Homologous recombination repair is essential for repair of vosaroxin-induced DNA double-strand breaks

Vosaroxin (formerly voreloxin) is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, inducing site-selective double-strand breaks (DSB), G2 arrest and apoptosis. Objective responses and complete remissions were observed in phase 2 studies of vosaroxin in patients with solid and hematologic malignancies, and responses were seen in patients whose cancers were resistant to anthracyclines. The quinolone-based scaffold differentiates vosaroxin from the anthracyclines and anthracenediones, broadly used DNA intercalating topoisomerase II poisons. Here we report that vosaroxin induces a cell cycle specific pattern of DNA damage and repair that is distinct from the anthracycline, doxorubicin. Both drugs stall replication and preferentially induce DNA damage in replicating cells, with damage in G2 / M > S >> G1. However, detectable replication fork collapse, as evidenced by DNA fragmentation and long tract recombination during S phase, is induced only by doxorubicin. Furthermore, vosaroxin induces less overall DNA fragmentation. Homologous recombination repair (HRR) is critical for recovery from DNA damage induced by both agents, identifying the potential to clinically exploit synthetic lethality

Web-Based Virtual Microscopy for Parasitology: A Novel Tool for Education and Quality Assurance

Here, we describe a novel tool to observe parasites by virtual microscopy on the Internet. Microscopy-based identification of parasites is the basis for both diagnostics and epidemiological assessment of parasite burden globally. Yet, quality assessment of diagnostic parasitology laboratories is difficult, as delivering identical educational specimens has been impossible. In this study, a series of parasite specimens on ordinary glass slides were digitized using a recently developed microscope scanner technique. Up to 50,000 images captured at high magnification are digitally stitched together to form a representation of the entire glass slide. These “virtual slides” digitized at a thousand-fold magnification can hold more than 60 gigabytes of data. Handling such large amounts of data was made possible because of efficient compression techniques and a viewing system adopted from the geospatial imaging industry. Viewing the samples on the Internet very much resembles, for example, the use of Google Maps, and puts only modest requirements on the viewer's computer. In addition, we captured image stacks at different focal planes, and developed a web-based viewing system for three-dimensional navigation in the specimens. This novel technique is especially valuable for detailed visualization of large objects such as helminth eggs in stool specimens

The ERCC1/XPF endonuclease is required for completion of homologous recombination at DNA replication forks stalled by inter-strand cross-links

Both the ERCC1-XPF complex and the proteins involved in homoIogous recombination (HR) have critical roles in inter-strand cross-link (ICL) repair. Here, we report that mitomycin C-induced lesions inhibit replication fork elongation. Furthermore, mitomycin C-induced DNA double-strand breaks (DSBs) are the result of the collapse of ICL-stalled replication forks. These are not formed through replication run off, as we show that mitomycin C or cisplatin-induced DNA lesions are not incised by global genome nucleotide excision repair (GGR). We also suggest that ICL-lesion repair is initiated either by replication or transcription, as the GGR does not incise ICL-lesions. Furthermore, we report that RAD51 foci are induced by cisplatin or mitomycin C independently of ERCC1, but that mitomycin C-induced HR measured in a reporter construct is impaired in ERCC1-defective cells. These data suggest that ERCC1–XPF plays a role in completion of HR in ICL repair. We also find no additional sensitivity to cisplatin by siRNA co-depletion of XRCC3 and ERCC1, showing that the two proteins act on the same pathway to promote survival

Hormonal contraception, mood and sexual function

Hormonal contraceptives (HCs) are used by millions of women worldwide. Apart from their contraceptive effect, they also offer additional health benefits such as decreased menstrual bleedings and amelioration of menstrual-related pain.  Adverse mood and sexual side-effects during HC-use are commonly reported, and women who discontinue treatment with HCs often claim these side effects as reason for cessation. Although several studies have investigated associations of HCs and adverse mood and sexual side-effects, little is known about causally drug-related outcomes. Few randomised controlled trials (RCTs) have been conducted, and observational studies in the field are subject to several methodological caveats which limit what conclusions that can be drawn from them. The overall aim of this thesis was to investigate the effect of HCs on various aspects of mood and sexual function. Study one was a randomised controlled trial where participant women received a combined oral contraceptive (COC) or placebo. Mood and sexual function were assessesed through daily ratings and questionnaires and measured at baseline and after three months treatment.  Study two was a cross-sectional study that assessed which demographic, reproductive, and psychiatric factors are associated with self-reported HC-induced adverse mood symptoms. Study three was a register-based cohort study including all Nordic-born women aged 15-24 residing in Sweden between 2010 and 2017. Risk of depression – captured as redeemed prescription of antidepressant treatment or a depression diagnosis – among HC-users compared to non-users were estimated.  Women who were randomised to a COC reported increased anxiety, mood swings and irritability compared to women randomised to placebo. In contrast, women who received a COC improved in depressive symptoms (paper I).  Compared to women randomised to placebo, women who received a COC deteriorated regarding sexual interest and vaginal lubrication. Only deterioration in sexual interest remained after adjustments for depressive symptoms (paper II).  Compared to women with no self-reported HC-induced adverse mood symptoms, women with such experience more often suffered from an ongoing minor depressive disorder, had more often experienced any previous mental health problem, and had more often undergone induced abortion (paper III).  No uniform associations between use of HCs and subsequent risk of depression were found. In general, oral contraceptives conferred lower or no risk, while non-oral contraceptives were associated with small increased risks. Higher risks were found among HC-users aged 15-19 years compared to older HC-users (paper IV)

Hormonal contraception, mood and sexual function

Hormonal contraceptives (HCs) are used by millions of women worldwide. Apart from their contraceptive effect, they also offer additional health benefits such as decreased menstrual bleedings and amelioration of menstrual-related pain.  Adverse mood and sexual side-effects during HC-use are commonly reported, and women who discontinue treatment with HCs often claim these side effects as reason for cessation. Although several studies have investigated associations of HCs and adverse mood and sexual side-effects, little is known about causally drug-related outcomes. Few randomised controlled trials (RCTs) have been conducted, and observational studies in the field are subject to several methodological caveats which limit what conclusions that can be drawn from them. The overall aim of this thesis was to investigate the effect of HCs on various aspects of mood and sexual function. Study one was a randomised controlled trial where participant women received a combined oral contraceptive (COC) or placebo. Mood and sexual function were assessesed through daily ratings and questionnaires and measured at baseline and after three months treatment.  Study two was a cross-sectional study that assessed which demographic, reproductive, and psychiatric factors are associated with self-reported HC-induced adverse mood symptoms. Study three was a register-based cohort study including all Nordic-born women aged 15-24 residing in Sweden between 2010 and 2017. Risk of depression – captured as redeemed prescription of antidepressant treatment or a depression diagnosis – among HC-users compared to non-users were estimated.  Women who were randomised to a COC reported increased anxiety, mood swings and irritability compared to women randomised to placebo. In contrast, women who received a COC improved in depressive symptoms (paper I).  Compared to women randomised to placebo, women who received a COC deteriorated regarding sexual interest and vaginal lubrication. Only deterioration in sexual interest remained after adjustments for depressive symptoms (paper II).  Compared to women with no self-reported HC-induced adverse mood symptoms, women with such experience more often suffered from an ongoing minor depressive disorder, had more often experienced any previous mental health problem, and had more often undergone induced abortion (paper III).  No uniform associations between use of HCs and subsequent risk of depression were found. In general, oral contraceptives conferred lower or no risk, while non-oral contraceptives were associated with small increased risks. Higher risks were found among HC-users aged 15-19 years compared to older HC-users (paper IV)

Vilka lärstilar har sex elever i grundskolans senare år?

Detta examensarbete handlar om att undersöka lärstilar hos elever i grundskolans senare år. Syftet är att undersöka vilka lärstilar sex elever ur grundskolans senare år har genom att utföra enklare teoretiska test. Frågeställningen jag vill undersöka är: Vilka lärstilar har sex elever i grundskolans senare år? Syftet är också att diskutera med var elev om hur de på bästa sätt lär sig kemi, detta med hjälp av intervjufrågor. Två metoder valdes i min undersökning, för att ta reda på vilka lärstilar som fanns representerade i en grupp elever. Enkätundersökning i form av teoretiskt test utfördes först med två grupper elever som ett första steg. Resultatet visade att de två vanligaste sinneslärstilarna i hela elevgruppen var kinestetisk och auditiv. 79 procent av eleverna hade något av dessa två alternativ som främsta sinneslärstil enligt enkätundersökningarna. Dessutom hade alla elever antingen kinestetisk och/eller auditiv sinneslärstil som någon av sina två främsta preferenser, så detta resultat innebär att genom undervisa med auditiva och kinestetiska lärstilsövningar så kan alla dessa elever nås. Även liknande resonemang kan föras gällande gruppens styrkor gällande intelligenser. Ett urval av sex elever ur grupperna gjordes sedan. I ett andra steg utfördes en intervju med var och en av dessa sex elever. Jämfört med tidigare forskning så erhöll denna studie också resultatet att det gick att kartlägga en lärstilsprofil av varje elev, och många intervjusvar stämde väl överens med den lärstil som sammanställdes efter enkäterna. Flera publikationer som använt Flemings VARK questionnaire har fått resultat där de kunnat identifiera elevernas lärstilar. Liu och Ginther (1999) visade i en amerikansk studie att mellan 20 och 30 procent föredrog auditiv sinneslärstil, 40 procent visuell och mellan 30 till 40 procent antingen read/write eller kinestetisk. Kartläggningen av elevernas lärstilar kan vara högst användbart som utgångspunkt i lektionsplanering i ämnet kemi. Inför varje undervisningsmoment så är det viktigt att vara medveten om hur man lägger upp planeringen. Andrews (1984) undersökning kring ordningen på teoretiska och praktiska undervisningsmoment i organisk kemiundervisning visade att om undervisningssättet varieras så att det matchade studenternas lärstilar, så kan studenternas lärande förbättras. Tidigare forskning har visat att en elev som får sin lärstil tillgodosedd i undervisningen kommer att prestera bättre (med 95 procentig säkerhet) (Boström 2007, s. 25)