collision tumors.

Alveolar adenoma is an extremely rare benign tumor of the lung derived from type II pneumocytes. To date, only a limited number of alveolar adenoma cases have been reported in the literature. These tumors are usually discovered incidentally on radiographic images. However, other tumor types must be excluded when the characteristics of alveolar adenoma are not typical on the radiographic images. Therefore, diagnosis of alveolar adenomas is based on the combination of gross structural analysis and immunohistochemistry. The present study described a case of alveolar adenoma in a 47-year-old female patient. A chest X-ray revealed a pulmonary lesion in the right lower lobe and, subsequently, the patient underwent a right lower lobectomy. Pathological examination of the surgically resected tissue confirmed the initial diagnosis of alveolar adenoma. In addition, intracranial vascular malformations were detected on a computed tomography scan, but the patient did not experience any notable symptoms. Considering the benign nature of the malformations, as determined by digital subtraction angiography, the patient selected to undergo follow-up with observation only. The postoperative course was uneventful and no recurrence of pulmonary lesions was noted after >4 years, while the condition of the intracranial lesion was stable. In conclusion, the current study described a unique case of adenoma alveolar coexisting with intracranial vascular malformations. A literature review of previously-reported alveolar adenoma cases was also conducted.