Final results from IMPROVE: a randomized, controlled, open-label, two-arm, cross-over phase IV study to determine patients' preference for everolimus in combination with exemestane or capecitabine in combination with bevacizumab in advanced HR-positive, HER2-negative breast cancer.

BACKGROUND: The objective of the IMPROVE study was patients' preference for either endocrine-based therapy or combined chemo- and anti-angiogenic therapy in advanced HR-positive/HER2-negative breast cancer. METHODS: In this randomized, cross-over phase IV study, 77 patients were recruited in 26 sites in Germany. Patients were randomized 1:1 to receive either capecitabine plus bevacizumab (Cap+Bev) as first-line therapy followed by cross-over to everolimus plus exemestane (Eve+Exe) as second-line therapy (Arm A) or the reverse sequence (Arm B). The primary endpoint was patients' preference for either regimen, assessed by the Patient Preference Questionnaire 12 weeks after cross-over. Key secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and quality of life (QoL). RESULTS: 61.5% of patients preferred Cap+Bev (p = 0.1653), whereas 15.4% preferred Eve+Exe and 23.1% were indecisive. Physicians showed a similar tendency towards Cap+Bev (58.1%) as the preferred regimen versus Eve+Exe (32.3%). Median first-line PFS was longer for Cap+Bev than for Eve+Exe (11.1 months versus 3.5 months). Median second-line PFS was similar between Cap+Bev and Eve+Exe (3.6 months versus 3.7 months). Median OS was comparable between Arm A (28.8 months) and Arm B (24.7 months). 73.0% and 52.6% (first-/second-line, Cap+Bev) and 54.1% and 52.9% (first-/second-line, Eve+Exe) of patients experienced grade 3/4 TEAEs. No treatment-related deaths occurred. QoL and treatment satisfaction were not significantly different between arms or treatment lines. CONCLUSIONS: Patients tended to favor Cap+Bev over Eve+Exe, which was in line with physicians' preference. Cap+Bev showed superior first-line PFS, while QoL was similar in both arms. No new safety signals were reported. TRIAL REGISTRATION: EudraCT No: 2013-005329-22. Registered on 19 August 20.

VicTORia: a randomised phase II study to compare vinorelbine in combination with the mTOR inhibitor everolimus versus vinorelbine monotherapy for second-line chemotherapy in advanced HER2-negative breast cancer.

PURPOSE: Improving the outcome of patients with HER2-negative metastatic breast cancer experiencing tumour progression following first-line chemotherapy remains an urgent medical need. The purpose of the VicTORia trial was to show superiority of everolimus in combination with vinorelbine versus vinorelbine monotherapy as second-line chemotherapy for patients with advanced HER2 negative breast cancer. METHODS: In this randomised phase II trial, 133 patients were recruited in 32 centres in Germany. Patients were randomised 1:1 to second-line chemotherapy either with vinorelbine plus everolimus (arm1) or vinorelbine alone (arm2). Primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS rate at 6 months, overall survival (OS), overall response rate (ORR) and safety. Baseline PI3 K mutational status was determined in plasma samples. RESULTS: Median progression-free survival was not different between arms (arm1 vs. arm2: 4.01 months, 95% CI 2.40-6.09 vs. 4.08, 95% CI 2.80-5.33). PFS rate at 6 months (arm1 vs. arm2: 39.4%, 95% CI 27.6-50.9% vs. 36.6%, 95% CI 24.6-48.6%), median OS (arm1 vs. arm2: 16.3 months, 95% CI 11.4-19.0 vs. 13.8 months, 95% CI 10.2-19.1) and ORR were not different between arms. Most frequent grade 3/4 adverse events were neutropenia (50% vs. 40%), gastrointestinal toxicities (19.1% vs. 6.1%), and infections (19.1% vs. 7.7%). PI3 K mutational status was neither associated with PFS nor with OS. CONCLUSION: Although well tolerated, the efficacy of everolimus and vinorelbine combination therapy was not superior to vinorelbine monotherapy. There was no correlation between PI3 K mutational status and efficacy. EudracCT No 2011-001024-38, ClinicalTrials.gov No NCT01520103.

Protons migrate along interfacial water without significant contributions from jumps between ionizable groups on the membrane surface.

Proton diffusion along membrane surfaces is thought to be essential for many cellular processes such as energy transduction. Commonly, it is treated as a succession of jumps between membrane-anchored proton-binding sites. Our experiments provide evidence for an alternative model. We released membrane-bound caged protons by UV flashes and monitored their arrival at distant sites by fluorescence measurements. The kinetics of the arrival is probed as a function of distance for different membranes and for different water isotopes. We found that proton diffusion along the membrane is fast even in the absence of ionizable groups in the membrane, and it decreases strongly in D(2)O as compared to H(2)O. We conclude that the fast proton transport along the membrane is dominated by diffusion via interfacial water, and not via ionizable lipid moieties.

Final Results from RIBBIT: A Randomized Phase III Study to Evaluate Efficacy and Quality of Life in Patients with Metastatic Hormone Receptor-Positive, HER2-Negative Breast Cancer Receiving Ribociclib in Combination with Endocrine Therapy or Chemotherapy with or without Bevacizumab in the First-Line Setting.

Background: We investigated the efficacy and health-related quality of life (HRQoL) in patients receiving either ribociclib plus endocrine therapy (ET) or chemotherapy with/without bevacizumab as first-line treatment of metastatic hormone receptor (HR)-positive, HER2-negative breast cancer (BC). Patients and Methods: In this randomized, phase III study (RIBBIT), 38 patients diagnosed with metastatic HR-positive, HER2-negative BC with presence of visceral metastases recruited between May 2018 and December 2020 were randomly assigned in a 1:1 ratio to either arm A (ribociclib + ET) or arm B (chemotherapy with/without bevacizumab) at 12 sites in Germany. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), overall survival (OS), patient-reported HRQoL, and frequency and type of adverse events. During study conduction, the recruitment rate was persistently and considerably lower than originally expected. Therefore, the recruitment was ended prematurely. The study was initially designed to enroll and randomize 158 patients. Results: Median [95% CI] PFS was 27.3 months [19.1 - NA, parameter not estimable] in arm A and 15.8 months [8.2 - NA] in arm B. Complete responses were achieved only in arm A (n = 2, 10.5%). The ORR [95% CI] between arm A (57.9% [33.5-79.7]) and arm B (52.6% [28.9-75.6]) was comparable. Median OS [95% CI] was not reached in arm A, while in arm B median OS was 28.4 months [25.0 - NA]. Patients in arm A reported less burden by side-effects. No new safety signals emerged. Conclusion: Treatment of patients with visceral metastatic HR-positive, HER2-negative BC with ribociclib in combination with ET showed a tendency toward a more favorable clinical outcome. Despite small numbers of patients and sites, this head-to-head comparison with chemotherapy supports the use of ribociclib with ET in patients with visceral metastasis at risk of fast disease progression.

A K+-selective cGMP-gated ion channel controls chemosensation of sperm.

Eggs attract sperm by chemical factors, a process called chemotaxis. Sperm from marine invertebrates use cGMP signalling to transduce incident chemoattractants into changes in the Ca2+ concentration in the flagellum, which control the swimming behaviour during chemotaxis. The signalling pathway downstream of the synthesis of cGMP by a guanylyl cyclase is ill-defined. In particular, the ion channels that are involved in Ca2+ influx and their mechanisms of gating are not known. Using rapid voltage-sensitive dyes and kinetic techniques, we record the voltage response that is evoked by the chemoattractant in sperm from the sea urchin Arbacia punctulata. We show that the chemoattractant evokes a brief hyperpolarization followed by a sustained depolarization. The hyperpolarization is caused by the opening of K+-selective cyclic-nucleotide-gated (CNG) channels in the flagellum. Ca2+ influx commences at the onset of recovery from hyperpolarization. The voltage threshold of Ca2+ entry indicates the involvement of low-voltage-activated Ca(v) channels. These results establish a model of chemosensory transduction in sperm whereby a cGMP-induced hyperpolarization opens Ca(v) channels by a 'recovery-from-inactivation' mechanism and unveil an evolutionary kinship between transduction mechanisms in sperm and photoreceptors.

Relating ligand binding to activation gating in CNGA2 channels.

Cyclic nucleotide-gated (CNG) ion channels mediate sensory signal transduction in photoreceptors and olfactory cells. Structurally, CNG channels are heterotetramers composed of either two or three homologue subunits. Although it is well established that activation is a cooperative process of these subunits, it remains unknown whether the cooperativity is generated by the ligand binding, the gating, or both, and how the subunits interact. In this study, the action of homotetrameric olfactory-type CNGA2 channels was studied in inside-out membrane patches by simultaneously determining channel activation and ligand binding, using the fluorescent cGMP analogue 8-DY547-cGMP as the ligand. At concentrations of 8-DY547-cGMP < 1 microM, steady-state binding was larger than steady-state activation, whereas at higher concentrations it was smaller, generating a crossover of the steady-state relationships. Global analysis of these relationships together with multiple activation time courses following cGMP jumps showed that four ligands bind to the channels and that there is significant interaction between the binding sites. Among the binding steps, the second is most critical for channel opening: its association constant is three orders of magnitude smaller than the others and it triggers a switch from a mostly closed to a maximally open state. These results contribute to unravelling the role of the subunits in the cooperative mechanism of CNGA2 channel activation and could be of general relevance for the action of other ion channels and receptors.

Endometrial Cancer. Guideline of the DGGG, DKG and DKH (S3-Level, AWMF Registry Number 032/034-OL, September 2022). Part 1 with Recommendations on the Epidemiology, Screening, Diagnosis and Hereditary Factors of Endometrial Cancer, Geriatric Assessment and Supply Structures.

Summary The S3-guideline on endometrial cancer, first published in April 2018, was reviewed in its entirety between April 2020 and January 2022 and updated. The review was carried out at the request of German Cancer Aid as part of the Oncology Guidelines Program and the lead coordinators were the German Society for Gynecology and Obstetrics (DGGG), the Gynecology Oncology Working Group (AGO) of the German Cancer Society (DKG) and the German Cancer Aid (DKH). The guideline update was based on a systematic search and assessment of the literature published between 2016 and 2020. All statements, recommendations and background texts were reviewed and either confirmed or amended. New statements and recommendations were included where necessary. Aim The use of evidence-based risk-adapted therapies to treat women with endometrial cancer of low risk prevents unnecessarily radical surgery and avoids non-beneficial adjuvant radiation therapy and/or chemotherapy. For women with endometrial cancer and a high risk of recurrence, the guideline defines the optimum level of radical surgery and indicates whether chemotherapy and/or adjuvant radiation therapy is necessary. This should improve the survival rates and quality of life of these patients. The S3-guideline on endometrial cancer and the quality indicators based on the guideline aim to provide the basis for the work of certified gynecological cancer centers. Methods The guideline was first compiled in 2018 in accordance with the requirements for S3-level guidelines and was updated in 2022. The update included an adaptation of the source guidelines identified using the German Instrument for Methodological Guideline Appraisal (DELBI). The update also used evidence reviews which were created based on selected literature obtained from systematic searches in selected literature databases using the PICO process. The Clinical Guidelines Service Group was tasked with carrying out a systematic search and assessment of the literature. Their results were used by interdisciplinary working groups as a basis for developing suggestions for recommendations and statements which were then modified during structured online consensus conferences and/or additionally amended online using the DELPHI process to achieve a consensus. Recommendations Part 1 of this short version of the guideline provides recommendations on epidemiology, screening, diagnosis, and hereditary factors. The epidemiology of endometrial cancer and the risk factors for developing endometrial cancer are presented. The options for screening and the methods used to diagnose endometrial cancer are outlined. Recommendations are given for the prevention, diagnosis, and therapy of hereditary forms of endometrial cancer. The use of geriatric assessment is considered and existing structures of care are presented.

Coumarin-based octopamine phototriggers and their effects on an insect octopamine receptor.

We have developed and characterized efficient caged compounds of the neurotransmitter octopamine. For derivatization, we introduced [6-bromo-8-(diethylaminomethyl)-7-hydroxycoumarin-4-yl]methoxycarbonyl (DBHCMOC) and {6-bromo-7-hydroxy-8-[(piperazin-1-yl)methyl]coumarin-4-yl}methoxycarbonyl (PBHCMOC) moieties as novel photo-removable protecting groups. The caged compounds were functionally inactive when applied to heterologously expressed octopamine receptors (AmOctα1R). Upon irradiation with UV-visible or IR light, bioactive octopamine was released and evoked Ca2+ signals in AmOctα1R-expressing cells. The pronounced water solubility of compounds 2-4 in particular holds great promise for these substances as excellent phototriggers of this important neurotransmitter.

Doxycycline-dependent photoactivated gene expression in eukaryotic systems.

High spatial and temporal resolution of conditional gene expression is typically difficult to achieve in whole tissues or organisms. We synthesized two reversibly inhibited, photoactivatable ('caged') doxycycline derivatives with different membrane permeabilities for precise spatial and temporal light-controlled activation of transgenes based on the 'Tet-on' system. After incubation with caged doxycycline or caged cyanodoxycycline, we induced gene expression by local irradiation with UV light or by two-photon uncaging in diverse biological systems, including mouse organotypic brain cultures, developing mouse embryos and Xenopus laevis tadpoles. The amount of UV light needed for induction was harmless as we detected no signs of toxicity. This method allows high-resolution conditional transgene expression at different spatial scales, ranging from single cells to entire complex organisms.

Diagnosis, Therapy and Follow-up of Cervical Cancer. Guideline of the DGGG, DKG and DKH (S3-Level, AWMF Registry No. 032/033OL, May 2021) - Part 2 with Recommendations on Psycho-oncology, Rehabilitation, Follow-up, Recurrence, Palliative Therapy and Healthcare Facilities.

Aim This is an update of the interdisciplinary S3-guideline on the Diagnosis, Therapy and Follow-up of Cervical Cancer (AWMF Registry No. 032/033OL), published in March 2021. The work on the updated guideline was funded by German Cancer Aid (Deutsche Krebshilfe) as part of the German Guideline Program in Oncology. The guideline was coordinated by the German Society of Gynecology and Obstetrics ( Deutsche Gesellschaft für Gynäkologie und Geburtshilfe , DGGG) and the Working Group on Gynecological Oncology ( Arbeitsgemeinschaft Gynäkologische Onkologie , AGO) of the German Cancer Society ( Deutsche Krebsgesellschaft , DKG). Method The process used to update the 2014 S3-guideline was based on an appraisal of the available evidence using the criteria of evidence-based medicine, adaptations of existing evidence-based national and international guidelines or - if evidence was lacking - on the consensus of the specialists involved in compiling the update. After an initial review of the current literature was carried out according to a prescribed algorithm, several areas were identified which, in contrast to the predecessor version from September 2014, required new recommendations or statements which would take account of more recently published literature and the recent appraisal of new evidence. Recommendations The short version of this guideline consists of recommendations and statements on palliative therapy and follow-up of patients with cervical cancer. The most important aspects included in this updated guideline are the new FIGO classification published in 2018, the radical open surgery approach used to treat cervical cancer up to FIGO stage IB1, and the use of the sentinel lymph node technique for tumors ≤ 2 cm. Other changes include the use of PET-CT, new options in radiotherapy (e.g., intensity-modulated radiotherapy, image-guided adaptive brachytherapy), and drug therapies to treat recurrence or metastasis.

Diagnosis, Therapy and Follow-up of Cervical Cancer. Guideline of the DGGG, DKG and DKH (S3-Level, AWMF Registry No. 032/033OL, May 2021) - Part 1 with Recommendations on Epidemiology, Screening, Diagnostics and Therapy.

Aim This update of the interdisciplinary S3 guideline on the Diagnosis, Therapy and Follow-up of Cervical Cancer (AWMF Registry No. 032/033OL) was published in March 2021. This updated guideline was funded by German Cancer Aid (Deutsche Krebshilfe) as part of the German Guideline Program in Oncology. The guideline was coordinated by the German Society of Gynecology and Obstetrics ( Deutsche Gesellschaft für Gynäkologie und Geburtshilfe , DGGG) and the Working Group on Gynecological Oncology ( Arbeitsgemeinschaft Gynäkologische Onkologie , AGO) of the German Cancer Society ( Deutsche Krebsgesellschaft , DKG). Method The process of updating the S3 guideline dating from 2014 was based on an appraisal of the available evidence using the criteria of evidence-based medicine, adaptations of existing evidence-based national and international guidelines or - if evidence was lacking - on a consensus of the specialists involved in compiling the update. After an initial review of the current literature was carried out according to a prescribed algorithm, several areas were identified which, in contrast to the predecessor version from September 2014, required new recommendations or statements which took account of more recently published literature and the appraisal of the new evidence. Recommendations The short version of this guideline consists of recommendations and statements on the epidemiology, screening, diagnostic workup and therapy of patients with cervical cancer. The most important new aspects included in this updated guideline include the newly published FIGO classification of 2018, the radical open surgery approach for cervical cancers up to FIGO stage IB1, and use of the sentinel lymph node technique for tumors ≤ 2 cm. Other changes include the use of PET-CT, new options in radiotherapy (e.g., intensity-modulated radiotherapy, image-guided adaptive brachytherapy), and drug therapies to treat recurrence or metastasis.

The signal flow and motor response controling chemotaxis of sea urchin sperm.

The signalling pathway and the behavioural strategy underlying chemotaxis of sperm are poorly understood. We have studied the cellular events and motor responses that mediate chemotaxis of sperm from the sea urchin Arbacia punctulata. Here we show that resact, a chemoattractant peptide, initiates a rapid and transient rise in the concentration of cyclic GMP, followed by a transient influx of Ca2+. The binding of a single resact molecule elicits a Ca2+ response, and 50-100 bound molecules saturate the response. The ability to register single molecules is reminiscent of the single-photon sensitivity of rod photoreceptors. Both resact and cyclic nucleotides cause a turn or brief tumbling in the swimming path of sperm. We conclude that a cGMP-mediated increase in the Ca2+ concentration induces the primary motor response of sperm to the chemoattractant.

[8-[Bis(carboxymethyl)aminomethyl]-6-bromo-7-hydroxycoumarin-4-yl]methyl moieties as photoremovable protecting groups for compounds with COOH, NH2, OH, and C=O functions.

We introduce a variant of coumarin-based photoactivatable protecting groups and use it exemplarily for caging of a carboxylic acid, an amine, a phenol, and a carbonyl compound. The caged compounds are efficiently photolyzed at long-wavelength UV/vis irradiation. Compared to the corresponding (6-bromo-7-hydroxycoumarin-4-yl)methyl (Bhc) derivatives, the novel coumarin-type caged compounds are distinguished by (i) dramatically increased solubilities in aqueous buffers, (ii) lower pK(a) values of the C7 hydroxyl of the coumarin chromophore, thus permitting efficient photorelease at lower pH, and (iii) higher photolysis quantum yields in the case of photoprotected carbonyl compounds. The primary step of the photocleavages occurs with rate constants of about 10(9) s(-1).

Association of Disease Progression With Health-Related Quality of Life Among Adults With Breast, Lung, Pancreatic, and Colorectal Cancer.

Importance: Mortality, morbidity, and health-related quality of life (HRQoL) are patient-relevant end points generally considered in the early benefit assessments of new cancer treatments. Progression-related end points, such as time to progression or progression-free survival, are not included, although patients and physicians testify to the detrimental association of disease progression with HRQoL. Objective: To examine the association of disease progression and HRQoL in 4 prevalent solid-cancer entities in routine clinical practice. Design, Setting, and Participants: This cohort study evaluated data from 4 prospective, nonintervention, multicenter registries collected between 2011 and 2018 in 203 centers in Germany. Patients' HRQoL was assessed regularly for up to 5 years. The change in HRQoL scores after disease progression was examined with linear mixed models, adjusting for demographic and clinical covariates. Patients with metastatic breast, pancreatic, lung, and colorectal cancer were recruited at the start of systemic first-line treatment. Data analysis was performed from February 2019 to April 2019. Exposures: All patients received systemic, palliative first-line treatment according to their physician's choice. Main Outcomes and Measures: The primary outcome was deterioration of HRQoL associated with disease progression, as measured by 4 validated questionnaires: Functional Assessment of Cancer Therapy-General version 4, European Organization for Research and Treatment of Cancer QLQ-C30 version 3.0, European Organization for Research and Treatment of Cancer QLQ-C15-PAL version 1, and Hospital Anxiety and Depression Scale. Results: More than 8000 questionnaires from 2314 patients with 2562 documented disease progressions were analyzed. In total, 464 patients had breast cancer (464 [100.0%] female; median [range] age, 61.6 [26.4-90.1] years), 807 patients had pancreatic cancer (352 [43.6%] female; median [range] age, 70.0 [39.0-93.0] years), 341 patients had lung cancer (118 [34.6%] female; median [range] age, 65.9 [28.4-88.2] years), and 702 patients had colorectal cancer (248 [35.3%] female; median [range] age, 66.9 [26.9-92.1] years). The first disease progression was associated with a statistically significant worsening of 37 of 45 HRQoL scales; for 17 of these scales, the worsening was clinically meaningful. Scale scores for appetite loss (pancreatic cancer, 10.2 points [95% CI, 6.8-13.5 points]; lung cancer, 10.8 points [95% CI, 5.4-16.2 points]; colorectal cancer, 8.8 points [95% CI, 5.5-12.2]; all P < .001), physical functioning (pancreatic cancer, 6.2 points [95% CI, 3.8-8.5 points]; lung cancer, 8.4 points [95% CI, 5.4-11.5 points]; colorectal cancer, 5.0 points [95% CI, 3.0-7.0 points]; all P < .001), and fatigue (pancreatic cancer, 5.5 points [95% CI, 3.0-7.9 points]; lung cancer, 7.7 points [95% CI, 4.3-11.1]; colorectal cancer, 4.5 points [95% CI, 2.1-6.9 points]; all P < .001) were most affected, irrespective of the type of cancer. The association with global HRQoL was most pronounced in lung cancer (6.7 points [95% CI, 3.5-9.9 points]; P < .001) and pancreatic cancer (5.4 points [95% CI, 3.3-7.5 points]; P < .001) and less in colorectal cancer (3.5 points [95% CI, 1.3-5.7 points]; P = .002) and breast cancer (2.4 points [95% CI, 1.0-3.9 points]; P = .001). The second progression was associated with an even larger decrease in HRQoL. Conclusions and Relevance: These findings suggest that disease progression is associated with a deterioration in HRQoL among patients with metastatic breast, pancreatic, lung, and colorectal cancer. This evidence highlights the importance of progression-related end points, such as time to progression and progression-free survival, as additional patient-relevant end points when evaluating the benefit of new treatments for patients with metastatic cancer.

Wavelength-selective photoactivatable protecting groups for thiols.

We developed and characterized efficient, remarkably water-soluble photolabile protecting groups for thiols based on 2-nitrobenzyl and (coumarin-4-yl)methyl chromophores, among them two new ones. The protecting groups allow, due to their different absorption maxima, wavelength-selective photocleavage of binary mixtures of cysteine derivatives protected at the thiol function with various photolabile protecting groups by irradiation with light. The concept was also functional with the two different S-protected cysteine residues in derivatives of the model peptide resact. Selective photolysis could be achieved for the peptides Ac(0)-Cys(1)(BCMACMOC),Cys(8)(7,8BCMCMOC)-resact and Ac(0)-Cys(1)(C4MNB),Cys(8)(BCMACMOC)-resact by irradiation with light of > or = 402 nm or > or = 436 nm wavelength, respectively, followed by irradiation at lambda > or = 325 nm.

Caged progesterone: a new tool for studying rapid nongenomic actions of progesterone.

Ketalization of the biomolecule progesterone with (6-bromo-7-hydroxycoumarin-4-yl)ethane-1,2-diol gives the photolabile progesterone derivatives 3 and 4. These compounds display dramatically reduced bioactivity and release progesterone upon irradiation with UV/vis or IR light. In particular, 4 can be used to perform concentration-jump experiments with high temporal and spatial resolution that allows one to study elegantly the mechanisms of rapid nongenomic cellular events evoked by progesterone. The usefulness of 4 was demonstrated by measurement of changes in swimming behavior of single human sperm caused by progesterone-induced Ca(2+) influx in the sperm flagellum.

Competition between cleavage and decarboxylation in photolysis of alpha-carboxy-2-nitrobenzyl protected cysteine derivatives.

Photolysis of model peptides containing alpha-carboxy-2-nitrobenzyl (CNB) or alpha-carboxy-4,5-dimethoxy-2-nitrobenzyl (CDMNB) protected cysteines in aqueous solution gives the expected 2-nitrobenzyl-type photocleavage and can be accompanied by photodecarboxylation depending on structural aspects.

Thermodynamics of activation gating in olfactory-type cyclic nucleotide-gated (CNGA2) channels.

Olfactory-type cyclic nucleotide-gated (CNG) ion channels open by the binding of cyclic nucleotides to a binding domain in the C-terminus. Employing the Eyring rate theory, we performed a thermodynamic analysis of the activation gating in homotetrameric CNGA2 channels. Lowering the temperature shifted the concentration-response relationship to lower concentrations, resulting in a decrease of both the enthalpy DeltaH and entropy DeltaS upon channel opening, suggesting that the order of an open CNGA2 channel plus its environment is higher than that of the closed channel. Activation time courses induced by cGMP concentration jumps were used to study thermodynamics of the transition state. The activation enthalpies DeltaH++ were positive at all cGMP concentrations. In contrast, the activation entropy DeltaS++ was positive at low cGMP concentrations and became then negative at increasing cGMP concentrations. The enthalpic and entropic parts of the activation energies approximately balance each other at all cGMP concentrations, leaving the free enthalpy of activation in the range between 19 and 21 kcal/mol. We conclude that channel activation proceeds through different pathways at different cGMP concentrations. Compared to the unliganded channel, low cGMP concentrations generate a transitional state of lower order whereas high cGMP concentrations generate a transitional state of higher order.

Interdisciplinary Diagnosis, Therapy and Follow-up of Patients with Endometrial Cancer. Guideline (S3-Level, AWMF Registry Nummer 032/034-OL, April 2018) - Part 1 with Recommendations on the Epidemiology, Screening, Diagnosis and Hereditary Factors of Endometrial Cancer.

Summary The first German interdisciplinary S3-guideline on the diagnosis, therapy and follow-up of patients with endometrial cancer was published in April 2018. Funded by German Cancer Aid as part of an Oncology Guidelines Program, the lead coordinators of the guideline were the German Society of Gynecology and Obstetrics (DGGG) and the Gynecological Oncology Working Group (AGO) of the German Cancer Society (DKG). Purpose The use of evidence-based, risk-adapted therapy to treat low-risk women with endometrial cancer avoids unnecessarily radical surgery and non-useful adjuvant radiotherapy and/or chemotherapy. This can significantly reduce therapy-induced morbidity and improve the patient's quality of life as well as avoiding unnecessary costs. For women with endometrial cancer and a high risk of recurrence, the guideline defines the optimal surgical radicality together with the appropriate chemotherapy and/or adjuvant radiotherapy where required. The evidence-based optimal use of different therapeutic modalities should improve survival rates and the quality of life of these patients. The S3-guideline on endometrial cancer is intended as a basis for certified gynecological cancer centers. The aim is that the quality indicators established in this guideline will be incorporated in the certification processes of these centers. Methods The guideline was compiled in accordance with the requirements for S3-level guidelines. This includes, in the first instance, the adaptation of source guidelines selected using the DELBI instrument for appraising guidelines. Other consulted sources include reviews of evidence which were compiled from literature selected during systematic searches of literature databases using the PICO scheme. In addition, an external biostatistics institute was commissioned to carry out a systematic search and assessment of the literature for one area of the guideline. The identified materials were used by the interdisciplinary working groups to develop suggestions for Recommendations and Statements, which were then modified during structured consensus conferences and/or additionally amended online using the DELPHI method with consent being reached online. The guideline report is freely available online. Recommendations Part 1 of this short version of the guideline presents recommendations on epidemiology, screening, diagnosis and hereditary factors, The epidemiology of endometrial cancer and the risk factors for developing endomentrial cancer are presented. The options for screening and the methods used to diagnose endometrial cancer including the pathology of the cancer are outlined. Recommendations are given for the prevention, diagnosis, and therapy of hereditary forms of endometrial cancer.

Interdisciplinary Diagnosis, Therapy and Follow-up of Patients with Endometrial Cancer. Guideline (S3-Level, AWMF Registry Number 032/034-OL, April 2018) - Part 2 with Recommendations on the Therapy and Follow-up of Endometrial Cancer, Palliative Care, Psycho-oncological/Psychosocial Care/Rehabilitation/Patient Information and Healthcare Facilities.

Summary The first German interdisciplinary S3-guideline on the diagnosis, therapy and follow-up of patients with endometrial cancer was published in April 2018. Funded by German Cancer Aid as part of an Oncology Guidelines Program, the lead coordinators of the guideline were the German Society of Gynecology and Obstetrics (DGGG) and the Gynecological Oncology Working Group (AGO) of the German Cancer Society (DKG). Purpose Using evidence-based, risk-adapted therapy to treat low-risk women with endometrial cancer avoids unnecessarily radical surgery and non-useful adjuvant radiotherapy and/or chemotherapy. This can significantly reduce therapy-induced morbidity and improve the patient's quality of life as well as avoiding unnecessary costs. For women with endometrial cancer and a high risk of recurrence, the guideline defines the optimal extent of surgical radicality together with the appropriate chemotherapy and/or adjuvant radiotherapy if required. An evidence-based optimal use of different therapeutic modalities should improve the survival rates and quality of life of these patients. This S3-guideline on endometrial cancer is intended as a basis for certified gynecological cancer centers. The aim is that the quality indicators established in this guideline will be incorporated in the certification processes of these centers. Methods The guideline was compiled in accordance with the requirements for S3-level guidelines. This includes, in the first instance, the adaptation of source guidelines selected using the DELBI instrument for appraising guidelines. Other consulted sources included reviews of evidence, which were compiled from literature selected during systematic searches of literature databases using the PICO scheme. In addition, an external biostatistics institute was commissioned to carry out a systematic search and assessment of the literature for one part of the guideline. Identified materials were used by the interdisciplinary working groups to develop suggestions for Recommendations and Statements, which were then subsequently modified during structured consensus conferences and/or additionally amended online using the DELPHI method, with consent between members achieved online. The guideline report is freely available online. Recommendations Part 2 of this short version of the guideline presents recommendations for the therapy of endometrial cancer including precancers and early endometrial cancer as well as recommendations on palliative medicine, psycho-oncology, rehabilitation, patient information and healthcare facilities to treat endometrial cancer. The management of precancers of early endometrial precancerous conditions including fertility-preserving strategies is presented. The concept used for surgical primary therapy of endometrial cancer is described. Radiotherapy and adjuvant medical therapy to treat endometrial cancer and uterine carcinosarcomas are described. Recommendations are given for the follow-up care of endometrial cancer, recurrence and metastasis. Palliative medicine, psycho-oncology including psychosocial care, and patient information and rehabilitation are presented. Finally, the care algorithm and quality assurance steps for the diagnosis, therapy and follow-up of patients with endometrial cancer are outlined.