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Tiivistelmä. Tämä pro gradu -työ on osa avointa oppikirjaa lukion pitkän matematiikan Integraalilaskenta- kurssille (MAA7). Tässä osassa oppikirjaa käydään läpi pinta-alan laskeminen y-akselin suhteen, tilavuussovelluksia sekä pyörähdyskappaleen tilavuuden laskeminen. Cuocon ja muiden artikkelista Habits of Mind oppikirjan tavoitteiksi valittiin visualisointi, kuvailu sekä arvaaminen ja kokeilu. Oppikirjan tehtävien tehtävätyypit valittiin Swanin Collaborative Learning in Mathematics artikkelista. Oppikirjan tehtävät pyrkivät hyödyntämään tehtävätyyppeinä päättelyvirheiden korjausta ja erilaisten esitystapojen yhdistelemistä. Lukion opetussuunnitelma pitää tärkeänä tietokoneohjelmistojen hyödyntämistä opetuksessa. Tässä oppikirjassa hyödynnetään ilmaista, kaikkien ladattavissa olevaa GeoGebra-ohjelmaa, joka on käytössä myös sähköisessä matematiikan ylioppilaskokeessa. Tietokoneohjelmiston käyttö edesauttaa opiskelijaa havainnollistamaan, tutkimaan ja ymmärtämään opetettavaa asiaa. Oppikirjassa opetetaan myös tarvittavien toimintojen käyttöä GeoGebrassa. Tietokoneohjelmistojen käyttö opetuksessa voi aiheuttaa sen, että opiskelija oppii laskemaan laskut rutiininomaisesti ohjelman avulla kuitenkaan ymmärtämättä, mitä laskussa tehdään. Differentiaali- ja integraalilaskenta on tärkeä osa-alue matematiikassa ja käsiteltäviä aiheita sovelletaan monilla aloilla. Kirjassa opetetaan visualisoimaan pyörähdyskappale niin käsin kuin GeoGebran avulla, mikä voi auttaa monia opiskelijoita ymmärtämään tilavuuden laskemisen. Kirjaan on pyritty laatimaan pohdintatehtäviä, joiden avulla opiskelijat ymmärtävät opetettavan asian omatoimisesti, jopa ennen teorian esittämistä. Tutkimusten mukaan opiskelijoiden välinen kommunikointi ja ryhmätyö auttavat oppimista. Opettajan tehtävänä on havainnoida ja löytää opiskelijoiden väärinkäsitykset ja korjata ne esimerkiksi keskustelemalla ryhmän kesken. Väärinkäsitysten korjaamisen lisäksi opettajalla on tärkeä rooli motivoinnissa. Opettajan tulee pyrkiä tuomaan opetettava asia lähelle opiskelijoiden maailmaa, eli heille tuttuihin asioihin. Kirjan tehtävistä suurin osa on sanallisia tehtäviä. Opiskelijat joutuvat miettimään, mikä tekstissä on oleellista tehtävän ratkaisun kannalta.

Alexander disease (AxD) is a genetic leukodystrophy caused by GFAP mutations leading to astrocyte dysfunction. Neonatal AxD is a rare phenotype with onset in the first month of life. The proband, belonging to a large pedigree with dominantly inherited benign familial neonatal epilepsy (BFNE), had a phenotype distinct from the rest of the family, with hypotonia and macrocephaly in addition to drug-resistant neonatal seizures. The patient deteriorated and passed away at 6 weeks of age. The pathological and neuroimaging data were consistent with the diagnosis of AxD. Genetic analysis of the proband identified a novel de novo GFAP missense mutation and a KCNQ2 splice site mutation segregating with the BFNE phenotype in the family. The GFAP mutation was located in the coil 2B region of GFAP protein, similar to most neonatal-onset AxD cases with an early death. The clinical and neuroradiological features of the previously published neonatal AxD patients are presented. This study further supports the classification of neonatal-onset AxD as a distinct phenotype based on the age of onset.

Sarcomas are a relatively rare cancer, but often incurable at the late metastatic stage. Oncolytic immunotherapy has gained attention over the past years, and a wide range of oncolytic viruses have been delivered via intratumoral injection with positive safety and promising efficacy data. Here, we report preclinical and clinical results from treatment of sarcoma with oncolytic adenovirus Ad5/3-D24-GMCSF (CGTG-102). Ad5/3-D24-GMCSF is a serotype chimeric oncolytic adenovirus coding for human granulocyte-macrophage colony-stimulating factor (GM-CSF). The efficacy of Ad5/3-D24-GMCSF was evaluated on a panel of soft-tissue sarcoma (STS) cell lines and in two animal models. Sarcoma specific human data were also collected from the Advanced Therapy Access Program (ATAP), in preparation for further clinical development. Efficacy was seen in both in vitro and in vivo STS models. Fifteen patients with treatment-refractory STS (13/15) or primary bone sarcoma (2/15) were treated in ATAP, and treatments appeared safe and well-tolerated. A total of 12 radiological RECIST response evaluations were performed, and two cases of minor response, six cases of stable disease and four cases of progressive disease were detected in patients progressing prior to virus treatment. Overall, the median survival time post treatment was 170 days. One patient is still alive at 1,459 days post virus treatment. In summary, Ad5/3-D24-GMCSF appears promising for the treatment of advanced STS; a clinical trial for treatment of refractory injectable solid tumors including STS is ongoing.

Docetaxel administered every three weeks is the standard treatment for advanced hormone-refractory prostate cancer (HRPC). However, biweekly administration might be better tolerated due to the reduced peak drug concentrations. Therefore, we compared biweekly to triweekly docetaxel as first- or second-line chemotherapy for advanced HRPC in this prospective randomized multicenter trial.In this study, 360 patients were randomly allocated to receive docetaxel 75 mg/m(2) i.v. d1 q3 weeks (tT) or 50 mg/m(2) i.v. d1 and d 14, q4 weeks (bT) from March 2004 to May 2009. Oral prednisolone (10 mg/day) was administered in both groups. The groups were well balanced according to the WHO performance status in terms of mean age (70 vs. 68, range 45-87 years) and median serum PSA level at the time of study entry (109 vs. 98 μg/l, range 11-1490 μg/l). The primary endpoint was time to treatment failure (TTF). ClinicalTrials.gov study identifier: NCT00255606.Ultimately, 158 patients (tT=79; bT=79) were included in this preplanned interim safety analysis; 567 and 487 cycles (equivalent to 1701 and 1948 weeks of treatment) were administered in the tT and bT groups, respectively. The most common grade 3-4 adverse events (expressed as %/cycles) in tT /bT were neutropenia 20%/14%; infection with/without neutropenia 8%/3%; fatigue 3%/3%; febrile neutropenia 2%/1%; and bone pain 2%/1%. Serious adverse events occurred more frequently in the group tT (n=60, 10.6% of cycles) than in the group bT (n=29, 6.0%, p=0.012). One patient died due to coronary infarction, and another was diagnosed with acute lymphocytic leukemia (both in the bT group). Thirty patients (38%) in the bT group and 22 patients (28%) in the tT group were still receiving treatment at 6 months (p=0.176).Biweekly docetaxel was tolerated better than conventional triweekly with fewer serious adverse events and more patients were still on the therapy at 6 months. Biweekly docetaxel therapy might be considered as an option for elderly patients exhibiting a compromised general condition.

Usher syndrome type 3 (USH3) is an autosomal recessive disorder characterised by the association of post-lingual progressive hearing loss, progressive visual loss due to retinitis pigmentosa and variable presence of vestibular dysfunction. Because the previously defined transcripts do not account for all USH3 cases, we performed further analysis and revealed the presence of additional exons embedded in longer human and mouse USH3A transcripts and three novel USH3A mutations. Expression of Ush3a transcripts was localised by whole mount in situ hybridisation to cochlear hair cells and spiral ganglion cells. The full length USH3A transcript encodes clarin-1, a four-transmembrane-domain protein, which defines a novel vertebrate-specific family of three paralogues. Limited sequence homology to stargazin, a cerebellar synapse four-transmembrane-domain protein, suggests a role for clarin-1 in hair cell and photoreceptor cell synapses, as well as a common pathophysiological pathway for different Usher syndromes.