A highly conductive, robust, self-healable, and thermally responsive liquid metal-based hydrogel for reversible electrical switches.

This study introduces a thermally responsive smart hydrogel with enhanced electrical properties achieved through volume switching. This advancement was realized by incorporating multiscale liquid metal particles (LMPs) into the PNIPAM hydrogel during polymerization, using their inherent elasticity and conductivity when deswelled. Unlike traditional conductive additives, LMPs endow the PNIPAM hydrogel with a remarkably consistent volume switching ratio, significantly enhancing electrical switching. This is attributed to the minimal nucleation effect of LMPs during polymerization and their liquid-like behavior, like vacancies in the polymeric hydrogel under compression. The PNIPAM/LMP hydrogel exhibits the highest electrical switching, with an unprecedented switch of 6.1 orders of magnitude. Even after repeated swelling/deswelling cycles that merge some LMPs and increase the conductivity when swelled, the hydrogel consistently maintains an electrical switch exceeding 4.5 orders of magnitude, which is still the highest record to date. Comprehensive measurements reveal that the hydrogel possesses robust mechanical properties, a tissue-like compression modulus, biocompatibility, and self-healing capabilities. These features make the PNIPAM/LMP hydrogel an ideal candidate for long-term implantable bioelectronics, offering a solution to the mechanical mismatch with dynamic human tissues.

Functional succinate dehydrogenase deficiency is a common adverse feature of clear cell renal cancer.

Reduced succinate dehydrogenase (SDH) activity resulting in adverse succinate accumulation was previously considered relevant only in 0.05 to 0.5% of kidney cancers associated with germline SDH mutations. Here, we sought to examine a broader role for SDH loss in kidney cancer pathogenesis/progression. We report that underexpression of SDH subunits resulting in accumulation of oncogenic succinate is a common feature in clear cell renal cell carcinoma (ccRCC) (∼80% of all kidney cancers), with a marked adverse impact on survival in ccRCC patients (n = 516). We show that SDH down-regulation is a critical brake in the TCA cycle during ccRCC pathogenesis and progression. In exploring mechanisms of SDH down-regulation in ccRCC, we report that Von Hippel-Lindau loss-induced hypoxia-inducible factor-dependent up-regulation of miR-210 causes direct inhibition of the SDHD transcript. Moreover, shallow deletion of SDHB occurs in ∼20% of ccRCC. We then demonstrate that SDH loss-induced succinate accumulation contributes to adverse loss of 5-hydroxymethylcytosine, gain of 5-methylcytosine, and enhanced invasiveness in ccRCC via inhibition of ten-eleven translocation (TET)-2 activity. Intriguingly, binding affinity between the catalytic domain of recombinant TET-2 and succinate was found to be very low, suggesting that the mechanism of succinate-induced attenuation of TET-2 activity is likely via product inhibition rather than competitive inhibition. Finally, exogenous ascorbic acid, a TET-activating demethylating agent, led to reversal of the above oncogenic effects of succinate in ccRCC cells. Collectively, our study demonstrates that functional SDH deficiency is a common adverse feature of ccRCC and not just limited to the kidney cancers associated with germline SDH mutations.

TMEM9 promotes intestinal tumorigenesis through vacuolar-ATPase-activated Wnt/ß-catenin signalling.

Vesicular acidification and trafficking are associated with various cellular processes. However, their pathologic relevance to cancer remains elusive. We identified transmembrane protein 9 (TMEM9) as a vesicular acidification regulator. TMEM9 is highly upregulated in colorectal cancer. Proteomic and biochemical analyses show that TMEM9 binds to and facilitates assembly of vacuolar-ATPase (v-ATPase), a vacuolar proton pump, resulting in enhanced vesicular acidification and trafficking. TMEM9-v-ATPase hyperactivates Wnt/ß-catenin signalling via lysosomal degradation of adenomatous polyposis coli (APC). Moreover, TMEM9 transactivated by ß-catenin functions as a positive feedback regulator of Wnt signalling in colorectal cancer. Genetic ablation of TMEM9 inhibits colorectal cancer cell proliferation in vitro, ex vivo and in vivo mouse models. Moreover, administration of v-ATPase inhibitors suppresses intestinal tumorigenesis of APC mouse models and human patient-derived xenografts. Our results reveal the unexpected roles of TMEM9-controlled vesicular acidification in hyperactivating Wnt/ß-catenin signalling through APC degradation, and propose the blockade of TMEM9-v-ATPase as a viable option for colorectal cancer treatment.

Sinonasal renal cell-like adenocarcinoma, a unique variant of primary clear cell carcinoma of the head and neck: The first reported case in Korea.

RATIONALE: Primary sinonasal renal cell-like adenocarcinoma (SNRCLA) is a rare and unique neoplasm. PATIENT CONCERNS: A 63-year-old man presented with repeated epistaxis, nasal obstruction and hyposmia of 2-month duration. Radiological studies revealed a mass of the left ethmoid sinus involving anterior skull base. DIAGNOSIS: The patient was treated with craniofacial resection, bifrontal craniotomy combined with an endonasal endoscopic approach. Intraoperatively, a hypervascular paranasal mass invading the dura mater was removed en block. Histologically, the tumor resembled a clear cell renal cell carcinoma, with cuboidal shaped cells having clear cytoplasm. The tumor cells were positive for CK7, S100, vimentin and PAX-8 and negative for CD10 and PAX-2 by immunohistochemistry. No evidence of renal malignancy was found by radiological and clinical examinations. INTERVENTIONS AND OUTCOMES: Following local radiation therapy, the patient was in good health without recurrence for 15 months after the operation. LESSONS: To the best of the authors' knowledge, this is the first reported case of SNRCLA in Korea. Because of its histological feature of clear cytoplasm, SNRCLA needs to be differentiated from clear cell renal cell carcinoma and other salivary clear cell carcinomas. The prognosis of SNRCLA is generally favorable as shown in the previously reported cases. Considering the limited number and follow-up periods of the cases, however, delayed recurrence should be kept in mind for clinicians.

Human U87 glioblastoma cells with stemness features display enhanced sensitivity to natural killer cell cytotoxicity through altered expression of NKG2D ligand.

BACKGROUND: Glioblastoma (GBM) is one of the most lethal tumors with a poor prognosis. Its inevitable recurrence is frequently explained by the presence of cancer stem cells. We aimed to show that human GBM cells with stemness features are more sensitive to natural killer (NK) cells than GBM cells without stemness characteristics. METHODS: Natural killer cell cytotoxicity was measured using flow cytometry in neurosphere-forming U87 GBM cells cultured with neurobasal media (NBE condition) and compared with that in serum-cultured U87 GBM cells (serum condition). Cytotoxicity was examined after addition of blocking NKG2D monoclonal antibodies. The expression profile of NK ligands of NK cells were investigated by reverse transcription polymerase chain reaction and western blot analysis in the U87 GBM cells in both conditions. RESULTS: NBE U87 cells showed higher cytotoxicity to NK cells than serum U87 cells did (55 vs 35% at an effector to target cell ratio of 5:1). The increased cytotoxicity was diminished in NBE U87 cells by a larger gap than in serum U87 cells by adding NKG2D blocking antibodies. Of the NKG2D ligands, the expression of ULBP1 and ULBP3 was relatively increased in NBE U87 cells compared to serum U87 cells. CONCLUSIONS: U87 GBM cells with stemness features demonstrate increased cytotoxicity to NK cells in association with altered NKG2D ligand expression of NK cell activating receptor. Applying immune modulation to GBM treatment may be a promising adjuvant therapy in patients with intractable GBM.

KITENIN functions as a fine regulator of ErbB4 expression level in colorectal cancer via protection of ErbB4 from E3-ligase Nrdp1-mediated degradation.

Understanding the complex biological functions of E3-ubiquitin ligases may facilitate the development of mechanism-based anti-cancer drugs. We recently identified that the KITENIN/ErbB4-Dvl2-c-Jun axis works as a novel unconventional downstream signal of epidermal growth factor (EGF) in colorectal cancer (CRC) tissues. Here we addressed whether E3-ubiquitin ligases are required for operation of this axis. We found that Nrdp1, an E3-ligase for ErbB3/ErbB4, interacted with KITENIN (KAI1 C-terminal interacting tetraspanin) to form a functional KITENIN/ErbB4/Nrdp1 complex and is responsible for down-regulating Dvl2 within this complex. Interestingly, ErbB4 was resistant to degradation by Nrdp1 in KITENIN/Nrdp1-co-transfected CRC cells, and KITENIN bound to the C-terminal coiled-coil domain of Nrdp1. Chemical blockade of ErbB kinase did not block the action of EGF to increase in total/phospho-ErbB4 and phospho-ERK in KITENIN/ErbB4-cotransfected cells, whereas it blocked the action of EGF in ErbB4 alone-transfected CRC cells. In human CRC tissues, higher expressions of ErbB4 and KITENIN and lower expression of Dvl2 was observed in stage IV samples than in stage I, but a low level of Nrdp1 was expressed in both stages and it did not differ significantly by stage. These results indicated that Nrdp1 is necessary for the reduction in Dvl2 to generate c-Jun in the EGF-KITENIN/ErbB4-c-Jun axis, but more importantly, elevated KITENIN protects KITENIN-bound ErbB4 from Nrdp1-mediated degradation via physical collaboration between the KITENIN/ErbB4 complex and Nrdp1, but not via modulation of ErbB kinase activity. Thus, KITENIN functions in the maintenance of a higher expression level of ErbB4 in advanced CRC tissues, independent of ubiquitin-mediated degradation via Nrdp1. © 2016 Wiley Periodicals, Inc.

Lessons from surgical outcome for intracranial meningioma involving major venous sinus.

Intracranial meningiomas involving the major venous sinus (MVS) pose several complication risks upon performing radical resection. Some surgeons consider MVS invasion a contraindication for a complete resection of meningioma, and others suggest total resection followed by venous reconstruction. The aim of the study was to analyze our surgical results and discuss management strategy for intracranial meningiomas involving the MVS. Between 1993 and 2011, 107 patients with intracranial meningiomas involving MVS underwent surgery in our institution. Clinicoradiological features including pathological features and operative findings were retrospectively analyzed. Median follow-up duration was 60.2 months (range, 6.2-218.2 months). Distributions of tumor cases according to the involved sinus were as follows: 86% parasagittal, 10.3% tentorial, and 3.7% peritorcular. Simpson Grade I/II removal was achieved in 93 of 107 patients (87%). Partially or totally occluded MVS by their meningiomas (Sindou classification IV and V) was found in 39 patients (36%). Progression rate was 12% (13/107) and progression-free survival rates were 89%, 86%, and 80% at 5, 7, and 10 years, respectively. Sindou classification (IV/V) and Karnofsky performance status (KPS) score 6 month after the surgery (KPS < 90) were predictive factors for progression in our study (P = 0.044 and P = 0.001, respectively). The resection degree did not reach statistical significance (P = 0.484). Interestingly, there was no progression in patients that underwent radiation therapy or gamma knife radiosurgery for residual tumor. There were no perioperative deaths. Complication rate was 21% with brain swelling being the most common complication. There was no predictive factor for occurrence of postoperative complication in this study. In conclusion, complete tumor resection with sinus reconstruction did not significantly prevent tumor recurrence in intracranial meningioma involving MVS. Considering the complications from this procedure as it has possibly related with reduced postoperative KPS score, the tumor should be removed as much as possible while leaving remnant portion with significant invasion of sinus or drainage vein. Following radiation therapy or gamma knife radiosurgery for a remnant or recurred meningioma might then be justified.

Skeletal muscle fiber function and rate of disease progression in amyotrophic lateral sclerosis.

The contractile properties of single muscle fibers reflect the functional status of muscle at the cellular level and have not been described in amyotrophic lateral sclerosis (ALS). Chemically skinned single muscle fibers (n = 173), obtained by needle biopsy from six men with ALS, were activated with Ca(2+), allowing maximal force measurements and specific force (SF) estimates. Maximum unloaded shortening velocity (V(o)) was determined using the slack test. The results were compared with muscle from healthy controls. Markers of disease progression included rate of change of ALS functional rating scale score, rate of change of forced vital capacity, and disease duration. Compared with controls, ALS patients had decreased whole muscle SF (measured by a combination of computerized tomography and isokinetic testing) but normal single fiber SF. The V(o) was greater for type I fibers in ALS. Patients with slower disease progression had increased single fiber size and a high percentage of hybrid fibers (expressing multiple myosin heavy chain isoforms). A needle biopsy obtained at the time of ALS diagnosis may assist with predicting rate of disease progression.