BeEAM High-Dose Chemotherapy with Polatuzumab (Pola-BeEAM) before ASCT in Patients with DLBCL-A Pilot Study.

(1) Introduction: BEAM is a high-dose chemotherapy (HDCT) frequently administered before autologous stem cell transplantation (ASCT) in diffuse large B-cell lymphoma (DLBCL). Bendamustine replacing BCNU (BeEAM) is similarly effective at lower toxicities. However, relapse remains the major cause of death in DLBCL. (2) Methods: This is a 12-patient pilot study of the BeEAM preparative regimen with additional polatuzumab vedotin (PV, targeting CD79b) aiming to establish feasibility and to reduce toxicity without increasing the early progression rate. PV was given once at the standard dose of 1.8 mg/kg at day -6 together with BeEAM-HDCT (days -7 to -1) before ASCT. (3) Results: 8/12 patients (67%) received PV with BeEAM as a consolidation of first-line treatment, and 4/12 patients (33%) received PV with BeEAM after relapse treatment. All patients experienced complete engraftment (neutrophils: median 11 days; platelets: 13 days). Gastrointestinal toxicities occurred in 7/12 patients (58%, grade 3). All patients developed neutropenic infections with at least one identified pathogen (bacterial: 10/12 patients; viral: 2/12; and fungal: 1/12). The complete remission rate by PET-CT 100 days post-ASCT was 92%, with one mortality due to early progression. Eleven out of twelve patients (92%) were alive without progression after a median follow-up of 15 months. (4) Conclusions: Our study with 12 patients suggests that combining PV with BeEAM HDCT is feasible and safe, but the limited cohort prevents definite conclusions regarding efficacy. Larger cohorts must be evaluated

Possible impacts of climate change on debris-flow activity in the Swiss Alps

This study uses a long dataset of past debris flows from eight high-elevation catchments in the Swiss Alps for which triggering conditions since AD 1864 have been reconstructed. The torrents under investigation have unlimited sediment supply and the triggering of debris flows is thus mainly controlled by climatic factors. Based on point-based downscaled climate scenarios for meteorological stations located next to the catchments and for the periods 2001-2050 and 2051-2100, we study the evolution of temperature and rainfall above specific thresholds (10, 20, 30, 40 and 50mm) and durations (1, 2 or 3days). We conclude that the drier conditions in future summers and the wetting of springs, falls and early winters are likely to have significant impacts on the behavior of debris flows. Based on the current understanding of debris-flow systems and their reaction to rainfall inputs, one might expect only slight changes in the overall frequency of events by the mid-21st century, but possibly an increase in the overall magnitude of debris flows due to larger volumes of sediment delivered to the channels and an increase in extreme precipitation events. In the second half of the 21st century, the number of days with conditions favorable for the release of debris flows will likely decrease, especially in summer. The anticipated increase of rainfall during the shoulder seasons (March, April, November, December) is not expected to compensate for the decrease in future heavy summer rainfall over 2 or 3days

Working up rectal bleeding in adult primary care practices

Rationale, aims and objectivesVariation in the workup of rectal bleeding may result in guideline‐discordant care and delayed diagnosis of colorectal cancer. Accordingly, we undertook this study to characterize primary care clinicians’ initial rectal bleeding evaluation.MethodsWe studied 438 patients at 10 adult primary care practices affiliated with three Boston, Massachusetts, academic medical centres and a multispecialty group practice, performing medical record reviews of subjects with visit codes for rectal bleeding, haemorrhoids or bloody stool. Nurse reviewers abstracted patients’ sociodemographic characteristics, rectal bleeding‐related symptoms and components of the rectal bleeding workup. Bivariate and multivariable logistic regression models examined factors associated with guideline‐discordant workups.ResultsClinicians documented a family history of colorectal cancer or polyps at the index visit in 27% of cases and failed to document an abdominal or rectal examination in 21% and 29%. Failure to order imaging or a diagnostic procedure occurred in 32% of cases and was the only component of the workup associated with guideline‐discordant care, which occurred in 27% of cases. Compared with patients at hospital‐based teaching sites, patients at urban clinics or community health centres had 2.9 (95% confidence interval 1.3–6.3) times the odds of having had an incomplete workup. Network affiliation was also associated with guideline concordance.ConclusionWorkup of rectal bleeding was inconsistent, incomplete and discordant with guidelines in one‐quarter of cases. Research and improvements strategies are needed to understand and manage practice and provider variation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136454/1/jep12596.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136454/2/jep12596_am.pd

Alterations of Homocysteine Serum Levels during Alcohol Withdrawal Are Influenced by Folate and Riboflavin: Results from the German Investigation on Neurobiology in Alcoholism (GINA)

Aims: Various studies have shown that plasma homocysteine (HCY) serum levels are elevated in actively drinking alcohol-dependent patients a during alcohol withdrawal, while rapidly declining during abstinence. Hyperhomocysteinemia has been associated not only with blood alcohol concentration (BAC), but also with deficiency of different B-vitamins, particularly folate, pyridoxine and cobalamin. Methods: Our study included 168 inpatients (110 men, 58 women) after admission for detoxification treatment. BAC, folate, cobalamin, pyridoxine, thiamine and riboflavin were obtained on admission (Day 1). HCY was assessed on Days 1, 7 and 11. Results: HCY levels significantly declined during withdrawal. General linear models and linear regression analysis showed an influence of BAC, folate and riboflavin on the HCY levels on admission as well as on HCY changes occurring during alcohol withdrawal. No significant influence was found for thiamine, cobalamin and pyridoxine. Conclusions: These findings show that not only BAC and plasma folate levels, but also plasma levels of riboflavin influence HCY plasma levels in alcohol-dependent patient

Iron homeostasis during anemia of inflammation: a prospective study in patients with tuberculosis.

Anemia of inflammation is a hallmark of tuberculosis. Factors controlling iron metabolism during anemia of inflammation and its resolution are uncertain. Whether iron supplements should be given during anti-tuberculosis treatment to support Hb recovery is unclear. Before and during treatment of tuberculosis, we assessed iron kinetics, and changes in inflammation and iron metabolism indices. In a 26-wk prospective study, Tanzanian adults with tuberculosis (n=18) were studied before treatment and then every two weeks during treatment; oral and intravenous iron tracers were administered before treatment, after intensive phase (8/12 wk) and complete treatment (24 wk); no iron supplements were given. Before treatment, hepcidin and erythroferrone (ERFE) were greatly elevated, erythrocyte iron utilization was high (~80%) and iron absorption was negligible (<1%). During treatment, hepcidin and IL-6 decreased ~70% after only 2 wk (p<0.001); in contrast, ERFE did not significantly decrease until 8 wk (p<0.01). ERFE and IL-6 were the main opposing determinants of hepcidin (p<0.05) and greater ERFE was associated with reticulocytosis and hemoglobin (Hb) repletion (p<0.01). Dilution of baseline tracer concentration was 2.6-fold higher during intensive phase treatment (p<0.01) indicating enhanced erythropoiesis. After treatment completion, iron absorption increased ~20-fold (p<0.001); Hb increased ~25% (p<0.001). In tuberculosis-associated anemia of inflammation, our findings suggest elevated ERFE is unable to suppress hepcidin and iron absorption is negligible. During treatment, as inflammation resolves, ERFE may remain elevated, contributing to hepcidin suppression and Hb repletion. Iron is well-absorbed only after tuberculosis treatment and supplementation should be reserved for patients remaining anemic after treatment. (ClinicalTrials.gov Identifier:NCT02176772)

An oncocytic adrenal tumour in a patient with Birt‐Hogg‐Dubé syndrome

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106917/1/cen12292.pd

Saliva molecular inflammatory profiling in female migraine patients responsive to adjunctive cervical non-invasive vagus nerve stimulation : the MOXY Study

BackgroundRising evidence indicate that oxytocin and IL-1 impact trigemino-nociceptive signaling. Current perspectives on migraine physiopathology emphasize a cytokine bias towards a pro-inflammatory status. The anti-nociceptive impact of oxytocin has been reported in preclinical and human trials. Cervical non-invasive vagus nerve stimulation (nVNS) emerges as an add-on treatment for the preventive and abortive use in migraine. Less is known about its potential to modulate saliva inflammatory signaling in migraine patients. The rationale was to perform inter-ictal saliva measures of oxytocin and IL-1 ss along with headache assessment in migraine patients with 10weeks adjunctive nVNS compared to healthy controls.Methods12 migraineurs and 12 suitably matched healthy control were studied with inter-ictal saliva assay of pro- and anti-neuroinflammatory cytokines using enzyme-linked immuno assay techniques along with assessment of headache severity/frequency and associated functional capacity at baseline and after 10weeks adjunctive cervical nVNS.ResultsnVNS significantly reduced headache severity (VAS), frequency (headache days and total number of attacks) and significantly improved sleep quality compared to baseline (pPeer reviewe

Mutant SF3B1 promotes malignancy in PDAC

The splicing factor SF3B1 is recurrently mutated in various tumors, including pancreatic ductal adenocarcinoma (PDAC). The impact of the hotspot mutation SF3B1$^{K700E}$ on the PDAC pathogenesis, however, remains elusive. Here, we demonstrate that Sf3b1$^{K700E}$ alone is insufficient to induce malignant transformation of the murine pancreas, but that it increases aggressiveness of PDAC if it co-occurs with mutated KRAS and p53. We further show that Sf3b1$^{K700E}$ already plays a role during early stages of pancreatic tumor progression and reduces the expression of TGF-β1-responsive epithelial-mesenchymal transition (EMT) genes. Moreover, we found that SF3B1$^{K700E}$ confers resistance to TGF-β1-induced cell death in pancreatic organoids and cell lines, partly mediated through aberrant splicing of Map3k7. Overall, our findings demonstrate that SF3B1$^{K700E}$ acts as an oncogenic driver in PDAC, and suggest that it promotes the progression of early stage tumors by impeding the cellular response to tumor suppressive effects of TGF-β

Nestemäisten jätteiden vastaanotto ja käsittely Tarastenjärven jätekeskuksessa : Selvitys vaihtoehtoisista menetelmistä

Nestemäiset jätteet ovat erilaisia loka-autoilla kuljetettavia jätteitä, jotka koostuvat nesteestä ja kiintoaineksesta. Tällaisia jätteitä ovat esimerkiksi hiekan- ja rasvanerotuskaivoista imetyt nesteet sekä teollisuudessa syntyvät jätevesilietteet. Nestemäisiä jätteitä ei ole Valtioneuvoston päätöksestä enää vuoden 2002 jälkeen saanut sijoittaa sellaisenaan kaatopaikkapenkkaan, vaan ne on tullut esikäsitellä nesteen poistamiseksi. Tähän asti nestemäiset jätteet on käsitelty Tarastenjärven jätekeskuksessa painovoimaisesti erottelemalla. Menetelmä on ollut toimiva, mutta on päivityksen tarpeessa. Tämän opinnäytetyön tarkoituksena olikin tutkia erilaisia vaihtoehtoja nestemäisten jätteiden vastaanotolle sekä käsittelylle Tarastenjärven jätekeskuksessa, sekä arvioida eri vaihtoehtojen kustannuksia mikäli mahdollista. Myös tarvetta haitta-aineiden, kuten metallien ja öljyjen poistamiselle tutkittiin. Työn laatimisessa hyödynnettiin olemassa olevaa tieteellistä kirjallisuutta sekä asiantuntijahaastatteluja. Työn tilaajana toimi Pirkanmaan Jätehuolto Oy. Selvitystyön tuloksena kävi ilmi, että yleisimmät menetelmät nesteiden ja kiinteiden ainesten erottamiseen ovat painovoimainen erottelu ja suodatus. Painovoimaiset erottelijat ovat useimmiten kiinteäseinäisiä altaita, joissa kiintoaines laskeutuu painovoimaisesti altaan pohjalle ja pinnalle jäänyt kirkastunut neste ohjataan ylivuotona jatkokäsittelyyn. Kiintoaineksen ollessa kevyempää kuin vesi, se erottuu nesteen pinnalle. Suodattimien toiminta taas perustuu puoliläpäisevään suodatusmediaan, joka päästää nesteen läpi, mutta jättää kiintoaineksen suodattimeen. Suodattimet voivat olla esimerkiksi paineistettuja tai painovoimalla toimivia. Geotuubit ovat eräänlaisia paineistettuja säkkisuodattimia, joita on käytössä myös jätekeskuksissa. Useissa käsittelymenetelmissä käytetään apuna myös saostuskemikaaleja, jotka edistävät kiintoaineksen erottumista nesteestä. Haitta-aineiden osalta helpoin ratkaisu on poistaa ne kiintoaineksen mukana ja käsitellä ne pilaantuneiden maiden kanssa jätekeskuksessa. Mikäli haitta-aineet ovat nesteessä liukoisessa muodossa, voidaan apuna käyttää saostuskemikaaleja, kuten alumiini- tai rautasuoloja. Öljyjen erottamisessa olisi mahdollista hyödyntää öljynerotuskaivoa. Kirjallisuuden sekä haastattelujen perusteella päivitetty versio painovoimaisesta erottelujärjestelmästä sekä geotuubimenetelmä vaikuttavat parhailta käytettävissä olevilta ratkaisuilta. Suurin haaste jätekeskuksen nestemäisten jätteiden käsittelyssä on kuitenkin se, että nesteiden ominaisuudet eroavat kuormittain hyvin paljon toisistaan. Tähän voitaisiin vaikuttaa jätteiden tarkemmalla lajittelulla vastaanottovaiheessa. Käsittelymenetelmää valittaessa tulee kuitenkin pohtia järjestelmän kuluja sekä hyötyjä pitkällä aikavälillä niin, että päästään parhaaseen mahdolliseen puhdistuslopputulokseen.Liquid wastes are solid-liquid mixtures such as wastes from sand and grease separation wells and industrial wastewaters. Since 2002 liquid wastes have no longer been allowed to be placed at a waste disposal site according to the decree 1049/1999 of the Finnish Council of State. Therefore liquid wastes have to be dewatered before final disposal. At the moment liquid wastes are treated at the Tarastenjärvi waste management centre with gravitational separation but the system needs updating. The aim of this study was to provide Pirkanmaan Jätehuolto Oy with different methods of liquid waste handling as well as evaluate the costs of a new system if possible. Also the need for contaminant removal was taken into consideration. The study was carried out by literature reviews and interviewing professionals of the industry. The results showed that the most common methods of solid-liquid separation are gravitational separation and filtration. Gravitational separators are usually containers in which the solid matter is allowed to separate either by sedimentation or flotation. Filters have a semi-permeable filter media which traps the solid matter but allows the liquid to flow through. Geotubes are an example of filters that are currently being used in several waste management centres. Many separation methods also require the use of polymers or flocculants to operate effectively. When contaminants are in a settleable form they are rather easy to be removed and treated with the solid matter. If the contaminants are dissolved in the liquid it might be possible to make them settle by adding aluminium or iron sulphate. Also an oil separation well could be used to separate oils from the liquid phase. Based on the literature reviews and interviews an upgraded gravitational system or the geotube method seem to be the best options. However, more tests should be conducted to see if these methods would work in practice. The biggest challenge is that the incoming liquid waste loads at Tarastenjärvi are not homogenous which makes it difficult to choose a solution that works well for all of them. The situation could be improved with more precise classification of the waste loads and handling them separately according to their characteristics. The most important aspect is to find a long-term cost-effective solution that can provide sufficient handling of the liquid wastes

Specificity, duplex degradation and subcellular localization of antagomirs

MicroRNAs (miRNAs) are an abundant class of 20–23-nt long regulators of gene expression. The study of miRNA function in mice and potential therapeutic approaches largely depend on modified oligonucleotides. We recently demonstrated silencing miRNA function in mice using chemically modified and cholesterol-conjugated RNAs termed ‘antagomirs’. Here, we further characterize the properties and function of antagomirs in mice. We demonstrate that antagomirs harbor optimized phosphorothioate modifications, require >19-nt length for highest efficiency and can discriminate between single nucleotide mismatches of the targeted miRNA. Degradation of different chemically protected miRNA/antagomir duplexes in mouse livers and localization of antagomirs in a cytosolic compartment that is distinct from processing (P)-bodies indicates a degradation mechanism independent of the RNA interference (RNAi) pathway. Finally, we show that antagomirs, although incapable of silencing miRNAs in the central nervous system (CNS) when injected systemically, efficiently target miRNAs when injected locally into the mouse cortex. Our data further validate the effectiveness of antagomirs in vivo and should facilitate future studies to silence miRNAs for functional analysis and in clinically relevant settings