•DLL3 is expressed in 74% of stage IV LCNEC patients•The majority (80%) has cytoplasmic/membranous expression•DLL3 is expressed in both SCLC- and NSCLC-like LCNEC subtype•6/6 STK11mt, 10/11 KEAP1mt ...and 9/9 TP53wt tumors were DLL3 positive•DLL3 expression is associated with expression of ASCL1 and neuroendocrine markers
For stage IV pulmonary large cell neuroendocrine carcinoma (LCNEC), the only therapeutic option is palliative chemotherapy. DLL3 is a new therapeutic target, which seems to be often expressed in SCLC and LCNEC. It has recently been reported that DLL3 mRNA expression is particularly upregulated in the LCNEC subgroup with STK11/KEAP1 and TP53 co-mutations, in contrast to lower expression levels in RB1 and TP53 co-mutated LCNEC. Our aim was to investigate DLL3 protein expression in stage IV LCNEC and correlate data with mutational profiles (i.e.STK11/KEAP1/RB1), immunostaining results (pRb, NE markers) and clinical characteristics.
Immunohistochemical analysis for DLL3 (SC16.65) and ASCL1 (SC72.201) was performed on 94 and 51 FFPE tissue sections, respectively, of pathologically reviewed stage IV LCNEC. DLL3 and ASCL1 were scored positive if ≥1% of the tumor cells showed cytoplasmic/membranous or dotlike (DLL3) or nuclear (ASCL1) immunostaining. Data were correlated with available sequencing (TP53, RB1, STK11, KEAP1), immunostaining (pRb, NE markers) and clinical data.
DLL3 was expressed in 70/94 (74%) LCNEC, 56 (80%) of which showed cytoplasmic/membranous staining. Median H-score was 55 (interquartile range 0–160). DLL3 staining was not different in pRb immunohistochemistry negative and positive patients (DLL3+ in 53/70 (76%) vs. 14/21 (67%), p = 0.409) or RB1 mutated and wildtype patients (DLL3+ in 27/34 (79%) vs. 23/33 (70%), p = 0.361). Nevertheless, 6/6 (100%) STK11 mutated, 10/11 (91%) KEAP1 mutated and 9/9 (100%) TP53 wildtype tumors were DLL3+ . Furthermore, DLL3 expression was associated with expression of ASCL1 and at least 2 out of 3 neuroendocrine markers.
The high percentage (74%) of DLL3 expression in stage IV LCNEC denotes the potential of DLL3 targeted therapy in this patient group.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Dark sectors charged under a new Abelian interaction have recently received much attention in the context of dark matter models. These models introduce a light new mediator, the so-called dark photon ...(A^{'}), connecting the dark sector to the standard model. We present a search for a dark photon in the reaction e^{+}e^{-}→γA^{'}, A^{'}→e^{+}e^{-}, μ^{+}μ^{-} using 514 fb^{-1} of data collected with the BABAR detector. We observe no statistically significant deviations from the standard model predictions, and we set 90% confidence level upper limits on the mixing strength between the photon and dark photon at the level of 10^{-4}-10^{-3} for dark photon masses in the range 0.02-10.2 GeV. We further constrain the range of the parameter space favored by interpretations of the discrepancy between the calculated and measured anomalous magnetic moment of the muon.
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Despite available targeted treatments for the disease, drug-resistant chronic lymphocytic leukemia (CLL) poses a clinical challenge. The objective of this study is to examine whether the ...dual-specific phosphatases DUSP1 and DUSP6 are required to negatively regulate mitogen-activated protein kinases (MAPKs) and thus counterbalance excessive MAPK activity. We show that high expression of DUSP6 in CLL correlates with poor clinical prognosis. Importantly, genetic deletion of the inhibitory phosphatase DUSP1 or DUSP6 and blocking DUSP1/6 function using a small-molecule inhibitor reduces CLL cell survival in vitro and in vivo. Using global phospho-proteome approaches, we observe acute activation of MAPK signaling by DUSP1/6 inhibition. This promotes accumulation of mitochondrial reactive oxygen species and, thereby, DNA damage and apoptotic cell death in CLL cells. Finally, we observe that DUSP1/6 inhibition is particularly effective against treatment-resistant CLL and therefore suggest transient DUSP1/6 inhibition as a promising treatment concept to eliminate drug-resistant CLL cells.
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•DUSP1/6 inhibition in CLL triggers rapid MAPK signaling and cell death•Enhanced MAPK signaling leads to mitochondrial ROS accumulation•This ROS accumulation leads to DNA damage and subsequent CLL cell apoptosis•DUSP1/6 inhibition is highly effective against treatment-resistant CLL
Ecker et al. show that targeting DUSP1/6, negative regulators, induces overwhelming intracellular signaling, causing harmful mitochondrial ROS accumulation in CLL cells. This leads to DNA damage and apoptotic CLL cell death. Their findings propose DUSP1/6 inhibition as a potential treatment strategy, even for drug-resistant CLL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Although CP violation in the B meson system has been well established by the B factories, there has been no direct observation of time-reversal violation. The decays of entangled neutral B mesons ...into definite flavor states (B(0) or B(0)), and J/ψK(L)(0) or ccK(S)(0) final states (referred to as B(+) or B(-)), allow comparisons between the probabilities of four pairs of T-conjugated transitions, for example, B(0) → B(-) and B(-) → B(0), as a function of the time difference between the two B decays. Using 468 × 10(6) BB pairs produced in Υ(4S) decays collected by the BABAR detector at SLAC, we measure T-violating parameters in the time evolution of neutral B mesons, yielding ΔS(T)(+) = -1.37 ± 0.14(stat) ± 0.06(syst) and ΔS(T)(-) = 1.17 ± 0.18(stat) ± 0.11(syst). These nonzero results represent the first direct observation of T violation through the exchange of initial and final states in transitions that can only be connected by a T-symmetry transformation.
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Objective
The aim of the study was to assess the efficacy and safety of fumaric acid esters (FAEs) in patients with cutaneous lupus erythematosus (CLE).
Methods
In this 24-week, prospective, ...open-label, phase II pilot study, 11 patients with CLE, refractory to topical corticosteroids, were included. The primary endpoint of the study was the evaluation of the efficacy of FAEs after 24 weeks of treatment as assessed by the Revised Cutaneous Lupus Disease Area and Severity Index (RCLASI).
Results
Compared to baseline, significant improvement in the mean total RCLASI activity score and the mean RCLASI activity score for skin lesions was observed in week 12 (p = 0.002, p = 0.002, respectively) and in week 24 (p = 0.009, p = 0.009, respectively). Most common adverse events included abdominal cramps and headache.
Conclusions
FAEs could be an alternative and safe treatment in patients with therapy-refractory CLE; however, randomized controlled trials are warranted to evaluate the efficacy and safety of FAEs in this disease.
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DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
While Web-based interventions have been shown to assist a wide range of patients successfully in managing their illness, few studies have examined the relative contribution of different Web-based ...components to improve outcomes. Further efficacy trials are needed to test the effects of Web support when offered as a part of routine care.
Our aim was to compare in regular care the effects of (1) an Internet-based patient provider communication service (IPPC), (2) WebChoice, a Web-based illness management system for breast cancer patients (IPPC included), and (3) usual care on symptom distress, anxiety, depression, (primary outcomes), and self-efficacy (secondary outcome). This study reports preliminary findings from 6 months' follow-up data in a 12-month trial.
We recruited 167 patients recently diagnosed with breast cancer and undergoing treatment from three Norwegian hospitals. The nurse-administered IPPC allowed patients to send secure e-messages to and receive e-messages from health care personnel at the hospital where they were treated. In addition to the IPPC, WebChoice contains components for symptom monitoring, tailored information and self-management support, a diary, and communication with other patients. A total of 20 care providers (11 nurses, 6 physicians, and 3 social workers) were trained to answer questions from patients. Outcomes were measured with questionnaires at study entry and at study months 2, 4, and 6. Linear mixed models for repeated measures were fitted to compare effects on outcomes over time.
Patients were randomly assigned to the WebChoice group (n=64), the IPPC group (n=45), or the usual care group (n=58). Response rates to questionnaires were 73.7% (123/167) at 2 months, 65.9 (110/167) at 4 months, and 62.3% (104/167) at 6 months. Attrition was similar in all study groups. Among those with access to WebChoice, 64% (41/64) logged on more than once and 39% (25/64) sent e-messages to care providers. In the IPPC group, 40% (18/45) sent e-messages. Linear mixed models analyses revealed that the WebChoice group reported significantly lower symptom distress (mean difference 0.16, 95% CI 0.06-0.25, P=.001), anxiety (mean difference 0.79, 95% CI 0.09-1.49, P=.03), and depression (mean difference 0.79, 95% CI 0.09-1.49, P=.03) compared with the usual care group. The IPPC group reported significant lower depression scores compared with the usual care group (mean difference 0.69, 95% CI 0.05-1.32, P=.03), but no differences were observed for symptom distress or anxiety. No significant differences in self-efficacy were found among the study groups.
In spite of practice variations and moderate use of the interventions, our results suggest that offering Web support as part of regular care can be a powerful tool to help patients manage their illness. Our finding that a nurse-administered IPPC alone can significantly reduce depression is particularly promising. However, the multicomponent intervention WebChoice had additional positive effects.
Clinicaltrials.gov:NCT00971009; http://clinicaltrials.gov/show/NCT00971009 (Archived by WebCite at http://www.webcitation.org/6USKezP0Y).
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We measure the mass difference Δm0 between the D*(2010)+ and the D0 and the natural linewidth Γ of the transition D*(2010)+ → D0π+. The data were recorded with the BABAR detector at center-of-mass ...energies at and near the Υ(4S) resonance, and correspond to an integrated luminosity of approximately 477 fb(-1). The D0 is reconstructed in the decay modes D0 → K- π+ and D0 → K- π+ π- π+. For the decay mode D0 → K- π+ we obtain Γ = (83.4±1.7±1.5) keV and Δm0 = (145425.6±0.6±1.7) keV, corrected where the quoted errors are statistical and systematic, respectively. For the D0 → K- π+ π- π+ mode we obtain Γ = (83.2±1.5±2.6) keV and Δm0 = (145426.6±0.5±1.9) keV. corrected The combined measurements yield Γ = (83.3±1.2±1.4) keV and Δm0 = (145425.9±0.4±1.7) keV; the width is a factor of approximately 12 times more precise than the previous value, while the mass difference is a factor of approximately 6 times more precise.
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Background: The definition of objective, clinically applicable evaluation criteria for FISH 1c/7c in laryngeal precursor lesions for the detection of chromosome instability (CI). Copy Number ...Variations (CNV) for chromosomes 1 and 7 reflect the general ploidy status of premalignant head and neck lesions and can therefore be used as a marker for CI. Methods: We performed dual-target FISH for chromosomes 1 and 7 centromeres on 4 µm formalin-fixed, paraffin-embedded tissue sections of 87 laryngeal premalignancies to detect CNVs. Thirty-five normal head and neck squamous cell samples were used as a control. First, the chromosome 7:1 ratio (CR) was evaluated per lesion. The normal range of CRs (≥0.84 ≤ 1.16) was based on the mean CR +/− 3 x SD found in the normal population. Second, the percentage of aberrant nuclei, harboring > 2 chromosomes of chromosome 1 and/or 7 (PAN), was established (cut-off value for abnormal PAN ≥ 10%). Results: PAN showed a stronger correlation with malignant progression than CR (resp. OR 5.6, p = 0.001 and OR 3.8, p = 0.009). PAN combined with histopathology resulted in a prognostic model with an area under the ROC curve (AUC) of 0.75 (s.e. 0.061, sensitivity 71%, specificity 70%). Conclusions: evaluation criteria for FISH 1c/7c based on PAN ≥ 10% provide the best prognostic information on the risk of malignant progression of premalignant laryngeal lesions as compared with criteria based on the CR. FISH 1c/7c detection can be applied in combination with histopathological assessment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We present results of a search for CP violation in B0- B0 mixing with the BABAR detector. We select a sample of B0→D*- Xℓ+ ν decays with a partial reconstruction method and use kaon tagging to assess ...the flavor of the other B meson in the event. We determine the CP violating asymmetry ACP≡N(B0B0)-N(B0B0)/N(B0B0)+N(B0B0)=(0.06±0.17(-0.32)(+0.38))%, corresponding to ΔCP=1-|q/p|=(0.29±0.84(-1.61)(+1.88))×10(-3).
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