The immunosuppressive cytokine interleukin-4 increases the clonogenic potential of prostate stem-like cells by activation of STAT6 signalling

Interleukin-4 plays a critical role in the regulation of immune responses and has been detected at high levels in the tumour microenvironment of cancer patients, where concentrations correlate with the grade of malignancy. In prostate cancer, interleukin-4 has been associated with activation of the androgen receptor, increased proliferation and activation of survival pathways such as Akt and NF-κB. However, its role in therapy resistance has not yet been determined. Here we investigate the influence of interleukin-4 on primary epithelial cells from prostate cancer patients. Our data demonstrate an increase in the clonogenic potential of these cells when cultured in the presence of interleukin-4. In addition, a Phospho-Kinase Array revealed that in contrast to previously published work, signal transducer and activator of transcription6 (STAT6) is the only signalling molecule activated after interleukin-4 treatment. Using the STAT6-specific inhibitor AS1517499 we could confirm the role of STAT6 in increasing colony-forming frequency. However, clonogenic recovery assays revealed that interleukin-4 does not rescue the effects of either irradiation or docetaxel treatment. We therefore propose that although the interleukin-4/STAT6 axis does not appear to be involved in therapy resistance, it does play a crucial role in the colony-forming abilities of the basal cell population in prostate cancer. IL-4 may therefore contribute to disease relapse by providing a niche that is favourable for the clonogenic growth of prostate cancer stem cells

L- and D-lactate enhance DNA repair and modulate the resistance of cervical carcinoma cells to anticancer drugs via histone deacetylase inhibition and hydroxycarboxylic acid receptor 1 activation

BACKGROUND: The consideration of lactate as an active metabolite is a newly emerging and attractive concept. Recently, lactate has been reported to regulate gene transcription via the inhibition of histone deacetylases (HDACs) and survival of cancer cells via hydroxycarboxylic acid receptor 1 (HCAR1). This study examined the role of L- and D-lactate in the DNA damage response in cervical cancer cells. METHODS: Three cervical cancer cell lines were examined: HeLa, Ca Ski and C33A. The inhibitory activity of lactate on HDACs was analysed using Western blot and biochemical methods. The lactate-mediated stimulation of DNA repair and cellular resistance to neocarzinostatin, doxorubicin and cisplatin were studied using γ-H2AX, comet and clonogenic assays. HCAR1 and DNA repair gene expression was quantified by real-time PCR. DNA-PKcs activity and HCAR1 protein expression were evaluated via immunocytochemistry and Western blot, respectively. HCAR1 activation was investigated by measuring intracellular cAMP accumulation and Erk phosphorylation. HCAR1 expression was silenced using shRNA. RESULTS: L- and D-lactate inhibited HDACs, induced histone H3 and H4 hyperacetylation, and decreased chromatin compactness in HeLa cells. Treating cells with lactate increased LIG4, NBS1, and APTX expression by nearly 2-fold and enhanced DNA-PKcs activity. Based on γ-H2AX and comet assays, incubation of cells in lactate-containing medium increased the DNA repair rate. Furthermore, clonogenic assays demonstrated that lactate mediates cellular resistance to clinically used chemotherapeutics. Western blot and immunocytochemistry showed that all studied cell lines express HCAR1 on the cellular surface. Inhibiting HCAR1 function via pertussis toxin pretreatment partially abolished the effects of lactate on DNA repair. Down-regulating HCAR1 decreased the efficiency of DNA repair, abolished the cellular response to L-lactate and decreased the effect of D-lactate. Moreover, HCAR1 shRNA-expressing cells produced significantly lower mRNA levels of monocarboxylate transporter 4. Finally, the enhancement of DNA repair and cell survival by lactate was suppressed by pharmacologically inhibiting monocarboxylate transporters using the inhibitor α-cyano-4-hydroxycinnamic acid (α-CHCA). CONCLUSIONS: Our data indicate that L- and D-lactate present in the uterine cervix may participate in the modulation of cellular DNA damage repair processes and in the resistance of cervical carcinoma cells to anticancer therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12964-015-0114-x) contains supplementary material, which is available to authorized users

C−H Functionalization of Heterocycles with Triplet Carbenes by means of an Unexpected 1,2-Alkyl Radical Migration

The C−H functionalization of indole heterocycles constitutes a key strategy to leverage the synthesis of endogenous signaling molecules such as tryptamine or tryptophol. Herein, we report on the photocatalytic reaction of ethyl diazoacetate with indole, which shows an unusual solvent dependency. While C2-functionalization occurs under protic conditions, the use of aprotic solvents leads to a complete reversal of selectivity and exclusive C3-functionalization occurs. To rationalize for this unexpected reactivity switch, we have conducted detailed theoretical and experimental studies, which suggest the participation of a triplet carbene intermediate that undergoes initial C2-functionalization. A distinct cationic [1,2]-alkyl radical migration then leads to formation of C3-functionalized indole. We conclude with the application of this photocatalytic reaction to access oxidized tryptophol derivatives including gram-scale synthesis and derivatization reactions.German Science Foundation; Fonds der Chemischen Industrie for a Kekulé scholarship; China Scholarship Council; National Science Centre, grant OPUS UMO-2019/35/B/ST4/03435; Projekt DEA

Comparison of the rhythm control treatment strategy versus the rate control strategy in patients with permanent or long-standing persistent atrial fibrillation and heart failure treated with cardiac resynchronization therapy - a pilot study of Cardiac Resynchronization in Atrial Fibrillation Trial (Pilot-CRAfT): study protocol for a randomized controlled trial

BACKGROUND: The only subgroups of patients with heart failure and atrial fibrillation in which the efficacy of cardiac resynchronization therapy has been scientifically proven are patients with indications for right ventricular pacing and patients after atrioventricular junction ablation. However it is unlikely that atrioventricular junction ablation would be a standard procedure in the majority of the heart failure patients with cardiac resynchronization therapy and concomitant atrial fibrillation due to the irreversible character of the procedure and a spontaneous sinus rhythm resumption that occurs in about 10% of these patients. METHODS/DESIGN: Pilot-CRAfT is the first randomized controlled trial evaluating the efficacy of a rhythm control strategy in atrial fibrillation patients with cardiac resynchronization therapy devices. The aim of this prospective, single center randomized controlled pilot study is to answer the question whether the patients with cardiac resynchronization therapy and permanent atrial fibrillation would benefit from a strategy to restore and maintain sinus rhythm (that is ‘rhythm control’ strategy) in comparison to rate control strategy. The study population consists of 60 patients with heart failure and concomitant long-standing persistent or permanent atrial fibrillation who underwent a cardiac resynchronization therapy device implantation at least 3 months before qualification. Study participants are randomly assigned to the rhythm control strategy (including electrical cardioversion and pharmacotherapy) or to the rate control group whose goal is to control ventricular rate. The follow-up time is 12 months. The primary endpoint is the ratio of effectively captured biventricular beats. The secondary endpoints include peak oxygen consumption, six-minute walk test distance, heart failure symptom escalation, reverse remodelling of the heart on echo and quality of life. TRIAL REGISTRATION: NCT01850277 registered on 22 April 2013 (ClinicalTrails.gov

Clinical, echocardiographic, and pacing parameters affecting atrial fibrillation burden in patients with tachycardia-bradycardia syndrome

Background: The influence of various factors on atrial fibrillation (AF) development in the population of tachycardia-bradycardia syndrome (TBS) patients remains unclear. There are no data on the impact of different right ventricular pacing percentage (RVp%) profiles. Aim: The purpose of the study was to evaluate the relationship between the AF burden (AFB) and various clinical, echocardiographic, and pacing parameters in TBS patients. Methods: We performed a prospective, one-year registry of TBS patients with documented AF referred for dual-chamber pacemaker (DDD) implantation. Results: The data of 65 patients were analysed. The median 12-month RVp% and AFB was 9.4% and 1.0%, respectively. During the follow-up 14% of patients had no AF (p = 0.003), and the withdrawal of AF symptoms was observed in 49% of patients (p < 0.0001). The AFB was related to the left atrium diameter (r = 0.31, p = 0.02), especially in the subjects with left ventricular ejection fraction < 60% (r = 0.44, p = 0.04). Based on the relative change of RVp%, three groups of various RVp% profile were established: stable, decreasing, and increasing RVp%. In the stable RVp% group (n = 21) there was a quadratic correlation between the 12-month RVp% and AFB (r = 0.71, p = 0.0003). In the stable RVp% > 20% subgroup there was a significant increase of AFB in comparison to the RVp% ≤ 20% subgroup (ΔAFB 1.8% vs. 0.0%, p = 0.03, respectively). In the increasing RVp% group (n = 28) the AFB increased whereas in the decreasing RVp% (n = 16) it remained stable (ΔAFB 0.67% vs. 0.0%, p = 0.034, respectively). Conclusions: DDD implantation in TBS patients is related to a significant reduction in AF symptoms, and left atrial diameter correlates with cumulative AFB in the mid-term observation. Stable RVp% > 20% is associated with AF progression whereas lower stable RVp% may stabilise AF development. Increasing RVp% may be associated with the AFB increase in comparison to the decreasing RVp% subgroup in which AFB remains stable.Background: The influence of various factors on atrial fibrillation (AF) development in the population of tachycardia-bradycardia syndrome (TBS) patients remains unclear. There are no data on the impact of different right ventricular pacing percentage (RVp%) profiles. Aim: The purpose of the study was to evaluate the relationship between the AF burden (AFB) and various clinical, echocardiographic, and pacing parameters in TBS patients. Methods: We performed a prospective, one-year registry of TBS patients with documented AF referred for dual-chamber pacemaker (DDD) implantation. Results: The data of 65 patients were analysed. The median 12-month RVp% and AFB was 9.4% and 1.0%, respectively. During the follow-up 14% of patients had no AF (p = 0.003), and the withdrawal of AF symptoms was observed in 49% of patients (p < 0.0001). The AFB was related to the left atrium diameter (r = 0.31, p = 0.02), especially in the subjects with left ventricular ejection fraction < 60% (r = 0.44, p = 0.04). Based on the relative change of RVp%, three groups of various RVp% profile were established: stable, decreasing, and increasing RVp%. In the stable RVp% group (n = 21) there was a quadratic correlation between the 12-month RVp% and AFB (r = 0.71, p = 0.0003). In the stable RVp% > 20% subgroup there was a significant increase of AFB in comparison to the RVp% ≤ 20% subgroup (ΔAFB 1.8% vs. 0.0%, p = 0.03, respectively). In the increasing RVp% group (n = 28) the AFB increased whereas in the decreasing RVp% (n = 16) it remained stable (ΔAFB 0.67% vs. 0.0%, p = 0.034, respectively). Conclusions: DDD implantation in TBS patients is related to a significant reduction in AF symptoms, and left atrial diameter correlates with cumulative AFB in the mid-term observation. Stable RVp% > 20% is associated with AF progression whereas lower stable RVp% may stabilise AF development. Increasing RVp% may be associated with the AFB increase in comparison to the decreasing RVp% subgroup in which AFB remains stable

Textbook Neoadjuvant Outcome—Novel Composite Measure of Oncological Outcomes among Gastric Cancer Patients Undergoing Multimodal Treatment

The incidence of gastric cancer (GC) is expected to increase to 1.77 million cases by 2040. To improve treatment outcomes, GC patients are increasingly treated with neoadjuvant chemotherapy (NAC) prior to curative-intent resection. Although NAC enhances locoregional control and comprehensive patient care, survival rates remain poor, and further investigations should establish outcomes assessment of current clinical pathways. Individually assessed parameters have served as benchmarks for treatment quality in the past decades. The Outcome4Medicine Consensus Conference underscores the inadequacy of isolated metrics, leading to increased recognition and adoption of composite measures. One of the most simple and comprehensive is the “All or None” method, which refers to an approach where a specific set of criteria must be fulfilled for an individual to achieve the overall measure. This narrative review aims to present the rationale for the implementation of a novel composite measure, Textbook Neoadjuvant Outcome (TNO). TNO integrates five objective and well-established components: Treatment Toxicity, Laboratory Tests, Imaging, Time to Surgery, and Nutrition. It represents a desired, multidisciplinary care and hospitalization of GC patients undergoing NAC to identify the treatment- and patient-related data required to establish high-quality oncological care further. A key strength of this narrative review is the clinical feasibility and research background supporting the implementation of the first and novel composite measure representing the “ideal” and holistic care among patients with locally advanced esophago-gastric junction (EGJ) and GC in the preoperative period after NAC. Further analysis will correlate clinical outcomes with the prognostic factors evaluated within the TNO framework.</p

Textbook Neoadjuvant Outcome—Novel Composite Measure of Oncological Outcomes among Gastric Cancer Patients Undergoing Multimodal Treatment

The incidence of gastric cancer (GC) is expected to increase to 1.77 million cases by 2040. To improve treatment outcomes, GC patients are increasingly treated with neoadjuvant chemotherapy (NAC) prior to curative-intent resection. Although NAC enhances locoregional control and comprehensive patient care, survival rates remain poor, and further investigations should establish outcomes assessment of current clinical pathways. Individually assessed parameters have served as benchmarks for treatment quality in the past decades. The Outcome4Medicine Consensus Conference underscores the inadequacy of isolated metrics, leading to increased recognition and adoption of composite measures. One of the most simple and comprehensive is the “All or None” method, which refers to an approach where a specific set of criteria must be fulfilled for an individual to achieve the overall measure. This narrative review aims to present the rationale for the implementation of a novel composite measure, Textbook Neoadjuvant Outcome (TNO). TNO integrates five objective and well-established components: Treatment Toxicity, Laboratory Tests, Imaging, Time to Surgery, and Nutrition. It represents a desired, multidisciplinary care and hospitalization of GC patients undergoing NAC to identify the treatment- and patient-related data required to establish high-quality oncological care further. A key strength of this narrative review is the clinical feasibility and research background supporting the implementation of the first and novel composite measure representing the “ideal” and holistic care among patients with locally advanced esophago-gastric junction (EGJ) and GC in the preoperative period after NAC. Further analysis will correlate clinical outcomes with the prognostic factors evaluated within the TNO framework.</p