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Abstract Temporal interference (TI) stimulation is a popular non-invasive neurostimulation technique that utilizes the following salient neural behavior: pure sinusoid (generated in off-target brain regions) appears to cause no stimulation, whereas modulated sinusoid (generated in target brain regions) does. To understand its effects and mechanisms, we examine responses of different cell types, excitatory pyramidal (Pyr) and inhibitory parvalbumin-expressing (PV) neurons, to pure and modulated sinusoids, in intact network as well as in isolation. In intact network, we present data showing that PV neurons are much less likely than Pyr neurons to exhibit TI stimulation. Remarkably, in isolation, our data shows that almost all Pyr neurons stop exhibiting TI stimulation. We conclude that TI stimulation is largely a network phenomenon. Indeed, PV neurons actively inhibit Pyr neurons in the off-target regions due to pure sinusoids (in off-target regions) generating much higher PV firing rates than modulated sinusoids in the target regions. Additionally, we use computational studies to support and extend our experimental observations.

Abstract Computational pharmacogenomics can potentially identify new indications for already approved drugs and pinpoint compounds with similar mechanism-of-action. Here, we used an integrated drug repositioning approach based on transcriptomics data and structure-based virtual screening to identify compounds with gene signatures similar to three known proteasome inhibitors (PIs; bortezomib, MG-132, and MLN-2238). In vitro validation of candidate compounds was then performed to assess proteasomal proteolytic activity, accumulation of ubiquitinated proteins, cell viability, and drug-induced expression in A375 melanoma and MCF7 breast cancer cells. Using this approach, we identified six compounds with PI properties ((-)-kinetin-riboside, manumycin-A, puromycin dihydrochloride, resistomycin, tegaserod maleate, and thapsigargin). Although the docking scores pinpointed their ability to bind to the β5 subunit, our in vitro study revealed that these compounds inhibited the β1, β2, and β5 catalytic sites to some extent. As shown with bortezomib, only manumycin-A, puromycin dihydrochloride, and tegaserod maleate resulted in excessive accumulation of ubiquitinated proteins and elevated HMOX1 expression. Taken together, our integrated drug repositioning approach and subsequent in vitro validation studies identified six compounds demonstrating properties similar to proteasome inhibitors.

Abstract Repurposing of FDA-approved drugs is a quick and cost-effective alternative to de novo drug development. Here, we identify genes involved in bortezomib sensitivity, predict cancer types that may benefit from treatment with bortezomib, and evaluate the mechanism-of-action of bortezomib in breast cancer (BT-474 and ZR-75–30), melanoma (A-375), and glioblastoma (A-172) cells in vitro. Cancer cell lines derived from cancers of the blood, kidney, nervous system, and skin were found to be significantly more sensitive to bortezomib than other organ systems. The in vitro studies confirmed that although bortezomib effectively inhibited the β5 catalytic site in all four cell lines, cell cycle arrest was only induced in G2/M phase and apoptosis in A-375 and A-172 after 24h. The genomic and transcriptomic analyses identified 33 genes (e.g. ALDH18A1, ATAD2) associated with bortezomib resistance. Taken together, we identified biomarkers predictive of bortezomib sensitivity and cancer types that might benefit from treatment with bortezomib.

Introduction: PET/CT and PET/MRI are valuable multimodality imaging techniques for visualizing both functional and anatomical information. The most used PET reconstruction algorithm is Ordered Subset Expectation Maximization (OSEM). In OSEM, the image noise increases with increased number of iterations, and the reconstruction needs to be stopped before complete convergence. The Bayesian penalized likelihood (BPL) algorithm, recently introduced, uses a noise penalty factor (β) to achieve full convergence while controlling noise. This study aims to evaluate how reconstruction algorithms and lesion radioactivity levels affect PET image quality and quantitative accuracy across three different PET systems. Materials and Methods: A NEMA phantom was filled with 18F and scanned by one PET/MRI and two PET/CT systems with sphere-to-background concentration ratio (SBR) of 2:1, 4:1, or 10:1. PET images were reconstructed with OSEM or BPL with TOF. The number of iterations and β-values were varied, while the matrix size, number of subsets, and filter size remained constant. Contrast recovery (CR) and background variability (BV) were measured in images. Results: CR increased with increased sphere size and SBR. CR and BV decreased with increased β for the 10mm sphere. Increased number of iterations in OSEM showed increased BV with limited variation in CR. BPL gave higher CR and lower BV values than OSEM. The optimal reconstruction was BPL with β between 150 and 350, where BPL was available, and OSEM with two iterations and 21 subsets for the PET/CT without BPL. Conclusion: BPL outperforms OSEM, and SBR significantly influences tracer uptake quantification in small lesions. Future studies should explore the clinical implications of these findings on diagnosis, staging, prognosis, and treatment follow-up.

The physiological process of iodine uptake in the thyroid is used for 131I treatment of thyroid diseases. Children are more sensitive to radiation compared to adults and may react differently to 131I exposure. The aims of this study were to evaluate the effects on thyroid protein expression in young and adult rats one year after 131I injection and identify potential biomarkers related to 131I exposure, absorbed dose, and age. Twelve Sprague Dawley rats (young and adults) were i.v. injected with 50 kBq or 500 kBq 131I and killed twelve months later. Twelve untreated rats were used as age-matched controls. Quantitative proteomics, statistical analysis, and evaluation of biological effects were performed. The effects of irradiation were most prominent in young rats. Protein biomarker candidates were proposed related to age, absorbed dose, thyroid function, and cancer, and a panel was proposed for 131I exposure. In conclusion, the proteome of rat thyroid was differentially regulated twelve months after low-intermediate dose exposure to 131I in both young and adult rats. Several biomarker candidates are proposed for 131I exposure, age, and many of them are known to be related to thyroid function or thyroid cancer. Further research on human samples is needed for validation. Data are avaiable via ProteomeXchange with identifier PXD024786.

Abstract Triple-negative breast cancer (TNBC) is associated with poor prognosis and limited treatment options due to the lack of important receptors (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]) used for targeted therapy. However, high-throughput in vitro drug screening of cell lines is a powerful tool for identifying effective drugs for a disease. Here, we determine the intrinsic chemosensitivity of TNBC cell lines to proteasome inhibitors (PIs), thereby identifying potentially potent 2-drug combinations for TNBC. Eight TNBC cell lines (BT-549, CAL-148, HCC1806, HCC38, HCC70, MDA-MB-436, MDA-MB-453, and MDA-MB-468) and two controls (MCF-10A and MCF-7) were first exposed to 18 drugs (11 PIs and 7 clinically relevant chemotherapeutic agents) as monotherapy, followed by prediction of potent 2-drug combinations using the IDACombo pipeline. The synergistic effects of the 2-drug combinations were evaluated with SynergyFinder in four TNBC cell lines (CAL-148, HCC1806, HCC38, and MDA-MB-468) and three controls (BT-474, MCF-7, and T47D) in vitro, followed by further evaluation of tumor regression in zebrafish tumor models established using HCC1806 and MCF-7 cells. Monotherapy identified nine effective drugs (bortezomib, carfilzomib, cisplatin, delanzomib, docetaxel, epoxomicin, MLN-2238, MLN-9708, and nedaplatin) across all cell lines. PIs (e.g., bortezomib, delanzomib, and epoxomicin) were highly potent drugs in TNBC cells, of which bortezomib and delanzomib inhibited the chymotrypsin-like activity of the 20 S proteasome by 100% at 10 µM. Moreover, several potent 2-drug combinations (e.g., bortezomib+nedaplatin and epoxomicin+epirubicin) that killed virtually 100% of cells were also identified. Although HCC1806- and MCF-7-derived xenografts treated with bortezomib+nedaplatin and carboplatin+paclitaxel were smaller, HCC1806 cells frequently metastasized to the trunk region. Taken together, we show that PIs used in combination with platinum agents or topoisomerase inhibitors exhibit increased efficiency with almost 100% inhibition in TNBC cell lines, indicating that PIs are therefore promising compounds to use as combination therapy for TNBC.

Background: Patients with high-risk neuroblastoma (NB) have a 5-year event-free survival of less than 50 %, and novel and improved treatment options are needed. Radiolabeled somatostatin analogs (SSTAs) could be a treatment option. The aims of this work were to compare the biodistribution and the therapeutic effects of 177Lu-octreotate and 177Lu-octreotide in mice bearing the human CLB-BAR NB cell line, and to evaluate their regulatory effects on apoptosis-related genes. Methods: The biodistribution of 177Lu-octreotide in mice bearing CLB-BAR tumors was studied at 1, 24, and 168 h after administration, and the absorbed dose was estimated to tumor and normal tissues. Further, animals were administered different amounts of 177Lu-octreotate or 177Lu-octreotide. Tumor volume was measured over time and compared to a control group given saline. RNA was extracted from tumors, and the expression of 84 selected genes involved in apoptosis was quantified with qPCR. Results: The activity concentration was generally lower in most tissues for 177Lu-octreotide compared to 177Lu-octreotate. Mean absorbed dose per administered activity to tumor after injection of 1.5 MBq and 15 MBq was 0.74 and 0.03 Gy/MBq for 177Lu-octreotide and 2.9 and 0.45 Gy/MBq for 177Lu-octreotate, respectively. 177Lu-octreotide treatment resulted in statistically significant differences compared to controls. Fractionated administration led to a higher survival fraction than after a single administration. The pro-apoptotic genes TNSFS8, TNSFS10, and TRADD were regulated after administration with 177Lu-octreotate. Treatment with 177Lu-octreotide yielded regulation of the pro-apoptotic genes CASP5 and TRADD, and of the anti-apoptotic gene IL10 as well as the apoptosis-related gene TNF. Conclusion: 177Lu-octreotide gave somewhat better anti-tumor effects than 177Lu-octreotate. The similar effect observed in the treated groups with 177Lu-octreotate suggests saturation of the somatostatin receptors. Pronounced anti-tumor effects following fractionated administration merited receptor saturation as an explanation. The gene expression analyses suggest apoptosis activation through the extrinsic pathway for both radiopharmaceuticals.

Recombinant α1-microglobulin (A1M) is proposed as a protector during 177Lu-octreotate treatment of neuroendocrine tumors, which is currently limited by bone marrow and renal toxicity. Co-administration of 177Lu-octreotate and A1M could result in a more effective treatment by protecting healthy tissue, but the radioprotective action of A1M is not fully understood. The aim of this study was to examine the proteomic response of kidneys and bone marrow early after 177Lu-octreotate and/or A1M administration. Mice were injected with 177Lu-octreotate and/or A1M, while control mice received saline or A1M vehicle solution. Bone marrow, kidney medulla, and kidney cortex were sampled after 24 h or 7 d. The differential protein expression was analyzed with tandem mass spectrometry. The dosimetric estimation was based on 177Lu activity in the kidney. PHLDA3 was the most prominent radiation-responsive protein in kidney tissue. In general, no statistically significant difference in the expression of radiation-related proteins was observed between the irradiated groups. Most canonical pathways were identified in bone marrow from the 177Lu-octreotate+A1M group. Altogether, a tissue-dependent proteomic response followed exposure to 177Lu-octreotate alone or together with A1M. Combining 177Lu-octreotate with A1M did not inhibit the radiation-induced protein expression early after exposure, and late effects should be further studied.

Abstract Recombinant α1-microglobulin (A1M) is a proposed radioprotector during 177Lu-octreotate therapy of neuroendocrine tumors (NETs). To ensure a maintained therapeutic effect, we previously demonstrated that A1M does not affect the 177Lu-octreotate induced decrease in GOT1 tumor volume. However, the underlying biological events of these findings are still unknown. The aim of this work was to examine the regulation of apoptosis-related genes in GOT1 tumors short-time after i.v. administration of 177Lu-octreotate with and without A1M or A1M alone. Human GOT1 tumor-bearing mice received 30 MBq 177Lu-octreotate or 5 mg/kg A1M or co-treatment with both. Animals were sacrificed after 1 or 7 days. Gene expression analysis of apoptosis-related genes in GOT1 tissue was performed with RT-PCR. In general, similar expression patterns of pro- and anti-apoptotic genes were found after 177Lu-octreotate exposure with or without co-administration of A1M. The highest regulated genes in both irradiated groups compared to untreated controls were FAS and TNFSFRS10B. Administration of A1M alone only resulted in significantly regulated genes after 7 days. Co-administration of A1M did not negatively affect the transcriptional apoptotic response of 177Lu-octreotate in GOT1 tumors.

Abstract Background The human proteasome gene family (PSM) consists of 49 genes that play a crucial role in cancer proteostasis. However, little is known about the effect of PSM gene expression and genetic alterations on clinical outcome in different cancer forms. Methods Here, we performed a comprehensive pan-cancer analysis of genetic alterations in PSM genes and the subsequent prognostic value of PSM expression using data from The Cancer Genome Atlas (TCGA) containing over 10,000 samples representing up to 33 different cancer types. External validation was performed using a breast cancer cohort and KM plotter with four cancer types. Results The PSM genetic alteration frequency was high in certain cancer types (e.g. 67%; esophageal adenocarcinoma), with DNA amplification being most common. Compared with normal tissue, most PSM genes were predominantly overexpressed in cancer. Survival analysis also established a relationship with PSM gene expression and adverse clinical outcome, where PSMA1 and PSMD11 expression were linked to more unfavorable prognosis in ≥ 30% of cancer types for both overall survival (OS) and relapse-free interval (PFI). Interestingly, PSMB5 gene expression was associated with OS (36%) and PFI (27%), and OS for PSMD2 (42%), especially when overexpressed. Conclusion These findings indicate that several PSM genes may potentially be prognostic biomarkers and novel therapeutic targets for different cancer forms.

Wild European perch (Perca fluviatilis) is one of the most important freshwater fish species, in Sweden, due to its widespread and his value for recreational fishing. Little it is known regarding the biodistribution of naturally occurring radionuclides such as 238U, 234U, 226Ra, 210Po in perch. Therefore, in this study, perches from five lakes located in different counties in Sweden were collected to investigate the biodistribution of 238U, 234U, 226Ra, 210Po and 137Cs in organs and tissues of perch as well as their radiological impact. The results showed that uranium radionuclides ranged between 0.1 and 6 Bq/kg with an average value of 1.1 ± 1.5 Bq/kg. 226Ra varied from 0.4 to 8 Bq/kg with a mean concentration of 1.7 ± 1.9 Bq/kg. The ranged of 210Po was 0.5 – 250 Bq/kg, with an average value of 24 ± 52 Bq/kg. On the other hand, the highest activity concentration of 137Cs, 151 ± 1 Bq/kg, was detected in muscle samples of perch from Redsjösjön lake. For uranium radionuclides and 226Ra uptake from water is the main source whereas for 210Po and 137Cs the uptake is controlled by the perch diet. Regarding naturally occurring radionuclides, the perch tended to accumulated uranium radionuclides in fins, gills, and skin; 226Ra in bones, fins and skin and 210Po in the organs linked to digestive system. Finally, in case of consumption, it is advised the consumption of skinned fillets of perch due to the higher bioaccumulation of the radionuclides investigated in the skin and scales.

Abstract Background Health‐related quality of life (HRQoL) of orofacial pain patients is lower than that of the general population and impaired in multiple dimensions. The aim of the present study was to investigate HRQoL of orofacial pain patients in comparison with patients suffering from other chronic pain disorders. Materials and Methods One hundred and fifty‐one tertiary care facial pain patients (mean age, 50 years; standard deviation [SD], 15; 119 females), were compared with 312 other non‐cancer chronic pain patients (mean age, 46 years; SD, 13; 204 women), recruited from three multidisciplinary pain clinics in Finland. The groups were compared using the 15D, and pain‐related measures such as pain interference, pain acceptance, anxiety, depression, and sleep. Statistical comparisons between groups were done using t test, χ2 test, or analysis of covariance. Multivariate linear regression analysis was used to study whether pain‐related aspects influencing HRQoL are similar between the patient groups. Results The 15D score was significantly higher in facial pain patients (0.823; SD, 0.114) indicating better HRQoL in comparison with other chronic pain patients (0.732; SD, 0.107) (p

Abstract Molecular biomarkers of ionizing radiation (IR) exposure are a promising new tool in various disciplines: they can give necessary information for adaptive treatment planning in cancer radiotherapy, enable risk projection for radiation-induced survivorship diseases, or facilitate triage and intervention in radiation hazard events. However, radiation biomarker discovery has not yet resolved the most basic features of personalized medicine: age and sex. To overcome this critical bias in biomarker identification, we quantitated age and sex effects and assessed their relevance in the radiation response across the blood proteome. We used high-throughput mass spectrometry on blood plasma collected 24 h after 0.5 Gy total body irradiation (15 MV nominal photon energy) from male and female C57BL/6 N mice at juvenile (7-weeks-old) or adult (18-weeks-old) age. We also assessed sex and strain effects using juvenile male and female BALB/c nude mice. We showed that age and sex created significant effects in the proteomic response regarding both extent and functional quality of IR-induced responses. Furthermore, we found that age and sex effects appeared non-linear and were often end-point specific. Overall, age contributed more to differences in the proteomic response than sex, most notably in immune responses, oxidative stress, and apoptotic cell death. Interestingly, sex effects were pronounced for DNA damage and repair pathways and associated cellular outcome (pro-survival vs. pro-apoptotic). Only one protein (AHSP) was identified as a potential general biomarker candidate across age and sex, while GMNN, REG3B, and SNCA indicated some response similarity across age. This low yield advocated that unisex or uniage biomarker screening approaches are not feasible. In conclusion, age- and sex-specific screening approaches should be implemented as standard protocol to ensure robustness and diagnostic power of biomarker candidates. Bias-free molecular biomarkers are a necessary progression towards personalized medicine and integral for advanced adaptive cancer radiotherapy and risk assessment.

Abstract 131I is used clinically for therapy, and may be released during nuclear accidents. After the Chernobyl accident papillary thyroid carcinoma incidence increased in children, but not adults. The aims of this study were to compare 131I irradiation-dependent differences in RNA and protein expression in the thyroid and plasma of young and adult rats, and identify potential age-dependent biomarkers for 131I exposure. Twelve young (5 weeks) and twelve adult Sprague Dawley rats (17 weeks) were i.v. injected with 50 kBq 131I (absorbed dose to thyroid = 0.1 Gy), and sixteen unexposed age-matched rats were used as controls. The rats were killed 3–9 months after administration. Microarray analysis was performed using RNA from thyroid samples, while LC–MS/MS analysis was performed on proteins extracted from thyroid tissue and plasma. Canonical pathways, biological functions and upstream regulators were analysed for the identified transcripts and proteins. Distinct age-dependent differences in gene and protein expression were observed. Novel biomarkers for thyroid 131I exposure were identified: (PTH), age-dependent dose response (CA1, FTL1, PVALB (youngsters) and HSPB6 (adults)), thyroid function (Vegfb (adults)). Further validation using clinical samples are needed to explore the role of the identified biomarkers.

177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) is used clinically to treat metastasized or unresectable neuroendocrine tumors (NETs). Although 177Lu-DOTATATE is mostly well tolerated in patients, bone marrow suppression and long-term renal toxicity are still side effects that should be considered. Amino acids are often used to minimize renal radiotoxicity, however, they are associated with nausea and vomiting in patients. α1-microglobulin (A1M) is an antioxidant with heme- and radical-scavenging abilities. A recombinant form (rA1M) has previously been shown to be renoprotective in preclinical models, including in PRRT-induced kidney damage. Here, we further investigated rA1M’s renal protective effect in a mouse 177Lu-DOTATATE model in terms of administration route and dosing regimen and as a combined therapy with amino acids (Vamin). Moreover, we investigated the protective effect of rA1M on peripheral blood and bone marrow cells, as well as circulatory biomarkers. Intravenous (i.v.) administration of rA1M reduced albuminuria levels and circulatory levels of the oxidative stress-related protein fibroblast growth factor-21 (FGF-21). Dual injections of rA1M (i.e., at 0 and 24 h post-177Lu-DOTATATE administration) preserved bone marrow cellularity and peripheral blood reticulocytes. Administration of Vamin, alone or in combination with rA1M, did not show any protection of bone marrow cellularity or peripheral reticulocytes. In conclusion, this study suggests that rA1M, administered i.v. for two consecutive days in conjunction with 177Lu-DOTATATE, may reduce hematopoietic and kidney toxicity during PRRT with 177Lu-DOTATATE.

Abstract Background Neuroblastoma (NB) is one of the most frequently diagnosed tumors in infants. NB is a neuroendocrine tumor type with various characteristics and features, and with diverse outcome. The most malignant NBs have a 5-year survival rate of only 40–50%, indicating the need for novel and improved treatment options. 177Lu-octreotate is routinely administered for treatment of neuroendocrine tumors overexpressing somatostatin receptors (SSTR). The aim of this study was to examine the biodistribution of 177Lu-octreotate in mice bearing aggressive human NB cell lines, in order to evaluate the potential usefulness of 177Lu-octreotate for treatment of NB. Methods BALB/c nude mice bearing CLB-BAR, CLB-GE or IMR-32 tumor xenografts (n = 5–7/group) were i.v. injected with 0.15 MBq, 1.5 MBq or 15 MBq 177Lu-octreotate and sacrificed 1 h, 24 h, 48 h and 168 h after administration. The radioactivity concentration was determined for collected tissue samples, tumor-to-normal-tissue activity concentration ratios (T/N) and mean absorbed dose for each tissue were calculated. Immunohistochemical (IHC) staining for SSTR1–5, and Ki67 were carried out for tumor xenografts from the three cell lines. Results High 177Lu concentration levels and T/N values were observed in all NB tumors, with the highest for CLB-GE tumor xenografts (72%IA/g 24 h p.i.; 1.5 MBq 177Lu-octreotate). The mean absorbed dose to the tumor was 6.8 Gy, 54 Gy and 29 Gy for CLB-BAR, CLB-GE and IMR-32, respectively, p.i. of 15 MBq 177Lu-octreotate. Receptor saturation was clearly observed in CLB-BAR, resulting in higher concentration levels in the tumor when lower activity levels where administered. IHC staining demonstrated highest expression of SSTR2 in CLB-GE, followed by CLB-BAR and IMR-32. Conclusion T/N values for all three human NB tumor xenograft types investigated were high relative to previously investigated neuroendocrine tumor types. The results indicate a clear potential of 177Lu-octreotate as a therapeutic alternative for metastatic NB.

Abstract Breast cancer (BC) patients are frequently at risk of developing other malignancies following treatment. Although studies have been conducted to elucidate the etiology of multiple primary malignancies (MPM) after a BC diagnosis, few studies have investigated other previously diagnosed primary malignancies (OPPM) before BC. Here, genome‐wide profiling was used to identify potential driver DNA copy number alterations and somatic mutations that promote the development of MPMs. To compare the genomic profiles for two primary tumors (BC and OPPM) from the same patient, tumor pairs from 26 young women (≤50 years) diagnosed with one or more primary malignancies before breast cancer were analyzed. Malignant melanoma was the most frequent OPPM, followed by gynecologic‐ and hematologic malignancies. However, significantly more genetic alterations were detected in BC compared to the OPPM. BC also showed more genetic similarity as a group than the tumor pairs. Clonality testing showed that genetic alterations on chromosomes 1, 3, 16, and 19 were concordant in both tumors in 13 patients. TP53 mutations were also found to be prevalent in BC, MM, and HM. Although all samples were classified as genetically unstable, chromothripsis‐like patterns were primarily observed in BC. Taken together, few recurrent genetic alterations were identified in both tumor pairs that can explain the development of MPMs in the same patient. However, larger studies are warranted to further investigate key driver mutations associated with MPMs.

Purpose: Cryoablation, which induces cellular death without extensive tissue damage, has been extensively used to denervate the myocardium. However, periadventitial external circumferential application of cryotherapy to denervate the renal artery sympathetic nerves has, to our knowledge, never been tested in humans. The main aim of this study was to examine the safety and potential effects of cryotherapy on ambulatory blood pressure levels and other outcomes that are indirectly related to sympathetic tone, including pulse-wave velocity, central pulse pressure, and glucose levels. Materials and Methods : : Five patients who underwent the denervation of the renal arteries during open surgery of the abdominal aortic aneurysm and four controls who did not undergo denervation during the surgery were enrolled. An argonpowered cryotherapy catheter (Cardioblate; Medtronic Inc., USA) was applied periadventitially to each renal artery in the five patients and then activated by infusion with liquid nitrogen for 1 minute. Results : : No cryoablation-related complications occurred in the five consecutive patients. Their ambulatory blood pressures 3 to 5 months after surgery did not demonstrate any general blood pressure-reducing effects, but two patients responded favorably with the reduction of antihypertensive medication and decreased 24-hour blood pressure. The patients’ mean HbA1C levels decreased from 5.9±0.78% to 5.6±0.71% (P=0.042). Conclusion : : This pilot study suggests that periadventitial cryoablation during open surgery can be used in the study of renal denervation in humans, as it had no complications in five patients in this study. The effectiveness of cryoablation for treating hypertension should be proven in a phase II clinical trial.

Northern Sweden has been the object of intense metal mining in the last decades producing several water-filled open-pits, or pit lakes. Most of these pit lakes have been limed to maintain a good water quality and to prevent generation of acidic water that could leach the exposed rocks and release metals into water. The aim of this work was to examine the concentration of stable elements and naturally occurring radionuclides in water and sediment samples from pit lakes originating from non-uranium mining activities in Northern Sweden. Surface water and surface sediments were collected from 27 pit lakes in Northern Sweden. Water quality parameters, concentration of stable elements and radionuclides were measured by a water probe, ICP-MS and XRF, and alpha and gamma spectrometry, respectively. Furthermore, a multivariate statistical analysis (PCA) was performed on the water samples and sediments. In general, the quality of the surface water was good, but some lakes had low pH values (2.5-5.7), and high concentrations of Fe (up to 200 mg/L) and other metals (e.g. Zn, Cu). When relating the metal concentrations in sediments in pit lakes with the concentration found in natural lakes, some sites had relatively high levels of Cu, As, Cr and Pb. The activity concentration of 210Po, and U and Th isotopes in water and sediment samples were at environmental levels, as was the ambient dose equivalent rate at these sites (range 0.08-0.14 μSv/h).

Baserat på en explorativ studie behandlar denna artikel frågan om utrikesfödd bakgrund, kön och ålder har någon betydelse för behovsbedömningsdokumentation inom svensk äldreomsorg. Med hjälp av kvantitativ innehållsanalys och multipel logistisk regressionsanalys av akter (n=202) innehållande utredningar (n=489) av ansökningar om välfärdstjänster, undersöker denna studie om identifikationsgrunder för äldre har någon betydelse för dokumentationspraktiker. Innehållsanalysen visade att beskrivningar i akterna av utlandsfödda äldre är mer omfattande än beskrivningarna av svenskfödda. Den multipla logistiska regressionsanalysen tyder på att kön och bakgrund verkar vara relevant för hur beslut motiverades i akterna. Ålder är inte lika relevant som de andra kategorierna. Det väsentligaste fyndet är att utlandsfödda äldre i detta material beviljas hemvårdsbidrag i större utsträckning än svenskfödda. Resultaten stöder delvis den kritiska debatten om hur klienter konstrueras i dokumentation av socialt arbete eftersom de indikerar att bakgrund, kön och ålder kan spela roll för hur äldre människors ansökningar om omsorgsinsatser behandlas i akter.

In an effort to understand teachers' technology use, recent scholarship has explored the idea of technological pedagogical content knowledge (TPCK or TPACK). Many studies have used self-reports to measure this knowledge (SR TPCK). Several studies have examined the construct validity of these assessments by analysing the internal relationships of the knowledge domains, but little attention has been paid to how SR TPCK relates to external criteria. We tackled this question of discriminant validity by reanalysing 2 data sets. We used correlation and multiple regression analyses to explore whether conceptually related constructs explain any variance in participants' SR TPCK. In Study 1, we applied this strategy to German pre-service teachers using technology use, attitudinal variables, and objective measures of teachers' knowledge of technology and pedagogy as external criteria. In Study 2, we examined measures of technology knowledge, experience, and pro-technology beliefs for in-service teachers in the United States. Across both studies, a sizeable amount of the variance in SR TPCK is explained by teachers' prior technology use and pro-technology attitudes. In contrast, fact-based tests of technology and pedagogy are distinct from SR TPCK. We discuss implications for these findings and argue that researchers should gather complementary measures in concert.

Background: In phenylketonuria (PKU), weaning is considered more challenging when compared to feeding healthy infants. The primary aim of weaning is to gradually replace natural protein from breast milk or standard infant formula with solids containing equivalent phenylalanine (Phe). In addition, a Phe-free second stage L-amino acid supplement is usually recommended from around 6 months to replace Phe-free infant formula. Our aim was to assess different weaning approaches used by health professionals across Europe. Methods: A cross sectional questionnaire (survey monkey®) composed of 31 multiple and single choice questions was sent to European colleagues caring for inherited metabolic disorders (IMD). Centres were grouped into geographical regions for analysis. Results: Weaning started at 17–26 weeks in 85% (n = 81/95) of centres, >26 weeks in 12% (n = 11/95) and 26 weeks. First solids were mainly low Phe vegetables (59%, n = 56/95) and fruit (34%, n = 32/95).A Phe exchange system to allocate dietary Phe was used by 52% (n = 49/95) of centres predominantly from Northern and Southern Europe and 48% (n = 46/95) calculated most Phe containing food sources (all centres in Eastern Europe and the majority from Germany and Austria). Some centres used a combination of both methods.A second stage Phe-free L-amino acid supplement containing a higher protein equivalent was introduced by 41% (n = 39/95) of centres at infant age 26–36 weeks (mainly from Germany, Austria, Northern and Eastern Europe) and 37% (n = 35/95) at infant age > 1y mainly from Southern Europe. 53% (n = 50/95) of centres recommended a second stage Phe-free L-amino acid supplement in a spoonable or semi-solid form. Conclusions: Weaning strategies vary throughout European PKU centres. There is evidence to suggest that different infant weaning strategies may influence longer term adherence to the PKU diet or acceptance of Phe-free L-amino acid supplements; rendering prospective long-term studies important. It is essential to identify an effective weaning strategy that reduces caregiver burden but is associated with acceptable dietary adherence and optimal infant feeding development. Keywords: Weaning, Infant, Phenylketonuria, Phenylalanine, Phe-free infant formula

Abstract Background 177Lu-octreotate is used for therapy of somatostatin receptor expressing neuroendocrine tumors with promising results, although complete tumor remission is rarely seen. Previous studies on nude mice bearing the human small intestine neuroendocrine tumor, GOT1, have shown that a priming injection of 177Lu-octreotate 24 h before the main injection of 177Lu-octreotate resulted in higher 177Lu concentration in tumor, resulting in increased absorbed dose, volume reduction, and time to regrowth. To our knowledge, the cellular effects of a priming treatment schedule have not yet been studied. The aim of this study was to identify transcriptional changes contributing to the enhanced therapeutic response of GOT1 tumors in nude mice to 177Lu-octreotate therapy with priming, compared with non-curative monotherapy. Results RNA microarray analysis was performed on tumor samples from GOT1-bearing BALB/c nude mice treated with a 5 MBq priming injection of 177Lu-octreotate followed by a second injection of 10 MBq of 177Lu-octreotate after 24 h and killed after 1, 3, 7, and 41 days after the last injection. Administered activity amounts were chosen to be non-curative, in order to facilitate the study of tumor regression and regrowth. Differentially regulated transcripts (RNA samples from treated vs. untreated animals) were identified (change ≥ 1.5-fold; adjusted p value

(1) Background: Protease-activated receptor 1 (PAR1) has regulatory functions in inflammation, atherogenesis, and atherothrombosis. Chronic iron administration accelerates arterial thrombosis. Intraplaque hemorrhage and hemoglobin catabolism by macrophages are associated with dysregulated iron metabolism and atherosclerotic lesion instability. However, it remains unknown whether expressions of PAR1 in human atherosclerotic lesions are related to plaque severity, accumulation of macrophages, and iron-related proteins. We investigated the expression of PAR1 and its relation to the expression of ferritin and transferrin receptors in human carotid atherosclerotic plaques and then explored potential connections between their expressions, plaque development, and classical risk factors. (2) Methods: Carotid samples from 39 patients (25 males and 14 females) were immunostained with PAR1, macrophages, ferritin, and transferrin receptor. Double immunocytochemistry of PAR1 and ferritin was performed on THP-1 macrophages exposed to iron. (3) Results: PAR1 expression significantly increases with the patient’s age and the progression of human atherosclerotic plaques. Expressions of PAR1 are significantly correlated with the accumulation of CD68-positive macrophages, ferritin, and transferrin receptor 1 (TfR1), and inversely correlated with levels of high-density lipoprotein. In vitro, PAR1 is significantly increased in macrophages exposed to iron, and the expression of PAR1 is colocalized with ferritin expression. (4) Conclusions: PAR1 is significantly related to the progression of human atherosclerotic lesions and the patient’s age. PAR1 is also associated with macrophage infiltration and accumulation of iron metabolic proteins in human atherosclerotic lesions. Cellular iron-mediated induction of PAR1 and its colocalization with ferritin in macrophages may further indicate an important role of cellular iron in atherothrombosis.