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Abstract The cardiac conduction system in large carnivores, such as the African lion (Panthera leo), represents a significant knowledge gap in both veterinary science and in cardiac electrophysiology. Short QT intervals have been reported from zoo‐kept, anaesthetized lions, and our goal was to record the first ECGs from wild, conscious lions roaming freely, and compare them to zoo‐kept lions under the hypothesis that short QT is unique to zoo‐kept lions. Macroscopic and histological examinations were performed on heart tissue removed from nine healthy zoo lions. ECGs were recorded from the nine anaesthetized zoo‐kept lions, and from 15 anaesthetized and conscious wild lions in Africa. Our histological and topographical description of the lion's heart matched what has previously been published. In conscious lions, the ECG recordings revealed a mean heart rate of 70 ± 4 beats/min, with faster heart rates during the night. PQ and QT intervals were heart rate dependent in the conscious lions. Interestingly, QT intervals recorded in wild lions were markedly longer than QT intervals from zoo lions (398 ± 40 vs. 297 ± 9 ms, respectively; P

Background Direct-to-implant breast reconstruction (DIR) is becoming more and more accepted. There is a lack of high-quality studies assessing differences in patient-reported quality of life (QoL) between different implant placement methods. The aim of this randomized controlled (clinical) trial was to compare QoL between women reconstructed by sub- or prepectoral implant placement.

Abstract Classically, G protein-coupled receptors (GPCRs) promote signaling at the plasma membrane through activation of heterotrimeric Gαβγ proteins, followed by the recruitment of GPCR kinases and βarrestin (βarr) to initiate receptor desensitization and internalization. However, studies demonstrated that some GPCRs continue to signal from internalized compartments, with distinct cellular responses. Both βarr and Gβγ contribute to such non-canonical endosomal G protein signaling, but their specific roles and contributions remain poorly understood. Here, we demonstrate that the vasopressin V2 receptor (V2R)–βarr complex scaffolds Gβγ at the plasma membrane through a direct interaction with βarr, enabling its transport to endosomes. Gβγ subsequently potentiates Gαs endosomal translocation, presumably to regenerate an endosomal pool of heterotrimeric Gs. This work shines light on the mechanism underlying G protein subunits translocation from the plasma membrane to the endosomes and provides a basis for understanding the role of βarr in mediating sustained G protein signaling.

Chronological records of elemental concentrations in fish otoliths are a widely used tool to infer the environmental conditions experienced by individual fish. To interpret elemental signals within the otolith, it is important to understand how both external and internal factors impact ion uptake, transport and incorporation. In this study, we have combined chronological records from otoliths and archival data storage tags to quantify the influence of internal (sex, size, age, growth) and external (temperature, depth, salinity) conditions on otolith elemental chemistry of cod (Gadus morhua) in natural settings of the Baltic Sea. This study focused on elements primarily under physiological control: Phosphorus (P), magnesium (Mg) and zinc (Zn); and elements under environmental control: Strontium (Sr), barium (Ba) and manganese (Mn). Based on known spatial and temporal patterns in environmental conditions and fish size, growth, and maturity, we posed a series of hypotheses of expected otolith element patterns. Partial effects of internal and external drivers on element concentration were analyzed using a Linear Mixed Model approach with random variables (fish and year). Predicted effects of otolith concentrations of all elements under physiological control (P, Mg, Zn) showed similar trends, with distinct seasonal patterns (lowest concentration in late spring, highest concentrations in winter), and a positive correlation with water temperature, in addition to higher Zn and lower P in spawning individuals. Predicted effects of otolith concentrations of elements expected to be predominantly under environmental control showed the predicted geographic and depth-related trends based on ambient salinity (Ba) and coastal hypoxia (Mn). However, contrary to expectation, Sr was unrelated to salinity. Predicted otolith Ba, Sr and Mn concentrations also exhibited pronounced seasonal patterns that were out of phase with each other but appeared to be partly explained by spawning/feeding migrations. While performing laboratory validation studies for adult fish is typically not possible, these results highlight the importance of assessing local water chemistry and freshwater endmembers in one’s study system before otolith elemental chemistry can be reliably used to reconstruct fish habitat use and environmental histories.

IntroductionDiabetic peripheral neuropathy (DPN) is a common complication of both type 1 (T1D) and type 2 diabetes (T2D). No cure for DPN is available, but several potential targets have been proposed for treatment. Heat shock proteins (HSPs) are known to respond to both hyper- and hypoglycemia. DPN can be diagnosed using electrophysiology and studied using peripheral nerve biopsies.AimThis study aimed to analyze the presence and patterns of HSPs in peripheral nerve biopsies from subjects with T1D, T2D, and healthy controls.MethodsPosterior interosseous nerves (PIN) from a total of 56 subjects with T1D (n = 9), with T2D (n = 24), and without diabetes (i.e., healthy controls, n = 23) were harvested under local anesthesia and prepared for quantitative mass spectrometry analysis. Protein intensities were associated with electrophysiology data of the ulnar nerve and morphometry of the same PIN, and differences in protein intensities between groups were analyzed.ResultsIn total, 32 different HSPs were identified and quantified in the nerve specimens. No statistically significant differences were observed regarding protein intensities between groups. Furthermore, protein intensities did not correlate with amplitude or conduction velocity in the ulnar nerve or with the myelinated nerve fiber density of PIN.ConclusionQuantitative proteomics can be used to study HSPs in nerve biopsies, but no clear differences in protein quantities were observed between groups in this cohort.

Background The incidence of breast animation deformity (BAD) is reported to be substantial after direct-to-implant breast reconstruction with subpectoral implant placement. It has, however, never been examined if BAD can occur following prepectoral implant placement. Our primary aim was to compare the incidence and degree of BAD after direct-to-implant breast reconstruction using either subpectoral or prepectoral implant placement. Secondary aim of this study was to assess and compare the level of pain between sub- and prepectoral reconstructed women. Methods In this randomized controlled trial, patients were allocated to reconstruction by either subpectoral or prepectoral implant placement in accordance with the CONSORT guidelines. The degree of BAD was assessed by the “Nipple, Surrounding skin, Entire breast (NSE)” grading scale 12 months after surgery. The level of postoperative pain was assessed on a numerical pain rating scale. Results We found a significant difference in the degree of BAD favoring patients in the prepectoral group (23.8 vs. 100%, p

Abstract Physiological properties and function of the lymphatic system is still somewhat of a mystery. We report the current knowledge about human lymphatic vessel contractility and capability of adaptation. A literature search in PubMed identified studies published January 2000–September 2022. Inclusion criteria were studies investigating parameters related to contraction frequency, fluid velocity, and lymphatic pressure in vivo and ex vivo in human lymphatic vessels. The search returned 2885 papers of which 28 met the inclusion criteria. In vivo vessels revealed baseline contraction frequencies between 0.2 ± 0.2 and 1.8 ± 0.1 min1, velocities between 0.008 ± 0.002 and 2.3 ± 0.3 cm/s, and pressures between 4.5 (range 0.5–9.2) and 60.3 ± 2.8 mm Hg. Gravitational forces, hyperthermia, and treatment with nifedipine caused increases in contraction frequency. Ex vivo lymphatic vessels displayed contraction frequencies between 1.2 ± 0.1 and 5.5 ± 1.2 min−1. Exposure to agents affecting cation and anion channels, adrenoceptors, HCN channels, and changes in diameter‐tension properties all resulted in changes in functional parameters as known from the blood vascular system. We find that the lymphatic system is dynamic and adaptable. Different investigative methods yields alternating results. Systematic approaches, consensus on investigative methods, and larger studies are needed to fully understand lymphatic transport and apply this in a clinical context.

Abstract Heart failure is a multifactorial disease that affects an estimated 38 million people worldwide. Current pharmacotherapy of heart failure with reduced ejection fraction (HFrEF) includes combination therapy with angiotensin-converting enzyme inhibitors (ACEi) and β-adrenergic receptor blockers (β-AR blockers), a therapy also used as treatment for non-cardiac conditions. Our knowledge of the molecular changes accompanying treatment with ACEi and β-AR blockers is limited. Here, we applied proteomics and phosphoproteomics approaches to profile the global changes in protein abundance and phosphorylation state in cardiac left ventricles consequent to combination therapy of β-AR blocker and ACE inhibitor in HFrEF and control hearts. The phosphorylation changes induced by treatment were profoundly different for failing than for non-failing hearts. HFrEF was characterized by profound downregulation of mitochondrial proteins coupled with derangement of β-adrenergic and pyruvate dehydrogenase signaling. Upon treatment, phosphorylation changes consequent to HFrEF were reversed. In control hearts, treatment mainly led to downregulation of canonical PKA signaling. The observation of divergent signaling outcomes depending on disease state underscores the importance of evaluating drug effects within the context of the specific conditions present in the recipient heart.

Purpose Twenty-four hours of ambulatory blood pressure monitoring (ABPM) is recommended in several guidelines as the best method for diagnosing hypertension. In general, the prognostic value of ABPM is superior to single office blood pressure (BP) measurements. Unfortunately, some patients experience considerable discomfort during frequently repeated forceful cuff inflations. Materials and methods In this study we investigated the difference in mean daytime systolic BP (SBP) between low-frequency ABPM (LF-ABPM), measuring once every hour, and high-frequency ABPM (HF-ABPM), measuring three times an hour during daytime, and two times an hour during night-time. Results Seventy-one patients were included in the analysis. All included patients had an HF-ABPM performed first and within a few weeks they underwent an LF-ABPM. The average day time difference in SBP between the two frequencies was 3.8 mmHg (p-value = 0.07) for mild, 8.2 mmHg (p-value < 0.01) for moderate and 15 mmHg (p-value < 0.001) for severe hypertension. A similar pattern was seen for night-time SBP. This study suggests that mean BP is similar between the two measuring frequencies for normotensive and mild hypertensive patients, while HF-ABPM results in a higher 24-h mean BP for moderate- and severe hypertensive patients. Conclusion LF-ABPM may more correctly reflect the resting blood pressure in patients with moderate and severe hypertension.

Satellite glia are the major glial cells in sympathetic ganglia, enveloping neuronal cell bodies. Despite this intimate association, the extent to which sympathetic functions are influenced by satellite glia in vivo remains unclear. Here, we show that satellite glia are critical for metabolism, survival, and activity of sympathetic neurons and modulate autonomic behaviors in mice. Adult ablation of satellite glia results in impaired mTOR signaling, soma atrophy, reduced noradrenergic enzymes, and loss of sympathetic neurons. However, persisting neurons have elevated activity, and satellite glia-ablated mice show increased pupil dilation and heart rate, indicative of enhanced sympathetic tone. Satellite glia-specific deletion of Kir4.1, an inward-rectifying potassium channel, largely recapitulates the cellular defects observed in glia-ablated mice, suggesting that satellite glia act in part via K+-dependent mechanisms. These findings highlight neuron–satellite glia as functional units in regulating sympathetic output, with implications for disorders linked to sympathetic hyper-activity such as cardiovascular disease and hypertension.

Abstract Loss-of-function (LoF) mutations in KCNQ1, encoding the voltage-gated K+ channel Kv7.1, lead to long QT syndrome 1 (LQT1). LQT1 patients also present with post-prandial hyperinsulinemia and hypoglycaemia. In contrast, KCNQ1 polymorphisms are associated with diabetes, and LQTS patients have a higher prevalence of diabetes. We developed a mouse model with a LoF Kcnq1 mutation using CRISPR-Cas9 and hypothesized that this mouse model would display QT prolongation, increased glucose-stimulated insulin secretion and allow for interrogation of Kv7.1 function in islets. Mice were characterized by electrocardiography and oral glucose tolerance tests. Ex vivo, islet glucose-induced insulin release was measured, and beta-cell area quantified by immunohistochemistry. Homozygous mice had QT prolongation. Ex vivo, glucose-stimulated insulin release was increased in islets from homozygous mice at 12–14 weeks, while beta-cell area was reduced. Non-fasting blood glucose levels were decreased at this age. In follow-up studies 8–10 weeks later, beta-cell area was similar in all groups, while glucose-stimulated insulin secretion was now reduced in islets from hetero- and homozygous mice. Non-fasting blood glucose levels had normalized. These data suggest that Kv7.1 dysfunction is involved in a transition from hyper- to hyposecretion of insulin, potentially explaining the association with both hypoglycemia and hyperglycemia in LQT1 patients.

Two α-isoforms of the Na+,K+-ATPase (α1 and α2) are expressed in the cardiovascular system, and it is unclear which isoform is the preferential regulator of contractility. Mice heterozygous for the familial hemiplegic migraine type 2 (FHM2) associated mutation in the α2-isoform (G301R; α2+/G301R mice) have decreased expression of cardiac α2-isoform but elevated expression of the α1-isoform. We aimed to investigate the contribution of the α2-isoform function to the cardiac phenotype of α2+/G301R hearts. We hypothesized that α2+/G301R hearts exhibit greater contractility due to reduced expression of cardiac α2-isoform. Variables for contractility and relaxation of isolated hearts were assessed in the Langendorff system without and in the presence of ouabain (1 µM). Atrial pacing was performed to investigate rate-dependent changes. The α2+/G301R hearts displayed greater contractility than WT hearts during sinus rhythm, which was rate-dependent. The inotropic effect of ouabain was more augmented in α2+/G301R hearts than in WT hearts during sinus rhythm and atrial pacing. In conclusion, cardiac contractility was greater in α2+/G301R hearts than in WT hearts under resting conditions. The inotropic effect of ouabain was rate-independent and enhanced in α2+/G301R hearts, which was associated with increased systolic work.

Abstract Background Skin-sparing mastectomy followed by immediate implant-based breast reconstruction is a commonly used treatment for breast cancer. However, when placing the implant in a subpectoral pocket, a high incidence of breast animation deformity (BAD) has been reported. Besides the nuisance that BAD can cause, lifting of the pectoralis major muscle (PMM) can result in a more extended postoperative recovery period. When placing the implant solely prepectorally leaving the PMM undisturbed, the incidence and severity of BAD might be mitigated. However, new challenges may occur because of thinner skin cover. Methods/design A prospective, multi-centre, randomised controlled trial will be carried out with the primary aim of assessing and comparing the incidence and degree of BAD in women having a direct-to-implant breast reconstruction with either a prepectorally or a subpectorally placed implant. The secondary outcomes are shoulder and arm function, quality of life, aesthetic evaluation, length of stay, complications, need for surgical corrections, and development of capsular contracture. A total of 70 included patients will be followed under admittance and at clinical check-ups 3 months and 1 year after surgery. Discussion To our knowledge, this trial is the first randomised controlled trial evaluating and comparing subpectoral and prepectoral implant placement when performing direct-to-implant breast reconstruction following skin-sparing mastectomy. The results will hopefully provide us with a broader knowledge of the outcomes of immediate breast reconstruction, making better preoperative planning possible in the future by providing our patients with a more objective information. Trial registration ClinicalTrials.gov, ID: NCT03143335. Prospectively registered on 8 May 2017.

ObjectiveInvestigating the cardiovascular system is challenging due to its complex regulation by humoral and neuronal factors. Despite this complexity, many existing research methods are limited to the assessment of a few parameters leading to an incomplete characterization of cardiovascular function. Thus, we aim to establish a murine in vivo model for integrated assessment of the cardiovascular system under conditions of controlled heart rate. Utilizing this model, we assessed blood pressure, cardiac output, stroke volume, total peripheral resistance, and electrocardiogram (ECG).HypothesisWe hypothesize that (i) our in vivo model can be utilized to investigate cardiac and vascular responses to pharmacological intervention with the α1-agonist phenylephrine, and (ii) we can study cardiovascular function during artificial pacing of the heart, modulating cardiac function without a direct vascular effect.MethodsWe included 12 mice that were randomly assigned to either vehicle or phenylephrine intervention through intraperitoneal administration. Mice were anesthetized with isoflurane and intubated endotracheally for mechanical ventilation. We measured blood pressure via a solid-state catheter in the aortic arch, blood flow via a probe on the ascending aorta, and ECG from needle electrodes on the extremities. Right atrium was electrically paced at a frequency ranging from 10 to 11.3 Hz before and after either vehicle or phenylephrine administration.ResultsPhenylephrine significantly increased blood pressure, stroke volume, and total peripheral resistance compared to the vehicle group. Moreover, heart rate was significantly decreased following phenylephrine administration. Pacing significantly decreased stroke volume and cardiac output both prior to and after drug administration. However, phenylephrine-induced changes in blood pressure and total peripheral resistance were maintained with increasing pacing frequencies compared to the vehicle group. Total peripheral resistance was not significantly altered with increasing pacing frequencies suggesting that the effect of phenylephrine is primarily of vascular origin.ConclusionIn conclusion, this in vivo murine model is capable of distinguishing between changes in peripheral vascular and cardiac functions. This study underlines the primary effect of phenylephrine on vascular function with secondary changes to cardiac function. Hence, this in vivo model is useful for the integrated assessment of the cardiovascular system.

Heterozygous mice (α2+/G301R mice) for the migraine-associated mutation (G301R) in the Na+,K+-ATPase α2-isoform have decreased expression of cardiovascular α2-isoform. The α2+/G301R mice exhibit a pro-contractile vascular phenotype associated with decreased left ventricular ejection fraction. However, the integrated functional cardiovascular consequences of this phenotype remain to be addressed in vivo. We hypothesized that the vascular response to α2-isoform-specific inhibition of the Na+,K+-ATPase by ouabain is augmented in α2+/G301R mice leading to reduced cardiac efficiency. Thus, we aimed to assess the functional contribution of the α2-isoform to in vivo cardiovascular function of wild-type (WT) and α2+/G301R mice. Blood pressure, stroke volume, heart rate, total peripheral resistance, arterial dP/dt, and systolic time intervals were assessed in anesthetized WT and α2+/G301R mice. To address rate-dependent cardiac changes, cardiovascular variables were compared before and after intraperitoneal injection of ouabain (1.5 mg/kg) or vehicle during atrial pacing. The α2+/G301R mice showed an enhanced ouabain-induced increase in total peripheral resistance associated with reduced efficiency of systolic development compared to WT. When the hearts were paced, ouabain reduced stroke volume in α2+/G301R mice. In conclusion, the ouabain-induced vascular response was augmented in α2+/G301R mice with consequent suppression of cardiac function.

INTRODUCTION: The aim of the present study was to analyze the possible correlation between Natural Killer (NK) cell activity as measured by the NK Vue assay and treatment efficacy in patients with disseminated cancer. MATERIALS AND METHODS: The study included four trials encompassing palliative treatment, i.e. one trial on prostate- and ovarian cancer, respectively, and two trials on colorectal cancer. The current results are based on 93 patients with mature data on treatment effect. Blood samples were collected at baseline and prior to each treatment cycle into NK Vue. Following 24 hours of stimulation the level of interferon-gamma (IFNγ) in the plasma was measured as a surrogate for NK cell activity. RESULTS: The relationship between NK cell activity and treatment response was similar across tumor types and treatment. The IFNγ either remained at or dropped to an abnormal level (200 pg/mL), while in group 3 (n = 28) it increased from an abnormal to a normal level. The response rate was 14%, 47%, and 82%, respectively, P

The significance of mineralogical maturity as a provenance indicator has long been debated and we use this study to demonstrate that it can indeed be a powerful tool to track the distribution of sandstone reservoirs. We investigate the cause of the pronounced geographic and stratigraphic differences in mineralogical composition that are found in the Upper Triassic–Lower Jurassic Gassum Formation across the Norwegian–Danish Basin and surrounding areas. Zircon U-Pb dating of 46 sandstone samples including analysis of 4816 detrital grains are combined with quantifications of the detrital mineralogical composition and placed in a sequence stratigraphic framework. The results show that the Gassum Formation can be divided into a southeastern region with high mineralogical maturity and a less mature region to the northwest with more feldspars, rock fragments, micas, and heavy minerals. Both the mineralogical assemblage and the provenance signature have been thoroughly homogenized in the SE region where sediment supplies from the Fennoscandian Shield and the Variscan Orogen are evident. In the NW region, sediment was initially supplied from Fennoscandia only, but the provenance abruptly changed from the Telemarkia Terrane to comprising also the more distant Caledonian Orogen resulting in a different mineralogical assemblage. The change occurred during a basinwide regression and may be caused by tectonic movements in the hinterland that permanently changed the composition of the sediment supplied to the basin.

Delineating human cardiac pathologies and their basic molecular mechanisms relies on research conducted in model organisms. Yet translating findings from preclinical models to humans present a significant challenge, in part due to differences in cardiac protein expression between humans and model organisms. Proteins immediately determine cellular function, yet their large-scale investigation in hearts has lagged behind those of genes and transcripts. Here, we set out to bridge this knowledge gap: By analyzing protein profiles in humans and commonly used model organisms across cardiac chambers, we determine their commonalities and regional differences. We analyzed cardiac tissue from each chamber of human, pig, horse, rat, mouse, and zebrafish in biological replicates. Using mass spectrometry-based proteomics workflows, we measured and evaluated the abundance of approximately 7,000 proteins in each species. The resulting knowledgebase of cardiac protein signatures is accessible through an online database: atlas.cardiacproteomics.com. Our combined analysis allows for quantitative evaluation of protein abundances across cardiac chambers, as well as comparisons of cardiac protein profiles across model organisms. Up to a quarter of proteins with differential abundances between atria and ventricles showed opposite chamber-specific enrichment between species; these included numerous proteins implicated in cardiac disease. The generated proteomics resource facilitates translational prospects of cardiac studies from model organisms to humans by comparisons of disease-linked protein networks across species.

Alpha-synuclein (a-syn) can aggregate and form toxic oligomers and insoluble fibrils which are the main component of Lewy bodies. Intra-neuronal Lewy bodies are a major pathological characteristic of Parkinson's disease (PD). These fibrillar structures can act as seeds and accelerate the aggregation of monomeric a-syn. Indeed, recent studies show that injection of preformed a-syn fibrils (PFF) into the rodent brain can induce aggregation of the endogenous monomeric a-syn resulting in neuronal dysfunction and eventual cell death.We injected 8 μg of murine a-syn PFF, or soluble monomeric a-syn into the right striatum of rats. The animals were monitored behaviourally using the cylinder test, which measures paw asymmetry, and the corridor task that measures lateralized sensorimotor response to sugar treats. In vivo PET imaging was performed after 6, 13 and 22 weeks using [11C]DTBZ, a marker of the vesicular monoamine 2 transporter (VMAT2), and after 15 and 22 weeks using [11C]UCB-J, a marker of synaptic SV2A protein in nerve terminals. Histology was performed at the three time points using antibodies against dopaminergic markers, aggregated a-syn, and MHCII to evaluate the immune response.While the a-syn PFF injection caused only mild behavioural changes, [11C]DTBZ PET showed a significant and progressive decrease of VMAT2 binding in the ipsilateral striatum. This was accompanied by a small progressive decrease in [11C]UCB-J binding in the same area. In addition, our histological analysis revealed a gradual spread of misfolded a-syn pathology in areas anatomically connected to striatum that became bilateral with time. The striatal a-syn PFF injection resulted in a progressive unilateral degeneration of dopamine terminals, and an early and sustained presence of MHCII positive ramified microglia in the ipsilateral striatum and substantia nigra.Our study shows that striatal injections of a-syn fibrils induce progressive pathological synaptic dysfunction prior to cell death that can be detected in vivo with PET. We confirm that intrastriatal injection of a-syn PFFs provides a model of progressive a-syn pathology with loss of dopaminergic and synaptic function accompanied by neuroinflammation, as found in human PD.

Background: The early identification of treatment effect is wanted in several settings, including the management of metastatic colorectal cancer (mCRC). A potential universal marker is circulating tumor DNA (ctDNA). Our prospective study explored the association between progression-free survival (PFS) and overall survival (OS), and early change of ctDNA after one cycle of chemotherapy in patients with mCRC. Methods: The study included mCRC patients receiving standard first line combination chemotherapy with 5-Fluorouracil (FU), oxaliplatin, and bevacizumab. Hypermethylated neuropeptide Y (NPY) ctDNA (meth-ctDNA) served as a marker analyzed by droplet digital polymerase chain reaction (PCR). The meth-ctDNA level was analyzed in plasma before treatment start and again before cycle two. The patients were divided into two groups according to the dynamics of meth-ctDNA. Low ctDNA (LctDNA) included patients with zero or values of meth-ctDNA decreasing to a level including zero in the 95% confidence interval. High ctDNA (HctDNA) included all other patients (stable, increasing, or slightly decreasing values). The two groups were compared as to PFS and OS. Results: The study included 123 patients. The PFS in the two groups differed significantly with a median of 9.2 and 6.7 months in LctDNA and HctDNA, respectively ( p = 0.0005). This translated into a 12-month difference in OS with a median of 25.4 and 13.5 months, respectively ( p = 0.0001). Conclusions: Early therapeutic reconsideration is of utmost importance. A low level of meth-ctDNA after one cycle of chemotherapy in the first line setting is a potential marker for excellent clinical outcomes. The clinical utility should be confirmed in randomized clinical trials.

The objective was to investigate the proportion of men with metastatic prostate cancer in groups defined by T stage, Gleason Grade Group (GGG) and serum levels of prostate-specific antigen (PSA) and if PSA can be used to rule in metastatic prostate cancer when combined with T stage and GGG. We identified 102,076 men in Prostate Cancer data Base Sweden 4.0 who were diagnosed with prostate cancer in 2006-2016. Risk of metastases was assessed for PSA stratified on T stage and five-tiered GGG. For men who had not undergone bone imaging, we used multiple imputation to classify metastatic prostate cancer. Advanced T stage, high GGG and high PSA were related to bone metastases. For example: only 79/38 190 (0.2%) of men with T1-2 and GGG 1 had PSA above 500 ng/mL, and 29/79 (44%) of these men had metastases; whereas 1 154/7 018 (16%) of men with T3-4 and GGG 5 had PSA above 500 ng/ml and 1 088/1 154 (94%) of these men had metastases. However, no PSA cut-off could accurately identify the majority of men with metastatic prostate cancer (i.e. high sensitivity) while also correctly classifying most men without metastasis (i.e. high specificity). In conclusion, these results support the use of imaging to confirm bone metastases in men with advanced prostate cancer as no PSA level in combination with T stage and GGG could accurately rule in metastatic prostate cancer and thereby safely omit bone imaging.

Abstract Background Precision medicine calls for an early indicator of treatment efficiency. Circulating tumor DNA (ctDNA) is a promising marker in this setting. Our prospective study explored the association between disease development and change of ctDNA during first line chemotherapy in patients with RAS/RAF mutated metastatic colorectal cancer (mCRC). Methods The study included 138 patients with mCRC receiving standard first line treatment. In patients with RAS/RAF mutated tumor DNA the same mutation was quantified in the plasma using droplet digital PCR. The fractional abundance of ctDNA was assessed in plasma before treatment start and at every treatment cycle until radiologically defined progressive disease. Results RAS/RAF mutations were detected in the plasma from 77 patients. Twenty patients progressed on treatment and 57 stopped treatment without progression. The presence of mutated DNA in plasma was correlated with poor overall survival. A low level of ctDNA after the first cycle of chemotherapy was associated with a low risk of progression. On the other hand, a significant increase of ctDNA at any time during the treatment course was associated with a high risk of progression on continuous treatment. The first increase in ctDNA level occurred at a median of 51 days before radiologically confirmed progression. Conclusions The results indicate that the ctDNA level holds potential as a clinically valuable marker in first line treatment of mCRC. A rapid decrease was associated with a prolonged progression free interval, whereas a significant increase gave notice of early progression with a relevant lead time.

Angiotensin II type 1 receptor (AT1R)-mediated acute catecholamine release is modulated by β-arrestin. Here the authors show that β-arrestin-1 recruits the Ca2+channel TRPC3 and the PLCγ to the AT1R-β-arrestin complex, triggering G protein-independent calcium influx and catecholamine secretion.

In order to meet the increasing demand to decarbonize the atmosphere, storage of CO2 in subsurface geological reservoirs is an effective measure. To maximize storage capacity, various types of saline aquifers should be considered including dynamic storage options with open or semi-open boundaries. In sloping aquifers, assessment of the immobilization potential for CO2 through dissolution and mineralization along the flow path is a crucial part of risk evaluations. The Gassum Formation in the Skagerrak is considered a nearshore CO2 storage option with sloping layers, facilitating buoyant migration of CO2 northwards along depositional and structural dip. In this study, petrographic data and provenance analysis provide the basis for estimating reactivity of the sandstones. Immobilization of CO2 in the reservoir through fluid dissolution and mineral reactions reduces risk of leakage. Petrographic analyses are integrated with seismic and well-log interpretation to identify sedimentary facies and to estimate mineral distribution with corresponding reactivity in the proposed injection area. Here the Gassum Formation comprises south-prograding, shoreface-fluvial para-sequences, sourced from northern hinterlands. Pronounced differences in the mineralogical maturity in the studied area are identified and explained by the sediment transport distances and the type of sediment source. This is possible because the U-Pb ages of zircon grains in the sediments can be used to pinpoint the areas where they originate from in the Fennoscandian Shield, such as the Telemarkia or Idefjorden terranes. Albite and Fe-rich chlorite are identified as the most reactive mineral phases in the Gassum sand, of which feldspar comprises the largest weight fraction and the grain-coating chlorite has largest surface area. Their distribution is partly controlled by provenance, so their abundance decreases basinwards with increasing sediment maturity. The abundance of fluvial sandstones presumably increases northwards in basal parts of para-sequences, while shoreface sandstones comprise the top part of sandy units. CO2 injected in the proposed area will migrate upwards within the reservoir, toward higher proportions of Telemarkian-derived sediment and up-dip along the seal, toward more immature sediments. Thus, the reactivity of sediments increases in younger deposits and up depositional dip, while kinetic reaction rates will decrease in shallower, lower temperature regions. Identifying these parameters is important to estimate the CO2 mineral sequestration potential as a function of sedimentary facies and ensure safe storage of CO2. This approach can advantageously be applied to all reservoirs considered for CO2 injection to improve the estimation of the possible CO2 storage volume by taking the provenance dependence of the mineralization potential into account.

Titanite (CaTiSiO5) occurs as a rare mineral in magmatic and metamorphic rocks. It is commonly found in clastic sedimentary rocks as an accessory heavy mineral – a mineral of high density. Recently, U-Pb dating of single-grains of detrital titanite has been shown to be a useful tool in sedimentary provenance studies (e.g. McAteer et al. 2010; Thomsen et al. 2015). Titanite U-Pb geochronologies can add important information to constrain the sediment sources of rocks and basins, and can help date precipitation of titanite. However, there are a number of complicating factors that must be taken into consideration for reliable application of titanite U-Pb dating in provenance studies. First, titanite is less stable than zircon – the most commonly employed dating target. For example, in Palaeocene sediments in the North Sea, titanite rarely occurs as detrital grains at burial depths greater than 1400 m (Morton 1984). It can also show dissolution features due to weathering and burial diagenesis (e.g. Morton 1984; Turner & Morton 2007). Second, titanite may precipitate during burial diagenesis, which would reflect the burial history of sediments and not their provenance. Precipitation of authigenic titanite is documented from deeply buried (i.e. at temperatures greater than 100°C) volcaniclastic sandstones and mudstones (Helmond & Van de Kamp 1984; Milliken 1992) and intrusion-associated mineralisation in volcanic Permian sandstones (van Panhuys-Sigler & Trewin 1990). Moreover, titanite also occurs in shallow-buried Jurassic sandstones with no volcanic affinity (Morad 1988). Thus, the formation of titanite is not necessarily linked to a volcaniclastic source, but nevertheless, the presence of volcanic material seems to promote titanite precipitation. If authigenic titanite precipitation was incorrectly identified as detrital, this would have considerable implications for provenance investigations, as apparently titanite-rich source rocks would be wrongly inferred to be present in the sediment source area. Here, we present examples from the Kangerlussuaq Basin in southern East Greenland of what appeared to be detrital titanite. However, new U-Pb dating reveals that the titanite formed authigenically, and hence contributed to the burial history, and not the provenance, of the sediments.

Background:. Restoring the nipple–areola complex completes the breast reconstructive process. Local flaps are often used for the nipple reconstruction; however, the number of techniques indicates the lack of a superior design. The aims of this study were to test the feasibility of a new triple flap design for nipple reconstruction and to evaluate complication rate and nipple projection. Methods:. From November 2015 to November 2018, we performed the triple flap nipple reconstruction guided by a template for preoperative mark-up. Patients were followed up postoperatively to evaluate healing and signs of complications including wound dehiscence, infection, and flap necrosis, and nipple projection. The areola was tattooed 3 months postoperatively. Results:. Twenty-six nipple reconstructions were successfully performed in 22 women. Four nipple reconstructions (15%) were performed in irradiated tissue. One reconstruction had a superficial infection, while there were no cases of wound dehiscence or flap necrosis. Three nipple reconstructions (12%) experienced prolonged healing that did not require intervention. None of these reconstructions had received radiation therapy. The nipple projection was 7.3 mm (range 6–9 mm) at the time of surgery and 3.1 mm (range 0–6 mm), 2.5 mm (range 2–3 mm), and 1.6 mm (range 0–3 mm) at follow-up of 3, 6, and 12 months, respectively. Conclusions:. We present the new triple flap design for nipple reconstruction guided by a template for mark-up. The preliminary results indicate a low complication rate in both irradiated and nonirradiated patients while sustaining the projection over time remains to be a challenge.

Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and β-arrestin-1 are essential for fluid reabsorption because they mediate coupling between an orphan receptor ADGRG2 (GPR64) and the ion channel CFTR. A reduction in protein level or deficiency of ADGRG2, Gq or β-arrestin-1 in a mouse model led to an imbalance in pH homeostasis in the efferent ductules due to decreased constitutive CFTR currents. Efferent ductule dysfunction was rescued by the specific activation of another GPCR, AGTR2. Further mechanistic analysis revealed that β-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, this specificity is critical for male fertility. Therefore, manipulation of the signaling components of the ADGRG2-Gq/β-arrestin-1/CFTR complex by small molecules may be an effective therapeutic strategy for male infertility.

The visual system consists of two major subsystems, image-forming circuits that drive conscious vision and non-image-forming circuits for behaviors such as circadian photoentrainment. While historically considered non-overlapping, recent evidence has uncovered crosstalk between these subsystems. Here, we investigated shared developmental mechanisms. We revealed an unprecedented role for light in the maturation of the circadian clock and discovered that intrinsically photosensitive retinal ganglion cells (ipRGCs) are critical for this refinement process. In addition, ipRGCs regulate retinal waves independent of light, and developmental ablation of a subset of ipRGCs disrupts eye-specific segregation of retinogeniculate projections. Specifically, a subset of ipRGCs, comprising ~200 cells and which project intraretinally and to circadian centers in the brain, are sufficient to mediate both of these developmental processes. Thus, this subset of ipRGCs constitute a shared node in the neural networks that mediate light-dependent maturation of the circadian clock and light-independent refinement of retinogeniculate projections.