Adenoviral Gene Therapy for Advanced Head and Neck Cancer

Advanced stage head and neck cancers (HNC) with distant metastasis, as well as prostate cancers (PC), are devastating diseases currently lacking efficient treatment options. One promising developmental approach in cancer treatment is the use of oncolytic adenoviruses, especially in combination therapy with conventional cancer therapies. The safety of the approach has been tested in many clinical trials. However, antitumor efficacy needs to be improved in order to establish oncolytic viruses as a viable treatment alternative. To be able to test in vivo the effects on anti-tumor efficiency of a multimodal combination therapy of oncolytic adenoviruses with the standard therapeutic combination of radiotherapy, chemotherapy and Cetuximab monoclonal antibody (mAb), a xenograft HNC tumor model was developed. This model mimics the typical clinical situation as it is initially sensitive to cetuximab, but resistance develops eventually. Surprisingly, but in agreement with recent findings for chemotherapy and radiotherapy, a higher proportion of cells positive for HNC cancer stem cell markers were found in the tumors refractory to cetuximab. In vitro as well as in vivo results found in this study support the multimodal combination therapy of oncolytic adenoviruses with chemotherapy, radiotherapy and monoclonal antibody therapy to achieve increased anti-tumor efficiency and even complete tumor eradication with lower treatment doses required. In this study, it was found that capsid modified oncolytic viruses have increased gene transfer to cancer cells as well as an increased antitumor effect. In order to elucidate the mechanism of how oncolytic viruses promote radiosensitization of tumor cells in vivo, replicative deficient viruses expressing several promising radiosensitizing viral proteins were tested. The results of this study indicated that oncolytic adenoviruses promote radiosensitization by delaying the repair of DNA double strand breaks in tumor cells. Based on the promising data of the first study, two tumor double-targeted oncolytic adenoviruses armed with the fusion suicide gene FCU1 or with a fully human mAb specific for human Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) were produced. FCU1 encodes a bifunctional fusion protein that efficiently catalyzes the direct conversion of 5-FC, a relatively nontoxic antifungal agent, into the toxic metabolites 5-fluorouracil and 5-fluorouridine monophosphate, bypassing the natural resistance of certain human tumor cells to 5-fluorouracil. Anti-CTLA4 mAb promotes direct killing of tumor cells via apoptosis and most importantly immune system activation against the tumors. These armed oncolytic viruses present increased anti-tumor efficacy both in vitro and in vivo. Furthermore, by taking advantage of the unique tumor targeted gene transfer of oncolytic adenoviruses, functional high tumor titers but low systemic concentrations of the armed proteins were generated. In addition, supernatants of tumor cells infected with Ad5/3-24aCTLA4, which contain anti-CTLA4 mAb, were able to effectively immunomodulate peripheral blood mononuclear cells (PBMC) of cancer patients with advanced tumors. -- In conclusion, the results presented in this thesis suggest that genetically engineered oncolytic adenoviruses have great potential in the treatment of advanced and metastatic HNC and PC.

Studio portrait of the six daughters of Solomon and Emilie Kohnberger: (l-r) Laura, Irene, Johanna, Melanie, Hermine and Martha.

Laura (1878-1917) died during a flu epidemic. She married Sigmund Stiassny and had two children, Lisbeth (Gersuny) (1900-1986) and Walter (1902-1912) who died of a ruptured appendix.

Grave of Josef Molling; Germany.

Josef Molling committed suicide. He had financial problems, either embezzelment from the Prussian State Lottery or over an aircraft plant.

Siegbert Springer Collection 1977-1984

Article about Siegbert Springer in Juristische Schulung, vol. 17, No. 7 and a report about a memorial plaque for Siegbert Springer in Berlin.

Erinnerungen 1857-1934

Genealogy; childhood in Tuebingen as the youngest of 14 brothers; student life in Tuebingen; professional career; because of his being Jewish no possibility to enter career as public prosecutor; active membership in National Liberal Party and in Free Mason Lodge; World War I; closing of his law office in 1933. Contains transcriptions of numerous congratulations for his golden wedding and his 80th birthday in 1937.

Visit to a Viennese cemetery /

"Visit to a Viennese Cemetary" is a personal reflection about Fireside's first trip back to Austria since his arrival in the USA. It was organised by the "Jewish Welcome Service" in September 2000. This trip brings forgotten memories back to life, questioning the role of Austrians in the Holocaust, and their denial afterwards. The author describes the trip, first days of sightseeing and conversations of his fellow travellers. On the last day, the group went to Zentralfreidhof, the main cemetery in Vienna.

Die letzten Lebensjahre meines Vaters Prof. Ernst Neisser 1939-1942

Description of Prof. Neisser's last years in form of a letter written by his daughter to a relative in the USA; concentrates mainly on suicide of Ernst Neisser and his cousin in 1942 to escape deportation.

The File Marked "Rita". Selections from the Letters of Herbert Mueller and Rita Klein (1939-1945) 1939-1946

Exchange of letters between Herbert Mueller and Rita Klein after Mueller's emigration to England in 1939; Rita Klein's attempt to obtain divorce; suicide attempt by her husband Leo Klein; correspondence through intermediaries after outbreak of World War II; notice of Rita Klein's deportation to Auschwitz; (translation from original German)

Comparing Notes 1918-1991

Memoir by Pierre Ferrand, written in 1992, including recollections of his meeting with Alfred Doeblin in the freight car of a military transport leaving occuppied Paris in 1940 for Cahors, information on Ferrand's family which Ferrand believes is portrayed in Doeblin's "Schicksalsreise," critical comments on Doeblin's work and character, and information on Ferrand's father's work as Advisor on German Affairs for the French government and on the family's emigration to the United States; newspaper clipping of 1991 with letter to the editor on Frederick the Great by Pierre Ferrand.

My First 6701 Days : July 31 1921 to December 1939 /

The memoirs contain photocopies of documents and photos as well as extracts from letters and were written in October 1989 in the United States. Description of life in Baden, a famous health resort near Vienna. The family lived in Vienna in the second district (Leopoldstadt). Recollections of schoolteachers and childhood friends. Occasional Friday night services in the Leopoldstadt temple. Theater and opera visits and cultural life in Vienna. Private piano and music lessons. Description of the family apartment and Jewish life in the Leopoldstadt. The family celebrated Christmas and observed the high Jewish holidays. Recollections of the author's bar mitzvah celebration. His mother Charlotte, nee Schwadron, was an artistic woman, who studied painting at the Frauenakademie with Tina Blau. Walter's father Leo Schaffir was born in Byalistock, Russia and studied in Berlin. He was a travelling businessmen. His family lived in Lemberg, Galicia. Leo and Charlotte Schaffir got married in 1919 in Vienna by rabbi Dr. Grunwald. Recollections of a family trip to Poland and to the World Fair in Posen in 1930. Suicide of the author's father due to business failure in 1930. Schaffir and Schwadron family history. Both families originated in Galicia, Poland. Family and social life. Summer vacation at the Semmering. Austrian politics in the 1930's and rising National Socialism. Life in Vienna after the "Anschluss" in 1938. Walter had to leave school and took lessons in graphic arts with the artist Heinrich Koerner. Preparations to emigrate. Walter was picked up in the streets in the days after Kristallnacht and released due to his mother's intervention. He was sent with his brother Kurt on a "Kindertransport" to Holland. They were sent to a quarantine camp at Heyplaat. Reunition with their mother in the United States in December 1939. Reflections on life as an emigre.

Staubkorn im Sandsturm.

Fate of the Jewish physician Karl Goldberg, novel written in 1944. Novel is only partially autobiographical.

A role to play: Investigating concepts of masculinity in Australia through theatre

Health professionals, academics, social commentators and the media are increasingly sending the same message – Australian men are in crisis. This message has been supported by documented rises in alcoholism, violence, depression, suicide and crime amongst men in Australia. A major cause of this crisis, it can be argued, is an over-reliance on the out-dated and limited model of hegemonic masculinity that all men are encouraged to imitate in their own behaviour. This paper, as part of a larger study, explores representations of masculinity in selected works of contemporary Australian theatre in order to investigate the concept of hegemonic masculinity and any influence it may have on the perceived ‘crisis of masculinity’. Theatre is but one of the artistic modes that can be used to investigate masculinity and issues associated with identity. The Australia Council for the Arts recognises theatre, along with literature, dance, film, television, inter-arts, music and visual arts, as critical to the understanding and expression of Australian culture and identity. Theatre has been chosen in this instance because of the opportunities available to this study for direct access to specific theatre performances and creators and, also, because of the researcher’s experience, as a theatre director, with the dramatic arts. Through interviews with writers, directors and actors, combined with the analysis of scripts, academic writings, reviews, articles, programmes, play rehearsals and workshops, this research utilises theatre as a medium to explore masculinity in Australia.

(Re)presenting Masculinity: A theatre director's critical observations of, and theatrical experimentation with, (re)presentations of masculinity in selected works of contemporary Australian theatre

Health professionals, academics, social commentators and the media are increasingly sending the same message – Australian men are in crisis. This message has been supported by documented rises in alcoholism, violence, depression, suicide and crime amongst men in Australia. A major cause of this crisis, it can be argued, is an over-reliance on the out-dated and limited model of hegemonic masculinity that all men are encouraged to imitate in their own behaviour. This paper, as part of a larger study, explores representations of masculinity in selected works of contemporary Australian theatre in order to investigate the concept of hegemonic masculinity and any influence it may have on the perceived ‘crisis of masculinity’. Theatre is but one of the artistic modes that can be used to investigate masculinity and issues associated with identity. The Australia Council for the Arts recognises theatre, along with literature, dance, film, television, inter-arts, music and visual arts, as critical to the understanding and expression of Australian culture and identity. Theatre has been chosen in this instance because of the opportunities available to this study for direct access to specific theatre performances and creators and, also, because of the researcher’s experience, as a theatre director, with the dramatic arts. Through interviews with writers, directors and actors, combined with the analysis of scripts, academic writings, reviews, articles, programmes, play rehearsals and workshops, this research utilises theatre as a medium to explore masculinity in Australia.

The Population Consequences of Sex and Conflict

Natural selection generally operates at the level of the individual, or more specifically at the level of the gene. As a result, individual selection does not always favour traits which benefit the population or species as a whole. The spread of an individual gene may even act to the detriment of the organism in which it finds. Thus selection at the level of the individual can affect processes at the level of the organism, group or even at the level of the species. As most behaviours ultimately affect births, deaths and the distribution of individuals, it seems inevitable that behavioural decisions will have an impact on population dynamics and population densities. Behavioural decisions can often involve costs through allocation of energy into behavioural strategies, such as the investment into armaments involved in fighting over resources or increased mortality due to injury or increased predation risk. Similarly, behaviour may act o to benefit the population, in terms of higher survival and increased fecundity. Examples include increased investment through parental care, choosing a mate based on the nuptial gifts they may supply and choosing territories in the face of competition. Investigating the impact of behaviour on population ecology may seem like a trivial task, but it is likely to have important consequences at different levels. For example, antagonistic behaviour may occasionally become so extreme that it increases the risk of extinction, and such extinction risk may have important implications for conservation. As a corollary, any such behaviour may also act as a macroevolutionary force, weeding out populations with traits which, whilst beneficial to the individuals in the short term, ultimately result in population extinction. In this thesis, I examine how behaviours, specifically conflict and competition over a resource and aspects of behaviour involved in sexual selection, can affect population densities, and what the implications are for the evolution and ecology of the populations in question. It is found that both behaviours related to individual conflict and mating strategies can have an effect at the level of the population, but that various factors, such as a feedback between selection and population densities or macroevolution caused by species extinctions, may act to limit the intensity of conflicts that we observe in nature.

Work-related well-being of Finnish anesthesiologists

Anesthesiologists, according to some studies, are highly stressed, die at a significantly earlier age than their colleagues and the general population,and are among the leaders in physicians' suicide records. Data are,however, sparse and contradictory. The aim of this study was to discover details of the work-related well-being of Finnish anesthesiologists. In 2004, a cross-sectional postal survey including all 550 working Finnish anesthesiologists produced a total of 328 responses (60%); 53% were men. The anesthesiologists had the greatest on-call workload among Finnish physicians. Their average in-hospital on-call period lasted 24 hours (range 14 to 38). Over two-thirds felt stressed. The most important causes of stress were work and combining work with family. Their main worries at work were: excessive workload and time constraints, especially being on call, organizational problems, and fear of harming patients. On-call workload correlated with burnout. Being frequently on call was correlated with severe stress symptoms--symptoms associated with sick leaves. Women were more affected by stress than men. High job control and organizational justice seemed to mitigate hospital-on-call stress symptoms. The respondents enjoyed fairly high job and life satisfaction. Job control and organizational justice were the most important correlates of these wellness indicators. Work-related factors were more important in males, whereas family life played a larger role in the well-being of female anesthesiologists. Women had less job control, fewer permanent job contracts, and a higher domestic workload. Of the respondents, 31% were willing to consider changing to another physician's specialty and 43% to a profession other than medicine. The most important correlates for these job turnover attitudes were conflicts at the workplace, low job control, organizational injustice, stress, and job dissatisfaction. One in four had at some time considered suicide. Respondents with poor health, low social support, and family problems were at the highest risk for suicidality. The highest risks at work were conflicts with co-workers and superiors, on-call-related stress symptoms, and low organizational justice. If a respondent had several risk factors, the risk for suicidality doubled with each additional factor. On-call work-burden, job control, fairness of decision-making procedures,and workplace relationships should be the focus in attempts to increase the work-related well-being of anesthesiologists.