CDK12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS1-ErbB-PI3K signaling.

Cyclin-dependent kinase 12 (CDK12) has emerged as an effective therapeutic target due to its ability to regulate DNA damage repair in human cancers, but little is known about the role of CDK12 in driving tumorigenesis. Here, we demonstrate that CDK12 promotes tumor initiation as a novel regulator of cancer stem cells (CSCs) and induces anti-HER2 therapy resistance in human breast cancer. High CDK12 expression caused by concurrent amplification of CDK12 and HER2 in breast cancer patients is associated with disease recurrence and poor survival. CDK12 induces self-renewal of breast CSCs and in vivo tumor-initiating ability, and also reduces susceptibility to trastuzumab. Furthermore, CDK12 kinase activity inhibition facilitates anticancer efficacy of trastuzumab in HER2+ tumors, and mice bearing trastuzumab-resistant HER2+ tumor show sensitivity to an inhibitor of CDK12. Mechanistically, the catalytic activity of CDK12 is required for the expression of genes involved in the activation of ErbB-PI3K-AKT or WNT-signaling cascades. These results suggest that CDK12 is a major oncogenic driver and an actionable target for HER2+ breast cancer to replace or augment current anti-HER2 therapies.

Comparison of core-needle biopsy and repeat fine-needle aspiration for thyroid nodules with inconclusive initial cytology.

PURPOSE: We aimed to compare the efficacy of ultrasound-guided core-needle biopsy (CNB) with repeat fine-needle aspiration (rFNA) cytology in thyroid nodules with inconclusive results in initial fine-needle aspiration cytology. METHODS: We studied 402 patients who required a repeat biopsy of thyroid nodules using ultrasound-guided CNB (n = 192) or rFNA (n = 210) because of inconclusive results in initial FNA, corresponding to categories I, III, and IV of the Bethesda System for Reporting Thyroid Cytopathology. If repeat biopsy results were benign (category II), suspicious malignancy (category V), or malignancy (category VI), they were defined as "diagnostic results". The diagnostic yield and performances of repeat biopsy were analyzed and compared between the rFNA and CNB groups. RESULTS: The diagnostic results were obtained significantly higher in the CNB group than in the rFNA group (72.4% vs. 52.4%; P < 0.001). In the subgroup analysis, the diagnostic results were significantly higher in the CNB group than in the rFNA group for patients of categories I and III (P < 0.001 in both) in initial FNA. However, in patients with category IV nodules, there were no significant differences in diagnostic results between the two groups (P = 0.46). CONCLUSION: Compared to rFNA, ultrasound-guided CNB is useful and effective as a repeat biopsy option for thyroid nodules with non-diagnostic results (category I) and atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS) (category III) in initial FNA.

Inflammatory mediators of prostate epithelial cells stimulated with Trichomonas vaginalis promote proliferative and invasive properties of prostate cancer cells.

BACKGROUND: Trichomonas vaginalis (Tv) is the most common sexually transmitted parasite. It is detected in prostatic tissue of benign prostatic hyperplasia, prostatitis, and prostate cancer (PCa) and has been suggested to cause chronic prostatitis. Moreover, up to 20% of all cancers worldwide are associated with chronic inflammation. Here, we investigated whether inflammatory mediators produced by normal human prostate epithelial cells (RWPE-1) stimulated with Tv could promote growth and invasiveness of PCa cells. METHODS: Conditioned medium of RWPE-1 cells was prepared by stimulating them with Tv (trichomonad-conditioned medium [TCM]) and without Tv (conditioned medium [CM]). Promotion of PCa cells (PC3, DU145, and LNCaP) was assessed by wound healing, proliferation, and invasion assays. RESULTS: We observed that the production of interleukin (IL)-1ß, IL-6, CCL2, CXCL8, prostaglandin-E2 (PGE2 ), and COX2 by RWPE-1 cells was increased by stimulating them with Tv. When PCa cells were incubated with TCM, their proliferation, invasion, and migration increased. Moreover, they showed increased epithelial-mesenchymal transition (EMT)-related markers by a reduction in epithelial markers and an increase in mesenchymal markers. In vivo, xenograft tumor tissues injected with TCM also showed increased expression of cyclin D1 and proliferating cell nuclear antigen, as well as induction of EMT. Receptors and signal molecules of PCa cells increased in response to exposure to TCM, and blocking receptors (CXCR1, CXCR2, C-C chemokine receptor 2, glycoprotein 130, EP2, and EP4) reduced the proliferation of PCa cells with decreased production of cytokines (CCL2, IL-6, and CXCL8) and PGE2 , and expression of NF-κB and Snail1. CONCLUSIONS: Our results suggest that Tv infection may be one of the factors creating the supportive microenvironment to promote proliferation and invasiveness of PCa cells.

Experimental rat prostatitis caused by Trichomonas vaginalis infection.

BACKGROUND: Trichomonas vaginalis (T. vaginalis) is the most common sexually transmitted parasite. It has been detected in prostatic tissue of patients with prostatitis and reported to be associated with chronic prostatitis and benign prostatic hyperplasia as well as prostate cancer. Recently, experimental rodent models of prostatitis induced by pathogen infection have been developed. However, there have so far been no reports of prostatitis caused by T. vaginalis infection in animals. Here, we investigated whether infection with T. vaginalis via the rat urethra could cause prostatitis. METHODS: T. vaginalis was injected into prostate through urethra of rat (Wistar rats), and the rats were killed 1, 2, or 4 weeks later. The presence of T. vaginalis trophozoites in the rat prostates was examined by immunohistochemistry, and pathological changes of the prostate were observed by hematoxylin-eosin staining and evaluated by grading from 0 to 5 for inflammatory cell infiltration, acinar changes, and interstitial fibrosis. Infiltrated mast cells were observed by toluidine blue staining of rat prostate tissue. Chemokine C-C motif ligand 2 (CCL2) levels of the rat prostates were measured by ELISA. RESULTS: T. vaginalis trophozoites were observed in acini in the prostates of the injected rats. The prostate tissues had higher pathological scores, and 83% (5/6) and 100% (6/6) of the ventral and dorsolateral lobes (n = 6), respectively, were inflamed. Infiltration and degranulation of mast cells were observed at higher rates in prostate sections of the T. vaginalis-infected rats. Also, prostate tissues of the injected rats had increased CCL2 levels. CONCLUSIONS: Injection of T. vaginalis in rats caused prostatitis as revealed by pathologic changes, mast cell infiltration and increased CCL2 production. Therefore, this study provides the first evidence that T. vaginalis infection in rats causes prostatitis.

NDR-effect vertical-illumination-type Ge-on-Si avalanche photodetector.

We present the enhanced performances of a vertical-illumination-type Ge-on-Si avalanche photodetector based on internal RF-gain effects operating up to 50 Gb/s. A fabricated Ge-on-Si avalanche photodetector (APD) exhibits three operational voltage regions associated with different aspects of the current (DC) gain and bandwidth characteristics. The measured current-voltage (I-V) curve of a Ge-on-Si APD exhibits a negative photoconductance (negative differential resistance [NDR]) in a high bias region beyond the avalanche breakdown voltage (V br ), where a device shows good eye openings up to 50 Gb/s (non-return-to-zero [NRZ] signal) with further improved signal-to-noise ratios and signal amplitudes. A ROSA packaged module, wherein a fabricated Ge-on-Si APD is wire-bonded to a commercial TIA with a ∼75% optical alignment for λ∼1310 nm and biased at a lower voltage than the V br , exhibits the sensitivities of -18.9 and -15.3 dBm for 30 and 35 Gb/s, respectively, and -13.9 dBm for 40 Gb/s at a 10-12 bit error rate. The experimental results indicate that considerable improvement in a module performance can be expected by utilizing the Ge-on-Si APD operated in the NDR region with a properly customized TIA.

Silicon photonic receiver and transmitter operating up to 36 Gb/s for λ~1550 nm.

We present the hybrid-integrated silicon photonic receiver and transmitter based on silicon photonic devices and 65 nm bulk CMOS interface circuits operating over 30 Gb/s with a 10(-12) bit error rate (BER) for λ ~1550nm. The silicon photonic receiver, operating up to 36 Gb/s, is based on a vertical-illumination type Ge-on-Si photodetector (Ge PD) hybrid-integrated with a CMOS receiver front-end circuit (CMOS Rx IC), and exhibits high sensitivities of -11 dBm, -8 dBm, and -2 dBm for data rates of 25 Gb/s, 30 Gb/s and 36 Gb/s, respectively, at a BER of 10(-12). The measured energy efficiency of the Si-photonic receiver is 2.6 pJ/bit at 25 Gb/s with an optical input power of -11 dBm, and 2.1 pJ/bit at 36 Gb/s with an optical power of -2 dBm. The hybrid-integrated silicon photonic transmitter, comprised of a depletion-type Mach-Zehnder modulator (MZM) and a CMOS driver circuit (CMOS Tx IC), shows better than 5.7 dB extinction ratio (ER) for 25 Gb/s, and 3 dB ER for 36 Gb/s. The silicon photonic transmitter achieves the data transmission with less than 10(-15) BER at 25 Gb/s, 10(-14) BER at 28 Gb/s, and 6 x 10(-13) BER with the energy efficiency of ~6 pJ/bit at 30 Gb/s.

Histopathological analyses of diabetic nephropathy in sucrose-fed Otsuka Long-Evans Tokushima fatty rats.

BACKGROUND: Otsuka Long-Evans Tokushima fatty (OLETF) rats are an established model of diabetic nephropathy. However, diabetes and diabetic nephropathy (DN) in OLETF rats develop later than in other animal type 2 diabetes models. OBJECTIVES: This study was conducted to investigate the serial changes in the histopathological characteristics of DN in sucrose-fed OLETF rats by biochemical and morphometric analyses. METHODS: We conducted sucrose feeding to examine the progression of DN. One group of OLETF rats was given water containing 30% sucrose ad libitum (SO) and the other group was given water without 30% sucrose (TO). Consecutive observations were made at 4-week intervals from 16 to 50 weeks of age in TO rats, and from 16 to 42 weeks of age in SO rats. Examination parameters included body weight, serum glucose level, urine albumin-to-creatinine ratio (UACR), light microscopy (LM) and electron microscopy (EM). RESULTS: The UACR was over 300 mg/g in 32-week-old SO rats (after 16 weeks of sucrose feeding) and in 38-week-old TO rats. LM indicated that glomerular hypertrophy and mesangial matrix expansion in SO rats increased compared to that of age-matched TO rats especially at 42 weeks of age (p < 0.05). EM also showed that glomerular basement membrane thickness and podocyte foot process width of SO rats were significantly greater than those of age-matched TO rats (p < 0.05). CONCLUSION: Our results suggested that dietary manipulation by sucrose feeding may cause deterioration of DN and could hasten the onset of diabetes and DN in OLETF rats.

Compact-sized high-modulation-efficiency silicon Mach-Zehnder modulator based on a vertically dipped depletion junction phase shifter for chip-level integration.

We present small-sized depletion-type silicon Mach-Zehnder (MZ) modulator with a vertically dipped PN depletion junction (VDJ) phase shifter based on a CMOS compatible process. The fabricated device with a 100 µm long VDJ phase shifter shows a VπLπ of ∼0.6 V·cm with a 3 dB bandwidth of ∼50 GHz at -2 V bias. The measured extinction ratios are 6 and 5.3 dB for 40 and 50 Gb/s operation under 2.5 Vpp differential drive, respectively. On-chip insertion loss is 3 dB for the maximum optical transmission. This includes the phase-shifter loss of 1.88 dB/100 µm, resulting mostly from the extra optical propagation loss through the polysilicon-plug structure for electrical contact, which can be readily minimized by utilizing finer-scaled lithography nodes. The experimental result indicates that a compact depletion-type MZ modulator based on the VDJ scheme can be a potential candidate for future chip-level integration.

Mast cell number, substance P and vasoactive intestinal peptide in irritable bowel syndrome with diarrhea.

BACKGROUND: Recent studies have shown that mast cells play an important role in irritable bowel syndrome (IBS). We investigated the relationship between mast cells and the gut hormones substance P and vasoactive intestinal peptide (VIP) in irritable bowel syndrome with diarrhea (IBS-D). METHODS: Colonoscopic biopsies were performed on the rectal mucosa of 43 subjects (IBS-D patients: 22, healthy volunteers: 21) diagnosed according to the Rome III criteria. Mast cells, and substance P & VIP were evaluated by quantitative immunohistology and image analysis. Mast cells were counted as tryptase-positive cells in the lamina propria, and substance P and VIP levels were expressed as percentages of total areas of staining. RESULTS: Mast cell counts were higher in IBS-D patients than healthy volunteers (9.6 ± 3.3 vs. 5.7 ± 2.5/high power field (HPF), p < 0.01). Substance P was also elevated (0.11 ± 0.08% vs. 0.03 ± 0.02 %, p < 0.01) while VIP was only high in women with IBS-D. Mast cell counts were positively correlated with levels of substance P & VIP in women but not men (women: r = 0.625, p < 0.01 for substance P and r = 0.651, p < 0.01 for VIP). However, mast cell counts were not correlated with IBS symptoms including abdominal pain. CONCLUSION: Mast cells are activated leading to the raised levels of substance P & VIP in IBS-D patients. However, the correlation between mast cells and levels of substance P & VIP differs according to gender.

High-performance photoreceivers based on vertical-illumination type Ge-on-Si photodetectors operating up to 43 Gb/s at λ~1550nm.

We present high-sensitivity photoreceivers based on a vertical- illumination-type 100% Ge-on-Si p-i-n photodetectors (PDs), which operate up to 50 Gb/s with high responsivity. A butterfly-packaged photoreceiver using a Ge PD with 3-dB bandwidth (f(-3dB)) of 29 GHz demonstrates the sensitivities of -10.15 dBm for 40 Gb/s data rate and -9.47 dBm for 43 Gb/s data rate, at BER of 10(-12) and λ ~1550 nm. Also a photoreceiver based on a Ge PD with f(-3dB)~19 GHz shows -14.14 dBm sensitivity at 25 Gb/s operation. These results prove the high performance levels of vertical-illumination type Ge PDs ready for practical high-speed network applications.

Collision of three histologically distinct endometrial cancers of the uterus.

A collision tumor is defined by the presence of two separate masses in one organ, which are pathologically distinct. We described a 70-yr-old patient who complained of abnormal vaginal bleeding with a collision tumor of the uterine corpus. The patient received total hysterectomy, bilateral salphingo-oophorectomy, bilateral pelvic-paraaortic lymphadenectomy, omentectomy, and intraperitoneal chemotherapy. The uterine corpus revealed three separate masses, which were located at the fundus, anterior and posterior wall. Each tumor revealed three pathologically different components, which were malignant mixed müllerian tumor, papillary serous carcinoma, and endometrioid adenocarcinoma. Among these components, only the papillary serous carcinoma component invaded the underlying myometrium and metastasized to the regional lymph node. Adjuvant chemotherapy and radiation therapy were performed. The patient is still alive and has been healthy for the last 8 yr. We have reviewed previously reported cases of collision tumors which have occurred in the uterine corpus.

A case of elderly-onset Crescentic Henoch-Schönlein purpura nephritis with hypocomplementemia and positive MPO-ANCA.

Henoch-Schönlein purpura (HSP) is common in childhood and often self-limiting. There have been limited studies on elderly-onset HSP nephritis (HSPN). A 76-yr-old man was transferred to our hospital with a 1-month history of oliguria, abdominal pain, edema and palpable purpura in the legs. Three months ago, he was admitted to another hospital with jaundice, and consequently diagnosed with early common bile duct cancer. The patient underwent a Whipple's operation. Antibiotics were administrated because of leakage in the suture from the surgery. However, he showed progressive renal failure with edema and purpura in the legs. Laboratory investigations showed serum creatinine 6.4 mg/dL, 24-hr urine protein 8,141 mg/day, myeloperoxidase anti-neutrophil cytoplasmic antibodies (MPO-ANCA) 1:40 and C(3) below 64.89 mg/dL. Renal biopsy showed crescentic glomerulonephritis, as well as mesangial and extracapillary Ig A deposition. We started steroid therapy and hemodialysis, but he progressed to end-stage renal failure and he has been under maintenance hemodialysis. We describe elderly onset HSPN with MPO-ANCA can be crescentic glomerulonephritis rapidly progressed to end stage renal failure.

Low-voltage high-performance silicon photonic devices and photonic integrated circuits operating up to 30 Gb/s.

We present high performance silicon photonic circuits (PICs) defined for off-chip or on-chip photonic interconnects, where PN depletion Mach-Zehnder modulators and evanescent-coupled waveguide Ge-on-Si photodetectors were monolithically integrated on an SOI wafer with CMOS-compatible process. The fabricated silicon PIC(off-chip) for off-chip optical interconnects showed operation up to 30 Gb/s. Under differential drive of low-voltage 1.2 V(pp), the integrated 1 mm-phase-shifter modulator in the PIC(off-chip) demonstrated an extinction ratio (ER) of 10.5dB for 12.5 Gb/s, an ER of 9.1dB for 20 Gb/s, and an ER of 7.2 dB for 30 Gb/s operation, without adoption of travelling-wave electrodes. The device showed the modulation efficiency of V(π)L(π) ~1.59 Vcm, and the phase-shifter loss of 3.2 dB/mm for maximum optical transmission. The Ge photodetector, which allows simpler integration process based on reduced pressure chemical vapor deposition exhibited operation over 30 Gb/s with a low dark current of 700 nA at -1V. The fabricated silicon PIC(intra-chip) for on-chip (intra-chip) photonic interconnects, where the monolithically integrated modulator and Ge photodetector were connected by a silicon waveguide on the same chip, showed on-chip data transmissions up to 20 Gb/s, indicating potential application in future silicon on-chip optical network. We also report the performance of the hybrid silicon electronic-photonic IC (EPIC), where a PIC(intra-chip) chip and 0.13µm CMOS interface IC chips were hybrid-integrated.

Effects of granulocyte-colony stimulating factor (G-CSF) on diabetic cardiomyopathy in Otsuka Long-Evans Tokushima fatty rats.

BACKGROUND: Diabetic cardiomyopathy (CMP) is a common and disabling disease in diabetic patients, however no effective treatments have been developed. Although granulocyte-colony stimulating factor (G-CSF) improves heart function in myocardial infarction, its effect on non-ischemic CMP such as diabetic CMP is unknown. In the present study, we investigated the effects of G-CSF on diabetic CMP in a rat model of type II diabetes. METHODS: Twenty 7-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF: a rat model of diabetes) rats and 10 male Long-Evans Tokushima Otsuka (LETO: normal controls) rats were used. All of the LETO and 8 OLETF rats were fed on tap water while the rest were fed on sucrose-containing water. After 10 weeks, saline or recombinant human G-CSF (100 µg/kg/day) was injected intraperitoneally for 5 days. Blood levels of glucose, total cholesterol and triglyceride, and Doppler echocardiograms for diastolic dysfunction were obtained just before and 4 weeks after the saline or G-CSF treatment. Light microscopy, electron microscopy (EM) and immunohistochemistry for transforming growth factor-ß were employed to examine myocardial histology 4 weeks after the saline or G-CSF treatment. RESULTS: Diastolic dysfunction developed at 17 weeks (before the saline or G-CSF treatment) in the OLETF rats whether or not they were fed sucrose water, but were more severe in those fed sucrose water. Four weeks after saline or G-CSF treatment, diastolic function had recovered in the G-CSF-treated group regardless of sucrose water feeding, and perivascular and/or interstitial fibrosis in the G-CSF-treated group had decreased significantly. TGF-ß immunoreactivity in the interstitial and perivascular tissue was also reduced in the G-CSF-treated group, and EM studies revealed less severe disruption of myofilaments and mitochondrial cristae, and decreased collagen deposition. CONCLUSIONS: G-CSF can ameliorate cardiac diastolic dysfunction and morphological damage, especially fibrosis of the myocardium, in OLETF rats with diabetic CMP.

Prevention of free fatty acid-induced hepatic lipotoxicity by carnitine via reversal of mitochondrial dysfunction.

BACKGROUND: Mitochondria are the main sites for fatty acid oxidation and play a central role in lipotoxicity and nonalcoholic steatohepatitis. AIMS: We investigated whether carnitine prevents free fatty acid (FFA)-induced lipotoxicity in vitro and in vivo. METHODS: HepG2 cells were incubated with FFA, along with carnitine and carnitine complexes. Mitochondrial ß-oxidation, transmembrane potential, intracellular ATP levels and changes in mitochondrial copy number and morphology were analysed. Otsuka Long-Evans Tokushima Fatty and Long-Evans Tokushima Otsuka rats were segregated into three experimental groups and fed for 8 weeks with (i) normal chow, (ii) a methionine choline-deficient (MCD) diet or (iii) an L-carnitine-supplemented MCD diet. RESULTS: Carnitine prevented FFA-induced apoptosis (16% vs. 3%, P < 0.05). FFA treatment resulted in swollen mitochondria with increased inner matrix density and loss of cristae. However, mitochondria co-treated with carnitine had normal ultrastructure. The mitochondrial DNA copy number was higher in the carnitine treatment group than in the palmitic acid treatment group (375 vs. 221 copies, P < 0.05). The carnitine group showed higher mitochondrial ß-oxidation than did the control and palmitic acid treatment groups (597 vs. 432 and 395 ccpm, P < 0.05). Carnitine treatment increased the mRNA expression of carnitine palmitoyltransferase 1A and peroxisome proliferator-activated receptor-γ, and carnitine-lipoic acid further augmented the mRNA expression. In the in vivo model, carnitine-treated rats showed lower alanine transaminase levels and lesser lobular inflammation than did the MCD-treated rats. CONCLUSIONS: Carnitine and carnitine-lipoic acid prevent lipotoxicity by increasing mitochondrial ß-oxidation and reducing intracellular oxidative stress.

Thermochemical Mechanism of the Epoxy-Glutamic Acid Reaction with Sn-3.0 Ag-0.5 Cu Solder Powder for Electrical Joining.

An epoxy-based solder paste (ESP) is a promising alternative to conventional solder pastes to improve the reliability of fine-pitch electrical joining because the epoxy encapsulates the solder joint. However, development of an appropriate epoxy formulation and investigation of its reaction mechanism with solder powder is challenging. In this study, we demonstrate a newly designed ESP consisting of diglycidyl ether of bisphenol F (DGEBF) resin, Sn-3.0 Ag-0.5 Cu (SAC305) solder powder, and L-glutamic acid (Glu), which is a proteinogenic amino acid for biosynthesis of proteins in living systems. The mechanism of the thermochemical reaction was explored and tentatively proposed, which reveals that the products of the reaction between SAC305 and Glu function as catalysts for the etherification of epoxides and alcohols produced by chemical bonding between DGEBF and Glu, consequently leading to highly crosslinked polymeric networks and an enhancement of impact resistance. Our findings provide further insight into the mechanism of the reaction between various formulations comprising an epoxy, amino acid, and solder powder, and their potential use as ESPs for electrical joining.

Is There Pathological Uniformity between the Periphery and Center of a Gastrointestinal Stromal Tumor?

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors and have some malignant potential. Mitotic count is important for predicting the malignant potential of GISTs. Proper treatment of GISTs requires accurate pathological diagnosis. In general, endoscopic ultrasound-guided fine-needle aspiration and deep biopsy are used for pathological diagnosis of GIST before making decisions about surgery. This study sought to evaluate the pathological uniformity of gastric GISTs for mitotic index of the center and periphery of the GIST. METHODS: We retrospectively reviewed the data of 37 gastric GIST patients who underwent wedge resection at Hanyang University Hospital. We used Armed Forces Institute of Pathology criteria to classify gastric GISTs. To determine the pathological uniformity of gastric GISTs, we compared GIST risk stratification between the center and periphery of GISTs. RESULTS: The mean size of GISTs was 3.56 ± 2.10 cm. Three lesions were located in the antrum, 11 in the fundus, 9 in the cardia, and 14 in the body. The mean age of patients was 58.65 ± 9.44 years; 18 patients were male and 19 were female. Thirty-five patients (94.6%) showed the same level of risk stratification between the center and periphery of gastric GISTs, while two patients (5.4%) presented different levels of risk between the two sites. No significant difference in mitotic count was observed between the two sites (kappa value = 0.863; p = 0.001). CONCLUSIONS: Mitotic index category (either more than five mitoses per high-power field or five or fewer mitoses per high-power field) of GISTs showed good concurrence between the center and periphery.

High-sensitivity 10 Gbps Ge-on-Si photoreceiver operating at lambda approximately 1.55 microm.

We present a high-sensitivity photoreceiver based on a vertical- illumination-type 100% Ge-on-Si photodetector. The fabricated p-i-n photodetector with a 90 microm-diameter mesa shows the -3 dB bandwidth of 7.7 GHz, and the responsivity of 0.9 A/W at lambda approximately 1.55 microm, corresponding to the external quantum efficiency of 72%. A TO-can packaged Ge photoreceiver exhibits the sensitivity of -18.5 dBm for a BER of 10(-12) at data rate of 10 Gbps. This result proves the capability of a cost-effective 100% Ge-on-Si photoreceiver which can readily replace the III-V counterparts for optical communications.

Clinicopathological significance of nuclear PTEN expression in colorectal adenocarcinoma.

AIMS: Tumour suppressor phosphatase and tensin homologue (PTEN) is an important negative regulator for the PIP3/Akt signalling pathway that promotes cell proliferation and inhibits apoptosis. Inactivation of PTEN by mutation, deletion and promoter hypermethylation has been demonstrated in a range of cancers. The aim was to investigate whether the loss of nuclear PTEN protein expression correlates with conventional clinicopathological parameters and patient survival. METHODS AND RESULTS: Immunohistochemistry staining for PTEN was performed on a tissue microarray of 19 samples of normal colonic mucosa, 14 adenomatous polyps, 482 adenocarcinomas and 56 metastatic lymph nodes. All 19 normal colonic mucosa samples (100%) were positive and 12 (85.7%) out of 14 adenomatous polyps were positive for PTEN. However, only 241 (50.0%) of the 482 colorectal adenocarcinomas and 26 (46.4%) of the 56 metastatic lymph nodes were positive for PTEN. Loss of PTEN expression was related to defective mismatch repair protein expression and colonic localization rather than rectal localization. On univariate survival analysis, patients with PTEN- adenocarcinoma revealed a poor overall and disease-free survival (P = 0.030 and P = 0.046, respectively). On multivariate analysis, a significant difference was observed in patients with stage II cancer that was not observed in other stages. CONCLUSIONS: Nuclear PTEN expression gradually decrease during the normal-adenoma-adenocarcinoma-metastasis sequence, which suggests an important role for PTEN in carcinogenesis. Moreover, loss of nuclear PTEN expression was a marker of poor clinical outcome in patients with stage II colorectal cancer.