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BACKGROUND Treatment of advanced lymphedema requires not only restoration of physiological lymph drainage, but also excision of fibrotic tissue and excess skin. The aim of this study is to show how the combination of double vascularized lymph node transfers (VLNTs) and a modified radical reduction with preservation of perforators (RRPP) can accomplish both of these treatment goals. METHODS Between 2010 and 2016, 16 patients (15 female and one male) with extremity lymphedema underwent a combined double gastroepiploic VLNTs and modified RRPP. Demographics, outcomes including circumference reduction rates, preoperative and postoperative lymphoscintigraphy, complications, and responses to the Lymphedema Quality of Life (LYMQOL) questionnaire were analyzed. RESULTS All flaps survived. The mean follow-up period was 14.2 months (range, 12-19). The mean circumference reduction rate was 74.5% ± 6.9% for the upper limb and 68.0% ± 4.2% for the lower limb. There were no major complications. Minor complications, including numbness and hyperesthesia, were treated conservatively. LYMQOL showed a 2.7-fold quality-of-life improvement (P

Background This study evaluated the long-term clinical outcomes among different vascularized lymph node transfers (VLNT) used at our institution. Methods Between July 2010 and July 2016, all patients with International Society of Lymphology (ISL) stages II-III who underwent VLNT were evaluated. Demographic and clinical data (limb circumference, infectious episodes, lymphoscintigraphic studies) were recorded pre-operatively. Clinical outcomes, complications, and additional excisional procedures were analyzed post-operatively. At least 2-year follow-up was required for inclusion. Results Overall, 83 patients (Stage II:47, Stage III:36) met the inclusion criterion. Mean follow-up was 32.8 months (range, 24-49). Lymph node flaps used were groin (n = 13), supraclavicular (n = 25), gastroepiploic (n = 42), ileocecal (n = 2), and appendicular (n = 1). Total mean circumference reduction rate was 29.1% (Stage II) and 17.9% (Stage III) (P

Vascularized lymph node (VLN) transfer has been of high interest in the past decade for the treatment of lymphedema, since it has been shown to be effective in reducing limb volumes, decreasing infectious episodes and improving quality of life. Multiple donor sites have been described in the quest for the optimal one. Herein, we describe a novel lymph node flap option based on the ileocolic artery and vein. The ileocecal vascularized lymph node (IC-VLN) flap was used in the management of a 33-year-old male patient with lower extremity lymphedema secondary to left inguinal trauma. The patient had previously underwent a pedicled omentum flap transposition with minimal improvement in limb size and persistent episodes of infection. At 15 month follow-up, the IC-VLN flap improved the lymphatic drainage in the affected limb with a mean limb circumference reduction rate of 26.3%. No donor site complications or further episodes of infection were noted. According to our findings, the IC-VLN flap may be another option for VLN transfer in very selected cases. Nevertheless, larger series with a longer follow-up are required to analyze the efficacy and long-term results of this flap.

A miniature 180° hybrid is proposed to demonstrate a 200-GHz subharmonic mixer (SHM) using a 0.18- $\mu \text{m}$ SiGe BiCMOS process. The reduced-size 180° hybrid is achieved by folding the shared coupled lines between the in-phase power divider and the out-of-phase Marchand balun. The shared coupled lines demand an equal length design for the coupled lines at both $\Delta $ and $\Sigma $ ports of an 180° hybrid. For the SHM, edge coupling for the $\Sigma $ section and broad-side coupling for the $\Delta $ section are employed to compensate the different input frequencies at $\Delta $ and $\Sigma $ ports. The SHM achieves a conversion gain around −21 dB from 175 to 200 GHz with 0-dBm LO pumping power. The LO-to-RF isolation is better than 32 dB within the operating bandwidth.

The rachises of extant feathers, composed of dense cortex and spongy internal medulla, are flexible and light, yet stiff enough to withstand the load required for flight, among other functions. Incomplete knowledge of early feathers prevents a full understanding of how cylindrical rachises have evolved. Bizarre feathers with unusually wide and flattened rachises, known as "rachis-dominated feathers" (RDFs), have been observed in fossil nonavian and avian theropods. Newly discovered RDFs embedded in early Late Cretaceous Burmese ambers (about 99 million year ago) suggest the unusually wide and flattened rachises mainly consist of a dorsal cortex, lacking a medulla and a ventral cortex. Coupled with findings on extant feather morphogenesis, known fossil RDFs were categorized into three morphotypes based on their rachidial configurations. For each morphotype, potential developmental scenarios were depicted by referring to the rachidial development in chickens, and relative stiffness of each morphotype was estimated through functional simulations. The results suggest rachises of RDFs are developmentally equivalent to a variety of immature stages of cylindrical rachises. Similar rachidial morphotypes documented in extant penguins suggest that the RDFs are not unique to Mesozoic theropods, although they are likely to have evolved independently in extant penguins.

A high isolation gate-pumped resistive sub-harmonic mixer with a miniature 180° hybrid is demonstrated using 90 nm CMOS process. An in-phase power divider and an out-of-phase Marchand balun form a reduced-size 180° hybrid with shared coupled lines. For a sub-harmonic mixer, the input matches at LO/RF ports of the 180° hybrid are achieved using high/low coupling coefficients of the shared equal-length coupled lines. Moreover, isolations between RF and LO ports are achieved at all frequencies because a Marchand balun maintains balanced signals and a power divider provides in-phase equal magnitude signals at all frequencies. The sub-harmonic mixer achieves a conversion gain around 0-3 dB from 58-67 GHz with 0 dBm LO pumping power. The LO-to-RF isolation is better than 36 dB within the operating bandwidth.

Vascularized lymph node transfer has demonstrated promising results for the treatment of extremity lymphedema. In an attempt to find the ideal donor site, several vascularized lymph nodes have been described. Each has a common goal of decreasing morbidity and avoiding iatrogenic lymphedema while obtaining good clinical results. Herein, we present the preliminary clinical outcomes of an intra-abdominal lymph node flap option based on the appendicular artery and vein used for the treatment of extremity lymphedema. A 62 year-old woman with moderate lower extremity lymphedema, on chronic antibiotics because of recurrent infections and unsatisfactory outcomes after conservative treatment underwent a vascularized appendicular lymph node (VALN) transfer. At a follow-up of 6 months, the reduction rate of the limb circumference was 17.4%, 15.1%, 12.0% and 9% above the knee, below the knee, above the ankle and foot respectively. In addition, no further episodes of infection or other complications were reported after VALN transfer. Postoperative lymphoscintigraphy demonstrated that the VALN flap was able to improve the lymphatic drainage of the affected limb. According to our findings, the use of VALN transfer minimizes donor-site morbidity, avoids iatrogenic lymphedema and may provide a strong clearance of infection because of the strong immunologic properties of the appendiceal lymphatic tissue in selected patients. Despite these promising results, further research with larger number of patients and longer follow- up is needed.

// Wohn-Jenn Leu 1, * , Sharada Prasanna Swain 2, * , She-Hung Chan 1 , Jui-Ling Hsu 1 , Shih-Ping Liu 3 , Mei-Ling Chan 1 , Chia-Chun Yu 1 , Lih-Ching Hsu 1 , Yen-Lin Chou 2 , Wei-Ling Chang 1 , Duen-Ren Hou 2 , Jih-Hwa Guh 1 1 School of Pharmacy, National Taiwan University, Taipei, Taiwan 2 Department of Chemistry, National Central University, Jhong-li, Taoyuan, Taiwan 3 Department of Urology, National Taiwan University Hospital, Taipei, Taiwan * These authors contributed equally to this work Correspondence to: Duen-Ren Hou, email: drhou@cc.ncu.edu.tw Jih-Hwa Guh, email: jhguh@ntu.edu.tw Keywords: triazole-base, non-immunosuppression, PI3K/Akt/mTOR signaling, Myc, autophagy Received: May 15, 2016 Accepted: October 14, 2016 Published: October 19, 2016 ABSTRACT A series of triazole-based small molecules that mimic FTY720-mediated anticancer activity but minimize its immunosuppressive effect have been produced. SPS-7 is the most effective derivative displaying higher activity than FTY720 in anti-proliferation against human hormone-refractory prostate cancer (HRPC). It induced G1 arrest of cell cycle and subsequent apoptosis in thymidine block-mediated synchronization model. The data were supported by a decrease of cyclin D1 expression, a dramatic increase of p21 expression and an associated decrease in RB phosphorylation. c-Myc overexpression replenished protein levels of cyclin D1 indicating that c-Myc was responsible for cell cycle regulation. PI3K/Akt/mTOR signaling pathways through p70S6K- and 4EBP1-mediated translational regulation are critical to cell proliferation and survival. SPS-7 significantly inhibited this translational pathway. Overexpression of Myr-Akt (constitutively active Akt) completely abolished SPS-7-induced inhibitory effect on mTOR/p70S6K/4EBP1 signaling and c-Myc protein expression, suggesting that PI3K/Akt serves as a key upstream regulator. SPS-7 also demonstrated substantial anti-tumor efficacy in an in vivo xenograft study using PC-3 mouse model. Notably, FTY720 but not SPS-7 induced a significant immunosuppressive effect as evidenced by depletion of marginal zone B cells, down-regulation of sphingosine-1-phosphate receptors and a decrease in peripheral blood lymphocytes. In conclusion, the data suggest that SPS-7 is not an immunosuppressant while induces anticancer effect against HRPC through inhibition of Akt/mTOR/p70S6K pathwaysthat down-regulate protein levels of both c-Myc and cyclin D1, leading to G1 arrest of cell cycle and subsequent apoptosis. The data also indicate the potential of SPS-7 since PI3K/Akt signalingis responsive for the genomic alterations in prostate cancer.

Between 2010 and 2016, 110 patients with extremity lymphedema underwent vascularized lymph node (VLN) transfer: groin (G-VLN = 20), supraclavicular (SC-VLN = 54), and right gastroepiploic (RGE-VLN = 36) open and laparoscopic approach. Herein, we discuss the pearls and pitfalls for VLN harvest and compare donor site morbidity and complications. Lymphatic leakage: G-VLN (n = 1) and SC-VLN (n = 1) and one hematoma: SC-VLN were found. Laparoscopic harvest of the RGE-VLN reduces donor site morbidity. However, surgeons experience is imperative to minimize donor site morbidity and complications. J. Surg. Oncol. 2017;115:37-42. © 2016 Wiley Periodicals, Inc.

In light of the unique ability of thiazolidinediones to mediate peroxisome proliferator-activated receptor (PPAR)gamma-independent activation of adenosine monophosphate-activated protein kinase (AMPK) and suppression of interleukin (IL)-6 production, we conducted a screening of an in-house, thiazolidinedione-based focused compound library to identify novel agents with these dual pharmacological activities. Cell-based assays pertinent to the activation status of AMPK and mammalian homologue of target of rapamycin (i.e., phosphorylation of AMPK and p70 ribosomal protein S6 kinase, respectively) and IL-6/IL-6 receptor signaling (i.e., IL-6 production and signal transducer and activator of transcription 3 phosphorylation, respectively) in lipopolysaccharide (LPS)-stimulated THP-1 human macrophages were used to screen this compound library, which led to the identification of compound 53 (N-{4-[3-(1-methyl-cyclohexylmethyl)-2,4-dioxo-thiazolidin-5-ylidene-methyl]-phenyl}-4-nitro-3-trifluoro-methyl-benzenesulfonamide) as the lead agent. Evidence indicates that this drug-induced suppression of LPS-stimulated IL-6 production was attributable to AMPK activation. Furthermore, compound 53-mediated AMPK activation was demonstrated in C-26 colon adenocarcinoma cells, indicating that it is not a cell line-specific event.

Zerumbone, a natural monocyclic sesquiterpene, is the main component of the tropical plant Zingiber zerumbet Smith. Zerumbone induced antiproliferative and apoptotic effects against PC-3 and DU-145, two human hormone-refractory prostate cancer (HRPC) cell lines. Zerumbone inhibited microtubule assembly and induced an increase of MPM-2 expression (specific recognition of mitotic proteins). It also caused an increase of phosphorylation of Bcl-2 and Bcl-xL, two key events in tubulin-binding effect, indicating tubulin-binding capability and mitotic arrest to zerumbone action. Furthermore, zerumbone induced several cellular effects distinct from tubulin-binding properties. First, zerumbone significantly increased, while paclitaxel (as a tubulin-binding control) decreased, Mcl-1 protein expression. Second, paclitaxel but not zerumbone induced Cdk1 activity. Third, zerumbone other than paclitaxel induced Cdc25C downregulation. The data suggest that, in addition to targeting tubulin/microtubule, zerumbone may act on other targets for signaling transduction. Zerumbone induced mitochondrial damage and endoplasmic reticulum (ER) stress as evidenced by the loss of mitochondrial membrane potential and upregulation of GRP-78 and CHOP/GADD153 expression. Zerumbone induced an increase of intracellular Ca(2+) levels, a crosstalk marker between ER stress and mitochondrial insult, associated with the formation of active calpain I fragment. It induced apoptosis through a caspase-dependent way and caused autophagy as evidenced by dramatic LC3-II formation. In summary, the data suggest that zerumbone is a multiple targeting compound that inhibits tubulin assembly and induces a crosstalk between ER stress and mitochondrial insult, leading to apoptosis and autophagy in HRPCs.

BACKGROUND Drug repurposing of phentolamine, an α-adrenoceptor antagonist, as an anticancer agent has been studied in human castration-resistant prostate cancer (CRPC). METHODS Cell proliferation was examined by sulforhodamine B and CFSE staining assays. Cell cycle progression and mitochondrial membrane potential (ΔΨm) were detected by flow cytometric analysis. Protein expression was detected by Western blotting. Effect on tubulin/microtubule was determined using confocal immunofluorescence microscopic examination, microtubule assembly detection, tubulin turbidity assay, and binding assay. Several assessments were used to characterize apoptotic signaling pathways and combinatory effect. RESULTS Phentolamine induced anti-proliferative effect in PC-3 and DU-145, two CRPC cell lines, and P-glycoprotein (P-gp) overexpressing cells. This effect was not significantly reduced in paclitaxel-resistant cells. Rhodamine 123 efflux assay showed that phentolamine was not a P-gp substrate. Phentolamine induced mitotic arrest of the cell cycle and formation of hyperdiploid cells, followed by an increase of apoptosis. Mitotic arrest was confirmed by cyclin B1 up-regulation, Cdk1 activation, and a dramatic increase of mitotic protein phosphorylation. Both in vitro and cellular identification demonstrated that phentolamine, similar to paclitaxel, induced tubulin polymerization and formation of multiple nuclei. Besides, it did not compete with paclitaxel binding on tubulin. Phentolamine induced the phosphorylation and degradation of Bcl-2 and Bcl-xL, two anti-apoptotic Bcl-2 family members, and the loss of ΔΨm indicating the induction of mitochondrial damage. It ultimately induced the activation of caspase-9, -8, and -3 and apoptotic cell death. Moreover, combination treatment with phentolamine and paclitaxel caused a synergistic apoptosis. CONCLUSIONS The data suggest that phentolamine is a potential anticancer agent. In contrast to a wide variety of microtubule disrupting agents, phentolamine induces microtubule assembly, leading to mitotic arrest of the cell cycle which “in turn” induces subsequent mitochondrial damage and activation of related apoptotic signaling pathways in CRPC cells. Furthermore, combination between phentolamine and paclitaxel induces a synergistic apoptotic cell death. Phentolamine has a simple chemical structure and is not a P-gp substrate. Optimization of phentolamine structure may also be a potential approach for further development. Prostate 75:1454–1466, 2015. © 2015 Wiley Periodicals, Inc.

Epi-reevesioside F, a new cardiac glycoside isolated from the root of Reevesia formosana, displayed potent activity against glioblastoma cells. Epi-reevesioside F was more potent than ouabain with IC50 values of 27.3±1.7 vs. 48.7±1.8 nM (P < 0.001) and 45.0±3.4 vs. 81.3±4.3 nM (P < 0.001) in glioblastoma T98 and U87 cells, respectively. However, both Epi-reevesioside F and ouabain were ineffective in A172 cells, a glioblastoma cell line with low Na+/K+-ATPase α3 subunit expression. Epi-reevesioside F induced cell cycle arrest at S and G2 phases and apoptosis. It also induced an increase of intracellular concentration of Na+ but not Ca2+, cleavage and exposure of N-terminus of Bak, loss of mitochondrial membrane potential, inhibition of Akt activity and induction of caspase cascades. Potassium supplements significantly inhibited Epi-reevesioside F-induced effects. Notably, Epi-reevesioside F caused cytosolic acidification that was highly correlated with the anti-proliferative activity. In summary, the data suggest that Epi-reevesioside F inhibits Na+/K+-ATPase, leading to overload of intracellular Na+ and cytosolic acidification, Bak activation and loss of mitochondrial membrane potential. The PI3-kinase/Akt pathway is inhibited and caspase-dependent apoptosis is ultimately triggered in Epi-reevesioside F-treated glioblastoma cells.

Background In a vessel-depleted neck, distant recipient sites may be the only option for secondary free flap reconstruction. While interposition vein grafts and arteriovenous loops can bridge the gap between the recipient and donor pedicle, they are not without risks. In these scenarios, we examinate the reliablity of a radial forearm free flap (RFFF) as an alternative vascular conduit. Patients and methods A retrospective review of cases between March 2005 and May 2016 was performed. Demographic data, prior surgical history, intraoperative details and outcomes were recorded. A total of ten patients, eight male and two female, with a mean age of 54.2 years (range, 39–74) were identified. The RFFF was initially anastomosed to either the thoracoacromial (n = 6) or internal mammary vessels (n = 4) and subsequently served as the recipient pedicle for the second “main” flap, an anterolateral thigh (n = 4), jejunum (n = 3) or fibula flap (n = 3). Results The average RFFF dimensions were 13.8 cm by 5.8 cm. All twenty flaps, ten RFFF and ten "main' flaps survived completely with only one case of minimal epidermal loss. One patient with esophageal reconstruction with jejunum developed a fistula that required closure with a local falp. At a mean follow-up of 18.4 months (range 8–29), the reconstructive goals had been achieved in all cases. Conclusions The RFFF serves as a reliable “vascular bridge” that extends the reach of distant recipient sites to free flaps in secondary head and neck reconstruction.

A dual-mode receiver architecture with tens-MHz channel bandwidth at microwave mode and GHz channel bandwidth at millimeter-wave mode is demonstrated in this work with a tunable active filter for RF channel selection at microwave mode using 0.18 μm SiGe BiCMOS technology. A dual conversion is employed to accommodate the wide-channel-bandwidth 60-GHz mode at the first conversion stage and the high-level-modulation 5-GHz mode is merged to the second conversion stage through sharing the 5-GHz switchable Gilbert IQ mixers with the 60-GHz mode. A tunable RF active filter is inserted between the 5-GHz LNA and the second stage mixer to serve as RF channel selection at the 5-GHz mode with the ability of relaxing the stringent linearity requirement imposed by high-level-modulation scheme. 10 dB gain with a 2-GHz channel bandwidth at the 60-GHz mode and 23 dB gain with a 20 MHz channel bandwidth within the 600 MHz tuning range at 5-GHz mode are demonstrated with a low-flicker-noise corner of less than 60 KHz at the 5-GHz mode because of the use of SiGe HBT as the IQ Gilbert mixer cores at the second conversion stage.

A V-band balanced two-stage power amplifier MMICs with Lange couplers is demonstrated using 0.15 µm GaAs pHEMT technology in this paper. A CPWG-MS-CPWG topology with via holes at the transistors as the transition between coplanar waveguide with backside ground (CPWG) and microstrip (MS) is employed for the two-stage amplifier. CPWG is applied to realize the flip-chip transition interface for both input and output ports of the amplifier and interstage MS matching has the advantage of small size. The structure parameters of the CPWG Lange coupler and matching network are designed and optimized for power combining. Finally, a 60-GHz balanced two-stage power amplifier using a CPWG-MS-CPWG structure delivers the small signal gain of 18 dB, OP 1dB of 12 dBm and P sat of 15 dBm.

The evolution of flight in feathered dinosaurs and early birds over millions of years required flight feathers whose architecture features hierarchical branches. While barb-based feather forms were investigated, feather shafts and vanes are understudied. Here, we take a multi-disciplinary approach to study their molecular control and bio-architectural organizations. In rachidial ridges, epidermal progenitors generate cortex and medullary keratinocytes, guided by Bmp and transforming growth factor β (TGF-β) signaling that convert rachides into adaptable bilayer composite beams. In barb ridges, epidermal progenitors generate cylindrical, plate-, or hooklet-shaped barbule cells that form fluffy branches or pennaceous vanes, mediated by asymmetric cell junction and keratin expression. Transcriptome analyses and functional studies show anterior-posterior Wnt2b signaling within the dermal papilla controls barbule cell fates with spatiotemporal collinearity. Quantitative bio-physical analyses of feathers from birds with different flight characteristics and feathers in Burmese amber reveal how multi-dimensional functionality can be achieved and may inspire future composite material designs. VIDEO ABSTRACT.

The exostosin (EXT) genes encode glycosyltransferases required for glycosaminoglycan chain polymerization in the biosynthesis of heparan sulfate proteoglycans (HSPGs). Mutations in the tumor suppressor genes EXT1 and EXT2 disturb HSPG biosynthesis and cause multiple osteochondroma (MO). How EXT1 and EXT2 traffic within the Golgi complex is not clear. Here, we show that Rotini (Rti), the Drosophila GOLPH3, regulates the retrograde trafficking of EXTs. A reduction in Rti shifts the steady-state distribution of EXTs to the trans-Golgi. These accumulated EXTs tend to be degraded and their re-entrance towards the route for polymerizing GAG chains is disengaged. Conversely, EXTs are mislocalized towards the transitional endoplasmic reticulum/cis-Golgi when Rti is overexpressed. Both loss of function and overexpression of rti result in incomplete HSPGs and perturb Hedgehog signaling. Consistent with Drosophila, GOLPH3 modulates the dynamic retention and protein stability of EXT1/2 in mammalian species. Our data demonstrate that GOLPH3 modulates the activities of EXTs, thus implicating a putative role for GOLPH3 in the formation of MO.

A 2.4/5.8-GHz dual-band programmable-gain upconverter with a constant IF bandwidth is demonstrated using 0.35-µm SiGe BiCMOS technology. Using a current-mode design approach, the input IF bandwidth remains the same at different gain settings. A dual-band LC current combiner is used at the mixer RF output to combine differential signals to a single-ended one at two bands. Then, a wideband amplifier is cascaded after the dual-band mixer. The demonstrated upconverter achieves maximum gain of −4/−3 dB at 2.4/5.8 GHz, respectively. In addition, four gain steps with 5-dB gain difference between each step are controlled by a two-bit digital circuit. The total current consumption is 26 mA at a 4-V supply.

The effect of layout on silicon SBD in CMOS process is studied in this paper. The size of anode area not only affects the series resistance and SBD junction capacitance but also causes serious parasitic effect from cathode to the p-substrate. Typically, an SBD of a small unit anode has a better cut-off frequency than that of a large unit anode. The cutoff frequency of a small anode Schottky diode is about 700 GHz in a standard 0.18 µm CMOS process. However, a SBD with a small unit anode is prone to the effect of p-substrate to N-well pn junction capacitor. This paper has characterized SBDs of different anode sizes with bottom and side-wall effect of p-substrate to N-well to select an optimal unit-anode area by reducing the substrate effect and providing sufficient f T for high frequency applications.

Background Reconstruction in a vessel-depleted neck is challenging. The success rates can be markedly decreased because of unavailability of suitable recipient vessels. In order to obtain a reliable flow, recipient vessels away from the zone of fibrosis, radiation, or infection need to be explored. The aim of this report is to present our experience and clinical outcomes using the retrograde flow coming from the distal transverse cervical artery (TCA) as a source for arterial inflow for complex head and neck reconstruction in patients with a vessel-depleted neck. Methods Between July 2010 and June 2016, nine patients with a vessel-depleted neck underwent secondary head and neck reconstruction using the retrograde TCA as recipient vessel for microanastomosis. The mean age was 49.6 years (range, 36 to 68 years). All patients had previous bilateral neck dissections and all, except one, had also received radiotherapy. Indications included neck contracture release (n = 3), oral (n = 1), mandibular (n = 3) and pharyngoesophageal (n = 2) reconstruction necessitating free anterolateral thigh (n = 3) and medial sural artery (n = 1) perforator flaps, fibula (n = 3) and ileocolon (n = 2) flaps respectively. Results There was 100% flap survival rate with no re-exploration or any partial flap loss. One case of intra-operative arterial vasospasm at the anastomotic suture line was managed intra-operatively with vein graft interposition. There were no other complications or donor site morbidity during the follow-up period. Conclusions In a vessel-depleted neck, the reverse flow of the TCA may be a reliable option for complex secondary head and neck reconstruction in selected patients.

In this paper, we propose An Android Behavior-Based Malware Detection Method using Machine Learning. We improve an Android application sandbox, Droidbox, by inserting a view-identification automatic trigger program which can click mobile applications in the meaningful order. Taking advantage of Droidbox result, we collect the behavior such as network activities, file read/write and permission as the feature data and use different machine learning algorithms to classify malware and evaluate the performance. We use a large number of malware and normal application samples to prove that our method has high accuracy.

A low-noise low-power direct conversion receiver with a differential RF VGA is demonstrated using 0.18um CMOS technology. A topology that uses a differential inductor load for a differential RF VGA is employed for the single-to-differential conversion. Since the common-mode rejection ratio of a differential variable gain amplifier is increased by the mutual magnetic coupling in a differential inductor load, this work achieves noise floor less than 5 dB covering the 5–6 GHz band. Moreover, the conversion gain is around 50 dB and the total current consumption is 4.75 mA at 1.8 V supply voltage.

Between 2010 and 2016, 110 patients with extremity lymphedema underwent vascularized lymph node (VLN) transfer: groin (G-VLN = 20), supraclavicular (SC-VLN = 54), and right gastroepiploic (RGE-VLN = 36) open and laparoscopic approach. Herein, we discuss the pearls and pitfalls for VLN harvest and compare donor site morbidity and complications. Lymphatic leakage: G-VLN (n = 1) and SC-VLN (n = 1) and one hematoma: SC-VLN were found. Laparoscopic harvest of the RGE-VLN reduces donor site morbidity. However, surgeons experience is imperative to minimize donor site morbidity and complications. J. Surg. Oncol. 2017;115:37-42. © 2016 Wiley Periodicals, Inc.

This paper demonstrates a millimeter-wave RF-to-DC converter based on Schottky-barrier diodes using 0.18-µm CMOS technology. The Schottky-barrier diode has a cutoff frequency of 400 GHz and a low turn-on voltage of 0.3 V. In the RF-to-DC quadrupler, the difference in turn-on voltages between the Schottky-barrier diode and n-well to p-substrate parasitic pn junction prevents the pn junction from turning on with an effect similar to the Schottky diode clamp in Schottky TTL circuits. The input matching has a better than 10 dB return loss from 50 GHz to 100 GHz. The RF-to-DC quadrupler generates a 3.15 V DC voltage at 84 GHz.

BACKGROUND: Biliary tract cancer (BTC) is a rapidly progressing cancer with limited response to chemotherapy. First line therapy (gem/cis) was defined in the ABC-02 study (Valle et al.), where a 26% response was seen. HER family receptors are overexpressed and may be involved in tumour proliferation and survival in BTC. Varlitinib, a reversible tyrosine kinase inhibitor of EGFR, HER2, and HER4, shows potent activity as monotherapy in preclinical BTC models and clinical activity in BTC patients (pts) in phase (Ph) 1 trials. We conducted a Ph1b/2 study of varlitinib plus gem/cis in BTC to understand the safety profile and determine the maximum tolerated dose (MTD) of the combination. METHODS: A modified 3+3+3 escalation design was used in Ph1b, with 2 varlitinib dose levels (200 and 300 mg BID) plus gem/cis on days 1 and 8 in a 3-week cycle. The primary objectives are to determine the MTD and to characterize the safety profile. Secondary objectives are to assess the preliminary efficacy and to evaluate the pharmacokinetics of varlitinib and any circulating metabolites. RESULTS: As of 10 Sep 2018, 21 pts were enrolled (11 in 200 mg cohort and 10 in 300 mg cohort, with 9 and 4 evaluable for MTD, respectively). Dose limiting toxicities (DLTs) were observed in 3 pts (1 G3 unconjugated hyperbilirubinemia and 1 G3 ALT transaminitis/G4 AST transaminitis in 200 mg cohort; 1 G4 thrombocytopenia/G3 febrile neutropenia/G3 AST elevation in 300 mg cohort). In 19 pts who were on varlitinib ≥1 month, 7 had partial response and 10 achieved stable disease (all >12 weeks), giving the overall response rate of 37% and the disease control rate of 89%. The median PFS for the 200 mg cohort was 248 days and was not reached for the 300 mg cohort. The most common (≥30%) all-grade adverse events (AEs) regardless of causality were thrombocytopenia (62%), neutropenia (52%), anorexia (38%), nausea (38%), diarrhoea (38%), and anaemia (33%); the most common (≥15%) grade ≥3 AEs were neutropenia (48%), thrombocytopenia (33%), and anaemia (19%). CONCLUSIONS: Varlitinib plus gem/cis was well tolerated in the 200 mg cohort; the 300 mg cohort is ongoing. Preliminary anti-tumour activity was observed. Data will be updated at the time of presentation.

BACKGROUND: Varlitinib is a nanomolar inhibitor of EGFR, HER2, and HER4 and has shown potent anti-tumor activity as monotherapy in preclinical BTC models. During phase (Ph) 1 development, significant tumor shrinkage was observed in biliary tract cancer (BTC) patients (pts). Tissue microarray analysis has revealed that ~70% of BTC pts exhibit HER overexpression, suggesting varlitinib could be beneficial in BTC. METHODS: Data from BTC pts were pooled from 3 Ph1 trials of varlitinib (dosed 200–500 mg BID) in combination with cisplatin and 5-FU/capecitabine (cape) (study 002); oxaliplatin and 5-FU/cape (study 002SG); cisplatin and gemcitabine (study 007). The depth of tumor response, disease control rate (DCR), and treatment-related adverse events (TRAEs) were analysed. RESULTS: As of 12 June 2018, 43 pts were recruited: 12 (27.9%); 10 (23.3%) and 21 (48.8%) from study 002; 002SG and 007 respectively. Studies 002SG and 007 were still ongoing at data cut-off. Twenty (46.5%) pts were male and the median age was 62 years (range, 42–82 years). Most tumors were cholangiocarcinoma (74.4%), followed by gallbladder cancer (16.3%) and carcinoma of the ampulla of Vater (9.3%). Fourteen (32.6%) pts had received ≥1 prior lines of treatment. Of the 37 pts evaluable for efficacy (those with measurable disease and received ≥1 dose of treatment), partial responses were observed in 10 (27.0%) pts and stable disease in 16 (43.2%) pts, with a DCR of 70.3%. The median depth of tumor response was −10.8% (range, −87.1% to 49.5%). Of 43 pts, the most frequent (≥30%) TRAE (any grade) were fatigue (37%), decreased appetite (34%), and nausea (32%) and the most common grade ≥3 TRAE were hyperbilirubinemia (12%), increased AST (9%), and neutropenia (9%). The median PFS data is not matured and will be provided if evaluable at the time of presentation. CONCLUSIONS: Varlitinib with platinum-based chemotherapy has a promising efficacy and safety profile in BTC. A Ph2/3 randomised study of varlitinib and cape in 2nd line BTC and a Ph1b/2 study of varlitinib with platinum-based chemotherapy in 1st line BTC are ongoing.

331 Background: Varlitinib is a nanomolar inhibitor of EGFR, HER2, and HER4 and has shown potent anti-tumor activity as monotherapy in preclinical BTC models. During Phase (Ph) 1 development, significant tumor shrinkage was observed in biliary tract cancer (BTC) patients (pts). Tissue microarray analysis has revealed that ~70% of BTC pts exhibit HER overexpression, suggesting varlitinib could be beneficial in BTC. Methods: Data from BTC pts were pooled from 3 Ph1 trials of varlitinib (dosed 200-500 mg BID) in combination with cisplatin and 5-FU/capecitabine (cape) (Study 002); oxaliplatin and 5-FU/cape (Study 002SG); cisplatin and gemcitabine (Study 007). The depth of tumor response, disease control rate (DCR), and treatment-related adverse events (TRAEs) were analysed. Results: As of 12 June 2018, 43 pts were recruited: 12 (27.9%); 10 (23.3%) and 21 (48.8%) from study 002; 002SG and 007 respectively. 002SG and 007 were still ongoing at data cut-off. 20 (46.5%) pts were male and the median age was 62 years (range 42-82). Most tumors were cholangiocarcinoma (74.4%), followed by gallbladder cancer (16.3%) and carcinoma of the Ampulla of Vater (9.3%). 14 (32.6%) pts had received ≥ 1 prior lines of treatment. Of the 37 pts evaluable for efficacy (those with measurable disease and received ≥ 1 dose of treatment), partial responses were observed in 10 (27.0%) pts and stable disease in 16 (43.2%) pts, with a DCR of 70.3%. The median depth of tumor response was -10.8% (range 49.5% to -87.1%). Of 43 pts, the most frequent (≥ 30%) TRAE (any grade) were fatigue (37%), decreased appetite (34%), and nausea (32%) and the most common Grade ≥ 3 TRAE were hyperbilirubinemia (12%), increased AST (9%), and neutropenia (9%). The median PFS data is not matured and will be provided if evaluable at the time of presentation. Conclusions: Varlitinib with platinum-based chemotherapy has a promising efficacy and safety profile in BTC. A Ph2/3 randomised study of varlitinib and cape in 2nd line BTC and a Ph1b/2 study of varlitinib with platinum-based chemotherapy in 1st line BTC are ongoing. Clinical trial information: NCT02648425, NCT02435927, and NCT02992340.

319 Background: BTC is a rapidly progressing cancer with limited response to chemotherapy. First line therapy (gem/cis) was defined in the ABC-02 study (Valle et al), where a 26% response was seen. HER family receptors are overexpressed and may be involved in tumour proliferation and survival in BTC. Varlitinib, a reversible tyrosine kinase inhibitor of EGFR, HER2, and HER4, shows potent activity as monotherapy in preclinical BTC models and clinical activity in BTC patients (pts) in phase (ph) 1 trials. We conducted a ph Ib/2 study of varlitinib plus gem/cis in BTC to understand the safety profile and determine the maximum tolerated dose (MTD) of the combination. Methods: A modified 3+3+3 escalation design was used in Ph1b, with 2 varlitinib dose levels (200 and 300 mg BID) plus gem/cis on Day 1 and 8 in a 3 week cycle. The primary objectives are to determine the MTD and to characterize the safety profile. Secondary objectives are to assess the preliminary efficacy and to evaluate the pharmacokinetics of varlitinib and any circulating metabolites. Results: As of 10 Sep 2018, 21 pts were enrolled (11 in 200 mg cohort and 10 in 300 mg cohort, with 9 and 4 evaluable for MTD, respectively). Dose limiting toxicities (DLTs) were observed in 3 pts (1 G3 unconjugated hyperbilirubinemia and 1 G3 ALT transaminitis/G4 AST transaminitis in 200 mg cohort; 1 G4 thrombocytopenia/G3 febrile neutropenia/G3 AST elevation in 300 mg cohort). In 19 pts who were on varlitinib ≥ 1 month, 7 had partial response and 10 achieved stable disease (all > 12 weeks), giving the overall response rate of 37% and the disease control rate of 89%. The median PFS for the 200 mg cohort was 248 days and was not reached for the 300 mg cohort. The most common (≥ 30%) all-grade adverse events (AEs) regardless of causality were thrombocytopenia (62%), neutropenia (52%), anorexia (38%), nausea (38%), diarrhoea (38%), and anaemia (33%); the most common (≥ 15%) grade ≥ 3 AEs were neutropenia (48%), thrombocytopenia (33%), and anaemia (19%). Conclusions: Varlitinib plus gem/cis was well tolerated in the 200 mg cohort; the 300 mg cohort is ongoing. Preliminary anti-tumour activity was observed. Data will be updated at the time of presentation. Clinical trial information: NCT02992340.

Background: Dihydroorotate dehydrogenase (DHODH), catalyzing the ubiquinone-mediated oxidation of dihydroorotate to orotate, is the rate-limiting enzyme in the de novo synthesis of pyrimidines, and as such may control the rate of cell division. The enzyme is localised on the outer side of the inner mitochondrial membrane, and links both the electron transport chain to pyrimidine production and thus to the maintenance of cell viability. DHODH inhibitors were identified in a myeloid differentiation screen using an ER-HoxA9 GMP cell line, and ASLAN003, a novel small molecule DHODH oral inhibitor, has been found to be a potent inducer of myeloid differentiation in AML cell lines. ASLAN003 also demonstrated the ability to reduce leukemic burden and extend survival in AML xenograft models. ASLAN003 has previously been shown to exhibit a safe and tolerable profile in prior phase I studies in healthy volunteers. Methods: A multicenter, single arm phase IIA study was initiated to evaluate ASLAN003 monotherapy administered as a 28-day cycle in patients with AML who are ineligible for standard therapy. The primary objective is to determine the optimum dose of ASLAN003 in this AML cohort based on efficacy (Overall Complete Remission Rate, % of complete remission [CR] + CR with incomplete hematologic recovery [CRi]), tolerability and safety. The secondary objective is to assess the pharmacokinetics (PK) of ASLAN003 and its metabolites and to further assess the efficacy based on relapse-free survival and clinical benefit rate (CBR, % of partial remission + CR + CRi). Exploratory objectives are to examine the myeloid differentiation effects of ASLAN003 ex vivo and explore possible relationships between the clinical response and molecular profile of leukemic cells. The study contains 3 cohorts for the optimum dose determination (100 mg, 200 mg, and 300 mg once daily [QD], with planned enrollment for 6 patients for each cohort), and an additional expansion cohort with the selected optimum dose (20 patients). Results: Enrollment started in December 2017. As of 12 July 2018, 10 patients were enrolled and treated (6 in the 100 mg QD cohort and 4 in the 200 mg QD cohort). Although the data are immature, two patients to date have exhibited some evidence of clinical activity (one per cohort). A patient in the 100 mg QD cohort, with a baseline peripheral blood blast of 27%, experienced a reduction to 6% on Cycle 3 Day 10 (C3D10), coupled with an upward trend in the percentage of neutrophils (16% at baseline, 64% on C3D10). The patient had underlying chronic lung infection, but also showed suspected symptoms of differentiation syndrome (dyspnea, leukocytosis). After 126 days of ASLAN003 initiation, the patient expired due to AML related clinical deterioration. The second patient in the 200 mg QD cohort experienced a decrease in bone marrow blasts from 26% at baseline, to 12% on C2D1. Concomitantly, there was a slight decrease in peripheral blood blasts with an increase in neutrophil percentages from 7% to 51%. The patient remains on study with further efficacy data awaited. To date, the safety profile is consistent with the previous healthy volunteer studies. Treatment-related adverse events (AEs) are listed in Table 1. The most frequent treatment-related AEs include nausea (n=2, 20%) and leukocytosis (n=2, 20%). Two treatment-related Grade ≥ 3 AEs were observed (Grade 3 anaemia and Grade 3 leukocytosis). The study continues and is currently enrolling to the 200 mg cohort. Conclusion: At the date of submission, this is the first report of clinical activity of a DHODH inhibitor in AML patients. Monotherapy with ASLAN003 was well tolerated and has showed encouraging signs of clinical activity in AML patients. This study is on-going and the optimal dose for AML has not yet been determined. Safety, PK and efficacy data will be updated at the time of presentation. Clinical trial information: NCT03451084 Disclosures Chng: ASLAN Pharmaceuticals: Research Funding. McHale:ASLAN Pharmaceuticals: Employment, Equity Ownership. Hsieh:ASLAN Pharmaceuticals: Employment, Equity Ownership. Shih:ASLAN Pharmaceuticals: Employment; AstraZeneca Taiwan: Employment. McIntyre:ASLAN Pharmaceuticals: Consultancy. Kwek:ASLAN Pharmaceuticals: Employment. Chang:ASLAN Pharmaceuticals: Employment. Lindmark:ASLAN Pharmaceuticals: Employment, Equity Ownership.