Contractile effects of stimulation of D1-dopamine receptors in the isolated human atrium.

Dopamine receptors have been claimed not to directly increase contractility in the human heart. Therefore, we performed contraction experiments in isolated electrically driven human atrial preparations (HAP). For comparison, we performed contraction experiments with left atrial preparations of transgenic mice which harbor a cardiac overexpression of human D1-dopamine receptors (D1-TG). In D1-TG, first we noted that dopamine (10 nM-10 µM cumulatively applied) in the presence of propranolol exerted a concentration- and time-dependent positive inotropic effect in D1-TG. In a similar fashion, dopamine increased force of contraction in the presence of 0.4 µM propranolol in HAP and these effects were amplified by pre-treatment with inhibitor of phosphodiesterase III (1 µM) cilostamide. Moreover, contractile effects of dopamine in the presence of propranolol 0.4 µM in HAP were antagonized by odapipam, haloperidol, or raclopride. Ten micromolars of fenoldopam in the presence of cilostamide increased force of contraction in HAP and this effect was antagonized by SCH 23390. We conclude that stimulation of human D1-dopamine receptors can increase force of contraction in the HAP.

Cantharidin and sodium fluoride attenuate the negative inotropic effect of the A1-adenosine receptor agonist N6-(R)-phenylisopropyl adenosine in isolated human atria.

Cantharidin and sodium fluoride inhibit the activity of serine/threonine protein phosphatases 1 (PP1) and 2A (PP2A) and increase the force of contraction in human atrial preparations. R-phenylisopropyl adenosine (R-PIA) acts as an agonist at A1-adenosine receptors. R-PIA exerts a negative inotropic effect on human atria. The effect of R-PIA-and its various manifestations-are currently explained as a function of the inhibition of sarcolemmal adenylyl cyclase activity and/or opening of sarcolemmal potassium channels. We hypothesise that cantharidin and sodium fluoride may attenuate the negative inotropic effect of R-PIA. During open heart surgery, trabeculae carneae from the right atrium were obtained for human atrial preparations (HAPs). These trabeculae were mounted in organ baths and electrically stimulated at 1 Hz. Furthermore, we studied isolated electrically stimulated left atrial (LA) preparations from female wild-type mice (CD1). The force of contraction was recorded under isometric conditions. R-PIA (1 µM) exerted a rapid negative inotropic effect in the HAPs and mice LA preparations. These negative inotropic effects of R-PIA were attenuated by pre-incubation for 30 min with 100-µM cantharidin in HAPs, but not in mice LA preparations. Adenosine signals via A1 receptors in a species-specific pathway in mammalian atria. We postulate that R-PIA, at least in part, exerts a negative inotropic effect via activation of serine/threonine phosphatases in the human atrium.

Evaluation of the inflammation-based modified Glasgow Prognostic Score (mGPS) as a prognostic and predictive biomarker in patients with metastatic colorectal cancer receiving first-line chemotherapy: a post hoc analysis of the randomized phase III XELAVIRI trial (AIO KRK0110).

BACKGROUND: The inflammation-based modified Glasgow Prognostic Score (mGPS) combines serum levels of C-reactive protein and albumin and was shown to predict survival in advanced cancer. We aimed to elucidate the prognostic impact of mGPS on survival as well as its predictive value when combined with gender in unselected metastatic colorectal cancer (mCRC) patients receiving first-line chemotherapy in the randomized phase III XELAVIRI trial. PATIENTS AND METHODS: In XELAVIRI, mCRC patients were treated with either fluoropyrimidine/bevacizumab followed by additional irinotecan at first progression (sequential treatment arm; Arm A) or upfront combination of fluoropyrimidine/bevacizumab/irinotecan (intensive treatment arm; Arm B). In the present post hoc analysis, survival was evaluated with respect to the assorted mGPS categories 0, 1 or 2. Interaction between mGPS and gender was analyzed. RESULTS: Out of 421 mCRC patients treated in XELAVIRI, 362 [119 women (32.9%) and 243 men (67.1%)] were assessable. For the entire study population a significant association between mGPS and overall survival (OS) was observed [mGPS = 0: median 28.9 months, 95% confidence interval (CI) 25.9-33.6 months; mGPS = 1: median 21.4 months, 95% CI 17.6-26.1 months; mGPS = 2: median 16.8 months, 95% CI 14.3-21.2 months; P < 0.00001]. Similar results were found when comparing progression-free survival between groups. The effect of mGPS on survival did not depend on the applied treatment regimen (P = 0.21). In female patients, a trend towards longer OS was observed in Arm A versus Arm B, with this effect being clearly more pronounced in the mGPS cohort 0 (41.6 versus 25.5 months; P = 0.056). By contrast, median OS was longer in male patients with an mGPS of 1-2 treated in Arm B versus Arm A (20.8 versus 17.4 months; P = 0.022). CONCLUSION: We demonstrate the role of mGPS as an independent predictor of OS regardless of the treatment regimen in mCRC patients receiving first-line treatment. mGPS may help identify gender-specific subgroups that benefit more or less from upfront intensive therapy.

Prior Thrombectomy Does Not Affect the Surgical Complication Rate of Decompressive Hemicraniectomy in Patients with Malignant Ischemic Stroke.

BACKGROUND: Even though mechanical recanalization techniques have dramatically improved acute stroke care since the pivotal trials of decompressive hemicraniectomy for malignant courses of ischemic stroke, decompressive hemicraniectomy remains a mainstay of malignant stroke treatment. However, it is still unclear whether prior thrombectomy, which in most cases is associated with application of antiplatelets and/or anticoagulants, affects the surgical complication rate of decompressive hemicraniectomy and whether conclusions derived from prior trials of decompressive hemicraniectomy are still valid in times of modern stroke care. METHODS: A total of 103 consecutive patients who received a decompressive hemicraniectomy for malignant middle cerebral artery infarction were evaluated in this retrospective cohort study. Surgical and functional outcomes of patients who had received mechanical recanalization before surgery (thrombectomy group, n = 49) and of patients who had not received mechanical recanalization (medical group, n = 54) were compared. RESULTS: The baseline characteristics of the two groups did significantly differ regarding preoperative systemic thrombolysis (63.3% in the thrombectomy group vs. 18.5% in the medical group, p < 0.001), the rate of hemorrhagic transformation (44.9% vs. 24.1%, p = 0.04) and the preoperative Glasgow Coma Score (median of 7 in the thrombectomy group vs. 12 in the medical group, p = 0.04) were similar to those of prior randomized controlled trials of decompressive hemicraniectomy. There was no significant difference in the rates of surgical complications (10.2% in the thrombectomy group vs. 11.1% in the medical group), revision surgery within the first 30 days after surgery (4.1% vs. 5.6%, respectively), and functional outcome (median modified Rankin Score of 4 at 5 and 14 months in both groups) between the two groups. CONCLUSIONS: A prior mechanical recanalization with possibly associated systemic thrombolysis does not affect the early surgical complication rate and the functional outcome after decompressive hemicraniectomy for malignant ischemic stroke. Patient characteristics have not changed significantly since the introduction of mechanical recanalization; therefore, the results from former large randomized controlled trials are still valid in the modern era of stroke care.

Cantharidin increases the force of contraction and protein phosphorylation in isolated human atria.

Cantharidin, an inhibitor of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A), is known to increase the force of contraction and shorten the time to relaxation in human ventricular preparations. We hypothesized that cantharidin has similar positive inotropic effects in human right atrial appendage (RAA) preparations. RAA were obtained during bypass surgery performed on human patients. These trabeculae were mounted in organ baths and electrically stimulated at 1 Hz. For comparison, we studied isolated electrically stimulated left atrial (LA) preparations and isolated spontaneously beating right atrial (RA) preparations from wild-type mice. Cumulatively applied (starting at 10 to 30 µM), cantharidin exerted a positive concentration-dependent inotropic effect that plateaued at 300 µM in the RAA, LA, and RA preparations. This positive inotropic effect was accompanied by a shortening of the time to relaxation in human atrial preparations (HAPs). Notably, cantharidin did not alter the beating rate in the RA preparations. Furthermore, cantharidin (100 µM) increased the phosphorylation state of phospholamban and the inhibitory subunit of troponin I in RAA preparations, which may account for the faster relaxation observed. The generated data indicate that PP1 and/or PP2A play a functional role in human atrial contractility.

High-performance cavity-dumped Q-switched Alexandrite laser CW diode-pumped in double-pass configuration.

We present a high-performance Alexandrite laser for LIDAR applications with repetition rates up to 20 kHz in cavity-dumped Q-switched operation continuous-wave diode-pumped in the red spectral region. With a double-pass pump configuration, short pulses with 2.8 ns duration at repetition frequencies ranging from 1 kHz to 20 kHz could be demonstrated. At 5 kHz a - to our knowledge - record pulse energy of over 500 µJ could be achieved at 755 nm in TEM00. Furthermore, a stability measurement at an energy of around 350 µJ with 5 kHz showed no degradation over 150 Mega-shots. The influence of the crystal temperature on the laser performance is also investigated, first in continuous-wave and secondly in cavity-dumped Q-switched operation.

Age and metastasis - How age influences metastatic spread in cancer. Colorectal cancer as a model.

Metastasis is the major cause of death in cancer patients. Whereas colorectal cancer (CRC) incidence increases with age, metastatic spread seems to decline. Furthermore, the epidemiology of CRC is changing. There is an increase in CRC incidence in the young, presenting at an advanced stage with higher likelihood of synchronous or metachronous metastases, and a decline in CRC incidence and metastatic spread in the oldest-old. Emerging data suggest that age-related changes with regard to tumor biology (e.g. genomic instability), the tumor microenvironment (e.g. inflammaging) and the immune system (e.g. immunosenescence), complemented by interaction between the genome and exposome might contribute to the observed metastatic patterns. As aging is a key prognostic factor, this highlights the need for further studies investigating age-related patterns and underlying mechanisms of tumor growth and dissemination. Eventually, this might allow for better risk stratification, refinement of screening strategies and follow-up care as well as therapies tailored to reflect patient age and that might possibly target responsible biomarkers in a precision medicine approach. This review aims to discuss the influence of aging on metastatic spread in colorectal cancer and elucidate underlying mechanisms responsible for the observed metastatic patterns.

LIN28 promotes tumorigenesis in colorectal cancer but is not associated with metastatic spread.

BACKGROUND: Tumor stem cells play a role in metastatic spread in colorectal cancer (CRC). The oncogene LIN28A/B, a prognostic marker in CRC, is involved in tumorigenesis and maintains stem cell function. Therefore, it was the aim of the present study to clarify whether LIN28A/B is involved in metastatic spread in CRC. METHODS: Expression of LIN28A/B was analyzed in patients with colon adenocarcinoma in a matched case-control study comparing patients with corresponding liver metastases (n = 42) and patients without hepatic spread within five years (n = 42) by applying immunohistochemistry. Further, LIN28A/B expression was correlated with stem cell associated markers (SOX2, CD133). RESULTS: LIN28A and B expression significantly correlated with SOX2 expression (p = .02, and p = .04 respectively) but not with CD133 expression. This correlation between LIN28 A/B and SOX2 was not reflected in differences in hepatic spread. In this respect, there was no significant association between LIN28A/B expression and liver metastases. CONCLUSION: LIN28A/B might be involved in tumor initiation and progression in CRC but is not associated with hepatic spread.

Three-dimensional nanothermometry below the diffraction limit.

Lanthanide-doped nanothermometers are used to measure temperature through changes in their emission characteristic with sensitivities of up to a few %/K. In contrast to their sensitivity, their spatial resolution, which is of critical importance for various applications, has not been thoroughly studied and optimized. We numerically investigated the improvement in spatial resolution of nanothermometers with a stimulated emission depletion microscopy approach. Fundamental relationships between spatial and temperature resolution were identified by using different beam parameters for the excitation and depletion beams. Our simulations predict contactless temperature measurement below the diffraction limit with temperature resolution of ±1.25K. We further studied the influence of sample thickness and position on both temperature and spatial resolution and showed the potential of three-dimensional measurements.