The Safety of Intra-arterial Tirofiban during Endovascular Therapy after Intravenous Thrombolysis.

BACKGROUND AND PURPOSE: The safety and efficacy of tirofiban during endovascular therapy in patients undergoing intravenous thrombolysis with recombinant IV tPA remain unclear. This study aimed to investigate the safety and efficacy of intra-arterial tirofiban use during endovascular therapy in patients treated with IV tPA. MATERIALS AND METHODS: Using a multicenter registry, we enrolled patients with acute ischemic stroke who underwent endovascular therapy. Safety outcomes included postprocedural parenchymal hematoma type 2 and/or thick subarachnoid hemorrhage, intraventricular hemorrhage, and 3-month mortality. Efficacy outcomes included the successful reperfusion rate, postprocedural reocclusion, and good outcomes at 3 months (mRS scores of 0-2). The tirofiban effect on the outcomes was evaluated using a multivariable analysis while adjusting for potential confounders. RESULTS: Among enrolled patients, we identified 314 patients with stroke (279 and 35 patients in the no tirofiban and tirofiban groups, respectively) due to an intracranial artery occlusion who underwent endovascular therapy with intravenous thrombolysis. A multivariable analysis revealed no association of intra-arterial tirofiban with postprocedural parenchymal hematoma type and/or thick subarachnoid hemorrhage (adjusted OR, 1.07; 95% CI, 0.20-4.10; P = .918), intraventricular hemorrhage (adjusted OR, 0.43; 95% CI, 0.02-2.85; P = .467), and 3-month mortality (adjusted OR, 0.38; 95% CI, 0.04-1.87; P = .299). Intra-arterial tirofiban was not associated with good outcome (adjusted OR, 2.22; 95% CI, 0.89 -6.12; P = .099). CONCLUSIONS: Using intra-arterial tirofiban during endovascular therapy after IV tPA could be safe.

Bronchovascular bundle thickening on CT as a predictor of survival and brain metastasis in patients with stage IA peripheral small cell lung cancer.

AIM: To determine if bronchovascular bundle (BVB) thickening on pretreatment computed tomography (CT) images helps predict survival in patients with peripheral small cell lung cancer (pSCLC) ≤3 cm. MATERIALS AND METHODS: The pretreatment CT examinations of 79 histopathologically proven pSCLC ≤3 cm (TNM stage I, 21; II, 13; III, 22; IV, 23) were reviewed retrospectively. The CT characteristics of the nodule and associated findings, including BVB thickening, were evaluated. Progression-free survival (PFS), overall survival (OS), and brain metastasis-free survival were compared with the presence of BVB thickening using Kaplan-Meier and Cox regression analysis. RESULTS: Among the 79 patients, 34 (43%) had BVB thickening. BVB thickening was prevalent in patients with mediastinal lymph node metastasis (50.9% versus 22.7%; p=0.024) and distant metastasis (60.9% versus 35.7%; p=0.049). Out of the 21 patients with TNM stage IA disease, the 16 patients (76.2%) without BVB thickening showed better PFS, OS, and brain metastasis-free survival (mean, 1,762 versus 483 days; p=0.019: 2,243 versus 1,328 days; p=0.038: 2,274 versus 1,287 days; p=0.038, respectively). Multivariate Cox regression analysis showed that the absence of BVB thickening (hazard ratio [HR], 7.806; 95% CI, 1.241-49.091; p=0.029) and surgery (HR, 0.075; 95% CI, 0.008-0.746; p=0.027) were independent and useful prognostic factors for PFS. CONCLUSIONS: BVB thickening was found more frequently in patients with advanced-stage pSCLC ≤3 cm, and the PFS was more favourable in patients without BVB thickening, with a similar tendency to that of OS and brain metastasis-free survival, in stage IA pSCLC.

Association between time to treatment and functional outcomes according to the Diffusion-Weighted Imaging Alberta Stroke Program Early Computed Tomography Score in endovascular stroke therapy.

BACKGROUND AND PURPOSE: The rate at which the chance of a good outcome of endovascular stroke therapy (EVT) decays with time when eligible patients are selected by baseline diffusion-weighted magnetic resonance imaging (DWI-MRI) and whether ischaemic core size affects this rate remain to be investigated. METHODS: This study analyses a prospective multicentre registry of stroke patients treated with EVT based on pretreatment DWI-MRI that was categorized into three groups: small [Diffusion-Weighted Imaging Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS)] (8-10), moderate (5-7) and large (<5) cores. The main outcome was a good outcome at 90 days (modified Rankin Scale 0-2). The interaction between onset-to-groin puncture time (OTP) and DWI-ASPECTS categories regarding functional outcomes was investigated. RESULTS: Ultimately, 985 patients (age 69 ± 11 years; male 55%) were analysed. Potential interaction effects between the DWI-ASPECTS categories and OTP on a good outcome at 90 days were observed (Pinteraction  = 0.06). Every 60-min delay in OTP was associated with a 16% reduced likelihood of a good outcome at 90 days amongst patients with large cores, although no associations were observed amongst patients with small to moderate cores. Interestingly, the adjusted rates of a good outcome at 90 days steeply declined between 65 and 213 min of OTP and then remained smooth throughout 24 h of OTP (Pnonlinearity  = 0.15). CONCLUSIONS: Our study showed that the probability of a good outcome after EVT nonlinearly decreased, with a steeper decline at earlier OTP than at later OTP. Discrepant effects of OTP on functional outcomes by baseline DWI-ASPECTS categories were observed. Thus, different strategies for EVT based on time and ischaemic core size are warranted.

Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: a multicenter, open-label, randomized, phase III, noninferiority trial.

BACKGROUND: Capecitabine plus oxaliplatin (XELOX) has shown modest activity and tolerable toxicity in a phase II trial for biliary tract cancers (BTCs). Meanwhile, gemcitabine plus oxaliplatin (GEMOX) has been the reference arm in recent phase II and III trials for BTCs. We aimed to investigate the efficacy of XELOX versus GEMOX as first-line therapy for advanced BCTs. PATIENTS AND METHODS: In this open-label, randomized, phase III, noninferiority trial, we randomly selected patients with metastatic BCTs to receive GEMOX (gemcitabine 1000 mg/m2 on days 1 and 8, and oxaliplatin 100 mg/m2 on day 1) or XELOX (capecitabine 1000 mg/m2, twice daily, on days 1-14 and oxaliplatin 130 mg/m2 on day 1) as first-line treatment, given every 3 weeks, totaling eight cycles. The primary end point was to prove the noninferiority of XELOX to GEMOX in terms of 6-month progression-free survival (PFS) rate. RESULTS: In total, 114 patients randomly received GEMOX and 108 randomly received XELOX. The median PFS was 5.3 months for the GEMOX group and 5.8 months for the XELOX group. The 6-month PFS rate was 44.5% for the GEMOX group and 46.7% for the XELOX group. The 95% confidence interval of the 6-month PFS rate difference between both groups was -12% to 16%, meeting the criteria for noninferiority of XELOX to GEMOX. There was no difference in objective response (P=0.171) and median overall survival (P=0.131) between both groups. The most common grade three to four adverse events were neutropenia and thrombocytopenia. No patient died of treatment-related causes. The XELOX group had significantly lower frequencies of hospital visits than the GEMOX group (P<0.001). CONCLUSION: XELOX showed significant noninferiority to GEMOX in terms of 6-month PFS rate. Thus, XELOX could be an alternative first-line treatment of BCTs. TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov (number NCT01470443).

VUV spectroscopy in impurity injection experiments at KSTAR using prototype ITER VUV spectrometer.

The ITER vacuum ultra-violet (VUV) core survey spectrometer has been designed as a 5-channel spectral system so that the high spectral resolving power of 200-500 could be achieved in the wavelength range of 2.4-160 nm. To verify the design of the ITER VUV core survey spectrometer, a two-channel prototype spectrometer was developed. As a subsequent step of the prototype test, the prototype VUV spectrometer has been operated at KSTAR since the 2012 experimental campaign. From impurity injection experiments in the years 2015 and 2016, strong emission lines, such as Kr xxv 15.8 nm, Kr xxvi 17.9 nm, Ne vii 46.5 nm, Ne vi 40.2 nm, and an array of largely unresolved tungsten lines (14-32 nm) could be measured successfully, showing the typical photon number of 1013-1015 photons/cm2 s.

A Case of Ectopic Paragonimiasis in a 17th Century Korean Mummy.

Archaeoparasitological studies on fossilized feces obtained from Joseon Dynasty (1392-1910 CE) mummies have provided invaluable data on the patterns of parasitic infection in pre-modern Korean societies. In our recent radiological investigation of a 17th century Joseon mummy discovered in Cheongdo (South Korea), we located a liver mass just below the diaphragm. Anatomical dissection confirmed the presence of a mass of unknown etiology. A subsequent parasitological examination of a sample of the mass revealed a large number of ancient Paragonimus sp. eggs, making the current report the first archaeoparasitological case of liver abscess caused by ectopic paragonimiasis.

Usefulness of mean platelet volume as a marker for clinical outcomes after out-of-hospital cardiac arrest: a retrospective cohort study.

Essentials It is unknown whether mean platelet volume (MPV) estimates outcomes after cardiac arrest (CA). We investigated whether MPV was associated with 30-day neurologic outcome and mortality after CA. Elevated MPV at admission was associated with poor neurological outcomes and mortality at 30 days. Identifying levels of MPV is helpful for estimating disease severity among resuscitated patients. SUMMARY: Background Whole-body ischemia followed by reperfusion during cardiac arrest and after return of spontaneous circulation (ROSC) triggers systemic sterile inflammatory responses, inducing a sepsis-like state during post-cardiac arrest syndrome. Activated platelets are enlarged, and contain vasoactive and prothrombic factors that aggravate systemic inflammation and endothelial dysfunction. Objectives To investigate whether mean platelet volume (MPV) is useful as a marker for early mortality and neurologic outcomes in patients who achieve ROSC after out-of-hospital cardiac arrest (OHCA). Methods OHCA records from the Emergency Department Cardiac Arrest Registry were retrospectively analyzed. Patients who survived for > 24 h after ROSC were included. We evaluated mortality and cerebral performance category scores after 30 days. Results We analyzed records from 184 patients with OHCA. Increased 30-day mortality among patients who achieved ROSC after OHCA was associated with MPV at admission (hazard ratio [HR] 1.36; 95% confidence interval [CI] 1.06-1.75). An elevated MPV at admission was also associated with poor neurologic outcomes (HR 1.28; 95% CI 1.06-1.55). Conclusions An elevated MPV was independently associated with increased 30-day mortality, with the highest discriminative value being obtained upon admission after OHCA. An elevated MPV on admission was associated with poor neurologic outcomes. High MPVs are helpful for estimating 30-day mortality and neurologic outcomes among patients who achieve ROSC after OHCA.

RandomizEd phase II trial of Sunitinib four weeks on and two weeks off versus Two weeks on and One week off in metastatic clear-cell type REnal cell carcinoma: RESTORE trial.

BACKGROUND: The standard sunitinib schedule, 4 weeks on, followed by 2 weeks off (4/2 schedule), is associated with troublesome toxicities, and maintenance of adequate sunitinib dosing and drug levels, which are essential for achieving an optimal treatment outcome, is challenging. The objective of this study was to investigate the efficacy and safety of an alternative sunitinib dosing schedule of 2 weeks on and 1 week off (2/1 schedule) compared with the standard sunitinib schedule of 4 weeks on and 2 weeks off (4/2 schedule). PATIENTS AND METHODS: In this multicenter, randomized, open-label, phase II trial, treatment-naïve patients with clear-cell type metastatic renal cell carcinoma (mRCC) were randomly assigned to 4/2 or 2/1 schedules after stratification by Memorial Sloan Kettering Cancer Center risk group and the presence or absence of measurable lesions. The primary end point was the 6-month failure-free survival (FFS) rate, determined by intention-to-treat analysis. RESULTS: From November 2007 to February 2014, 76 patients were accrued, and 74 were eligible. FFS rates at 6 months were 44% with the 4/2 schedule (N = 36) and 63% with the 2/1 schedule (N = 38). Neutropenia (all grades, 61% versus 37%; grade 3-4, 28% versus 11%) and fatigue (all grades, 83% versus 58%) were more frequently observed with schedule 4/2. There was a strong tendency toward a lower incidence of stomatitis, hand-foot syndrome, and rash with schedule 2/1. Objective response rates (ORRs) were 47% in schedule 2/1 and 36% in schedule 4/2. With a median follow-up of 30.0 months, the median time to progression (TTP) was 12.1 months in schedule 2/1 and 10.1 months in schedule 4/2. CONCLUSION: Sunitinib administered with a 2/1 schedule is associated with less toxicity and higher FFS at 6 months than a 4/2 schedule, without compromising the efficacy in terms of ORR and TTP (NCT00570882).

Phase II study of pemetrexed in combination with cisplatin in patients with advanced urothelial cancer: the PECULIAR study (KCSG 10-17).

BACKGROUND: Pemetrexed has shown a favourable response rate of about 30% with minimal toxicity when used as a single agent for treatment of advanced urothelial carcinoma. This phase II study evaluated the efficacy and safety of pemetrexed plus cisplatin in advanced urothelial carcinoma. METHODS: This multicentre, single-arm, open-label, phase II clinical trial enrolled patients who had advanced urothelial carcinoma, ECOG PS 0-2, and measurable disease. Pemetrexed 500 mg m(-2) with cisplatin 70 mg m(-2) on day 1 were administered every 3 weeks. The primary endpoint was the objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: A total of 42 patients were enrolled (median age, 66 years; ECOG 0-1, 100%; visceral metastasis, 54.8%; recurrent disease, 57.1%). Twenty-seven partial responses for an ORR of 64.3% (95% CI, 49.2%-77.0%) were documented. Seven patients had stable disease. Median PFS and OS were 6.9 (95% CI, 6.2-7.6) and 14.4 (95% CI, 10.4-18.4) months, respectively. Grade 3 or 4 neutropenia was observed in 28.6% of patients. No patients experienced febrile neutropenia. CONCLUSION: The combination of pemetrexed and cisplatin is active, and well tolerated in patients with advanced urothelial cancer as a first-line treatment.

Edge profile measurements using Thomson scattering on the KSTAR tokamak.

In the KSTAR Tokamak, a "Tangential Thomson Scattering" (TTS) diagnostic system has been designed and installed to measure electron density and temperature profiles. In the edge system, TTS has 12 optical fiber bundles to measure the edge profiles with 10-15 mm spatial resolution. These 12 optical fibers and their spatial resolution are not enough to measure the pedestal width with a high accuracy but allow observations of L-H transition or H-L transitions at the edge. For these measurements, the prototype ITER edge Thomson Nd:YAG laser system manufactured by JAEA in Japan is installed. In this paper, the KSTAR TTS system is briefly described and some TTS edge profiles are presented and compared against the KSTAR Charge Exchange Spectroscopy and other diagnostics. The future upgrade plan of the system is also discussed in this paper.

Test of prototype ITER vacuum ultraviolet spectrometer and its application to impurity study in KSTAR plasmas.

To optimize the design of ITER vacuum ultraviolet (VUV) spectrometer, a prototype VUV spectrometer was developed. The sensitivity calibration curve of the spectrometer was calculated from the mirror reflectivity, the grating efficiency, and the detector efficiency. The calibration curve was consistent with the calibration points derived in the experiment using the calibrated hollow cathode lamp. For the application of the prototype ITER VUV spectrometer, the prototype spectrometer was installed at KSTAR, and various impurity emission lines could be measured. By analyzing about 100 shots, strong positive correlation between the O VI and the C IV emission intensities could be found.

The role of each compartment in a two-compartment vertical flow reactor for ferruginous mine water treatment.

A vertical flow reactor (VFR) has been suggested for remediation of ferruginous mine drainage that passes down through an accreting bed of ochre. However, a VFR has a limited operation time until the system begins to overflow. In this study, a mathematical model was developed as a part of the effort to explore the operation of a VFR, showing dynamic changes in the head differences, ochre depths, and Fe(II)/Fe(III) concentrations in the effluent flow. The analysis showed that VFR operation time extended from 148.5 days to 163 days in an equally divided and to 168.4 days in asymmetrically (0.72:0.28) divided two-compartment VFR, suggesting that an optimum compartment ratio exists that maximizes the VFR operation time. A constant head filtration in the first compartment maximized filtration efficiency and thus prolonged VFR longevity in the two-compartment VFR. Fe(II) oxidation and ochre formation should be balanced with the permeability of the ochre bed to maximize the VFR operation time and minimize the residual Fe(II) in the effluent. Accelerated Fe(II) oxidation affected the optimum ratio of the compartment area and reduced the residual Fe(II) in the effluent. The VFR operation time can be prolonged significantly from 764 days to 3620 days by increasing the rate of ochre formation, much more than by accelerating the Fe(II) oxidation. During the prolonged VFR operation, ochre formed largely in the first compartment, while overflowing mine water with reduced iron content was effectively filtered in the second compartment. These results not only provide a better understanding of VFR operation but also suggest the direction of evolution of two-compartment VFR toward a compact and highly efficient facility integrated with an aerated cascade and with automatic coagulant feeding.

Gemcitabine-oxaliplatin plus prednisolone is active in patients with castration-resistant prostate cancer for whom docetaxel-based chemotherapy failed.

BACKGROUND: There has been no previous study on the activity of gemcitabine in combination with oxaliplatin (GemOx) for castration-resistant prostate cancer (CRPC). METHODS: The GemOx was preclinically tested for cytotoxic activity in human prostate cancer cell lines. Clinically, patients with CRPC who failed prior docetaxel were treated with gemcitabine 1000 mg m(-2) and oxaliplatin 100 mg m(-2) intravenously every 2 weeks and prednisolone 5 mg orally twice daily. The primary end point was the prostate-specific antigen (PSA) response rate. RESULTS: The GemOx displayed synergistic effects based on Chou and Talalay analysis. In the phase II study, 33 patients were accrued. The median dose of docetaxel exposure was 518 mg m(-2). A total of 270 cycles were administered with a median of eight cycles per patient. A PSA response rate was 55% (95% CI, 38-72) and radiologic response rate was 82% (9 out of 11). With a median follow-up duration of 20.5 months, the median time to PSA progression was 5.8 months (95% CI, 4.4-7.2) and the median overall survival was 17.6 months (95% CI, 12.6-22.6). The most frequently observed grade 3 or 4 toxicities were neutropenia (13%) and thrombocytopenia (13%). CONCLUSIONS: The GemOx is active and tolerable in patients with metastatic CRPC after docetaxel failure (NCT 01487720).

Canonical Wnt signalling activates TAZ through PP1A during osteogenic differentiation.

TAZ, a transcriptional modulator, has a key role in cell proliferation, differentiation and stem cell self-renewal. TAZ activity is regulated by several signalling pathways, including Hippo, GPCR and Wnt signalling, but the regulatory mechanisms of TAZ activation are not yet clearly understood. In this report, we show that TAZ is regulated by canonical Wnt signalling during osteogenic differentiation. Wnt3a increases TAZ expression and an inhibitor of GSK3ß, a downstream effector of Wnt signalling, induces TAZ. Wnt3a facilitates the dephosphorylation of TAZ, which stabilises TAZ and prevents it from binding 14-3-3 proteins, thus inducing the nuclear localisation of TAZ. Dephosphorylation of TAZ occurs via PP1A, and depletion of PP1A blocks Wnt3a-induced TAZ stabilisation. Wnt3a-induced TAZ activates osteoblastic differentiation and siRNA-induced TAZ depletion decreases Wnt3a-induced osteoblast differentiation. Taken together, these results show that TAZ mediates Wnt3a-stimulated osteogenic differentiation through PP1A, suggesting that the Wnt signal regulates the Hippo pathway.

Epidemiology and molecular characterization of bacteremia due to carbapenem-resistant Klebsiella pneumoniae in transplant recipients.

We conducted a retrospective study of 17 transplant recipients with carbapenem-resistant Klebsiella pneumoniae bacteremia, and described epidemiology, clinical characteristics and strain genotypes. Eighty-eight percent (15/17) of patients were liver or intestinal transplant recipients. Outcomes were death due to septic shock (18%), cure (24%) and persistent (>7 days) or recurrent bacteremia (29% each). Thirty- and 90-day mortality was 18% and 47%, respectively. Patients who were cured received at least one active antimicrobial agent and underwent source control interventions. Forty-one percent (7/17) of patients had intra-abdominal infections; all except one developed persistent/recurrent bacteremia despite drainage. Two patients tolerated persistent bacteremia for >300 days. All patients except one were infected with sequence type 258 (ST258), K. pneumoniae carbapenemase (KPC)-2-producing strains harboring a mutant ompK35 porin gene; the exception was infected with an ST37, KPC-3-producing strain. Seventy-one percent (12/17) of patients were infected with ST258 ompK36 mutant strains. In two patients, persistent bacteremia was caused by two strains with different ompK36 genotypes. Three ompK36 mutations were associated with significantly higher carbapenem minimum inhibitory concentrations than wild-type ompK36. Pulse-field gel electrophoresis identified a single ST258 lineage; serial strains from individual patients were indistinguishable. In conclusion, KPC-K. pneumoniae bacteremia exhibited highly diverse clinical courses following transplantation, and was caused by clonal ST258 strains with different ompK36 genotypes.

What association exists between hypertension and simple renal cyst in a screened population?

To assess the impact of simple renal cyst (SRC) on hypertension, we evaluated the prevalence of SRC as well as the relationship between SRC and hypertension. Data were obtained from 29 666 participants who underwent general health screening tests in 2006. Only participants who underwent contrast-enhanced computed tomography or abdominal ultrasonography were included in our study population. We then correlated the clinical characteristics and parameters of hypertension with the presence or absence of renal cysts. Of all the enrolled participants, 5674 (19.2%) had radiologic evidence of SRC, and hypertension was diagnosed in 9865 participants (33.4%). The SRC had a multivariable-adjusted odds ratio (OR) of 1.28 (95% confidence interval (CI), 1.20-1.36) for the presence of hypertension. In study participants with multiple cysts (>1), a large cyst (4 cm in diameter) or a peripheral cyst location, the ORs for the presence of hypertension were 1.31 (95% CI, 1.19-1.44), 1.29 (95% CI, 1.06-1.56) and 1.33 (95% CI, 1.11-1.64), respectively, compared with those for study participants without cyst after adjusting for other variables. We found the presence of SRC to be associated with a significantly increased incidence of hypertension. In addition, the cyst number, size and location are important characteristics of SRC related to hypertension.

Multicenter phase II study of sunitinib in patients with non-clear cell renal cell carcinoma.

BACKGROUND: Retrospective and molecular biologic data suggest that sunitinib may be effective in patients with non-clear cell renal cell carcinoma (nccRCC). PATIENTS AND METHODS: Eligibility criteria included advanced nccRCC except for collecting duct carcinoma and sarcomatoid carcinoma without identifiable renal cell carcinoma subtypes. Patients were treated with 50 mg/day oral sunitinib for 4 weeks, followed by 2 weeks of rest. The primary end point was overall response rate (RR). RESULTS: Thirty-one eligible patients were enrolled. Twenty-four patients (77%) had prior nephrectomy. By Memorial Sloan-Kettering Cancer Center criteria, 8 patients (26%) had poor risk and 14 (45%) had intermediate risk. Twenty-two patients had papillary renal cell carcinoma (RCC), and three had chromophobe RCC. Eleven patients had partial response with a RR of 36% (95% confidence interval (CI) 19% to 52%) and an additional 17 patients (55%) had stable disease. Median duration of response was 12.7 months (95% CI 6.3-19.1 months), and median progression-free survival was 6.4 months (95% CI 4.2-8.6 months). At a median follow-up duration of 18.7 months (95% CI 13.7-23.7 months), 13 patients (42%) had died, resulting in an estimated median survival of 25.6 months (95% CI 8.4-42.9 months). Toxicity profiles were commensurate with prior reports. CONCLUSIONS: Sunitinib has promising activity in patients with nccRCC (NCT01219751).

The closing and opening of TRPC channels by Homer1 and STIM1.

Influx of Ca(2+) is a central component of the receptor-evoked Ca(2+) signal. A ubiquitous form of Ca(2+) influx comes from Ca(2+) channels that are activated in response to depletion of the endoplasmic reticulum Ca(2+) stores and are thus named the store-operated Ca(2+) -influx channels (SOCs). One form of SOC is the transient receptor potential canonical (TRPC) channels. A major question in the field of Ca(2+) signalling is the molecular mechanism that regulates the opening and closing of these channels. All TRPC channels have a Homer-binding ligand and two conserved negative charges that interact with two terminal lysines of the stromal interacting molecule 1 (STIM1). The Homer and STIM1 sites are separated by only four amino acid residues. Based on available results, we propose a molecular mechanism by which Homer couples TRPC channels to IP(3) receptors (IP(3) Rs) to keep these channels in the closed state. Dissociation of the TRPCs-Homer-IP(3) Rs complex allows STIM1 access to the TRPC channels negative charges to gate open these channels.