264 research outputs found
Response to histone deacetylase inhibition of novel PML/RARalpha mutants detected in retinoic acid-resistant APL cells.
No full textResistance to all-trans retinoic acid (ATRA) remains a clinical problem in the treatment of acute promyelocytic leukemia (APL) and provides a model for the development of novel therapies. Molecular alterations in the ligand-binding domain (LBD) of the PML/RARalpha fusion gene that characterizes APL constitute one mechanism of acquired resistance to ATRA. We identified missense mutations in PML/RARalpha from an additional ATRA-resistant patient at relapse and in a novel ATRA-resistant cell line, NB4-MRA1. These cause altered binding to ligand and transcriptional coregulators, leading to a dominant-negative block of transcription. These mutations are in regions of the LBD that appear to be mutational hot spots occurring repeatedly in ATRA-resistant APL patient cells. We evaluated whether histone deacetylase (HDAC) inhibition could overcome the effects of these mutations on ATRA-induced gene expression. Cotreatment with ATRA and TSA restored RARbeta gene expression in NB4-MRA1 cells, whose PML/RARalpha mutation is in helix 12 of the LBD, but not in an APL cell line harboring the patient-derived PML/RARalpha mutation, which was between helix 5 and 6. Furthermore, ATRA combined with TSA increases histone 4 acetylation on the RARbeta promoter only in NB4-MRA1 cells. Consistent with these results, the combined treatment induces differentiation of NB4-MRA1 only. Thus, the ability of an HDAC inhibitor to restore ATRA sensitivity in resistant cells may depend on their specific molecular defects. The variety of PML/RARalpha mutations arising in ATRA-resistant patients begins to explain how APL patients in relapse may differ in response to transcription therapy with HDAC inhibitors
Obinutuzumab treatment in the elderly patient with chronic lymphocytic leukemia
No full textKaren Seiter, Aleksandra Mamorska-DygaDepartment of Medicine, Division of Hematology/Oncology, New York Medical College, Valhalla, NY, USA Abstract: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in Western countries. Fludarabine-based regimens demonstrate higher response rates in younger patients but have a significant risk of infection and are thus poorly tolerated by older, frail patients. Anti-CD20 monoclonal antibodies have added to the efficacy of chemotherapy in CLL. Obinutuzumab is a potent Type II anti-CD20 monoclonal antibody with enhanced antibody-dependent cellular toxicity and direct cell death compared with rituximab. In Phase I studies, infusion reactions and neutropenia were the predominant toxicities. Phase II studies demonstrated efficacy both as a single agent and in combination with chemotherapy in patients with CLL. The CLL11 trial was a Phase III randomized trial of chlorambucil alone or with either obinutuzumab or rituximab in elderly, unfit patients. Progression-free survival (the primary end point) was 26.7 months for patients receiving obinutuzumab plus chlorambucil versus 16.3 months for those receiving rituximab plus chlorambucil and 11.1 months for those receiving chlorambucil alone (P<0.001). Overall survival was improved for patients receiving obinutuzumab plus chlorambucil versus chlorambucil alone (P=0.002). This trial led to the US Food and Drug Administration (FDA) approval of obinutuzumab in this patient population.Keywords: chronic lymphocytic leukemia, obinutuzumab, chlorambucil, elderl
Teaching Students how to Analyze and Adapt to Audiences
No full textNot long ago, one of the author\u27s students told him, “I won\u27t be able to make it to your class today. I have to study for a test in another course. Will I miss anything important?” The author, of course, had heard this excuse before, as many of us probably have. What made this interaction more amusing was what, by coincidence, the student was going to miss that day: a discussion on analyzing and adapting to audiences. Had she attended the class, we wonder if she would understand the negative ways in which her excuse might be interpreted by a professor (e.g., “your class is not as important as others” or “you waste a lot of time on trivial topics”). If asked to name the most critical skill communication instructors can teach their students, we could probably nominate several candidates, but at or near the top of our list would be the topic covered in class that day. Indeed, we have argued elsewhere (Gass & Seiter, 2007) that, to be successful, a “persuader doesn\u27t move the receiver to a message, the persuader moves the message to the receiver” (p. 113). Even so, as our example suggests, students are not always adept at doing this. What is more, the simple act of telling students how important it is to identify and adapt their messages to an audience\u27s values, demographics, personalities, and so forth is not enough. Instead, we believe that students understand and attach more meaning to this skill when it is shown to them. For that reason, we have developed and used the exercise described below. The exercise involves providing students with a basic understanding and demonstration of audience adaptation and then asking them to practice and evaluate the skill. Although we use this exercise in our courses on persuasion, it could easily be adapted for use in courses in public speaking, advertising, marketing, and others
Cathepsine B, H, L und ihre Inhibitoren im Gewebe und in Zellkulturen der Prostata
No full textDie Cathepsine B, H und L sind lysosomale Enzyme, die zur Gruppe der Cysteinproteasen gehören. Erhöhte Aktivitäten dieser Proteasen fand man in Gewebeproben verschiedener Tumore, vermutlich Hinweis auf eine Beteiligung an Invasion und Metastasierung. Unter physiologischen Bedingungen werden die Cathepsine von endogenen Inhibitoren kontrolliert, eine Verminderung dieser Cysteinprotease-Inhibitoren (CPI) würde die proteolytische Dysbalance verstärken und zur Ausbreitung des malignen Prozesses beitragen. Für das Prostatakarzinom gab es bisher keine Untersuchungen. Die Aktivität der Cathepsine wurde mit Hilfe spezifischer Substrate bestimmt, die zur Bildung fluorogener Produkte führten. Zur Bestimmung der inhibitorischen Aktivität der CPI wurden die Proben nach einer Hitzeaktivierung gegen reines Cathepsin B getestet. Untersucht wurden Gewebeproben verschiedener Patientengruppen, Primärzellkulturen, die aus normalem und maligne veränderten Prostatagewebe angezüchtet wurden und vergleichend dazu die drei immortalisierten Zellinien LNCaP, PC3 und DU145. Die Ergebnisse der Gewebeproben zeigten höhere Aktivitäten der Cathepsine B und L im nichterkrankten Gewebe, nicht wie erwartet im Tumorgewebe der Prostata. Hingegen waren bei den Primärzellkulturen alle drei Cathepsine und der Quotient Cathepsine/CPI in den Tumorproben erhöht. Die immortalisierten Zellinien zeigten die gleiche Verteilung bei allen Cathepsinen, DU145 mit der höchsten Aktivität, gefolgt von LNCaP und PC3. Anhand der Ergebnisse schlußfolgern wir, daß die Untersuchung von Gewebe-proben der Prostata hinsichtlich der Beteiligung der Cathepsine am Tumor-geschehen keine eindeutigen Erkenntnisse erbringt. Dies ist vermutlich auf die Heterogenität des Gewebes zurückzuführen, das nicht nur epitheliale, sondern auch stromale Zellen enthält. Die aus dem Gewebe angezüchteten Primär-zellkulturen scheinen ein genaueres Bild des Verhältnisses von Cathepsinen und den Inhibitoren zu geben und sind unserer Meinung nach den Bestimmungen in Gewebeproben vorzuziehen.The cathepsins B, H and L (CB, CH, CL) are lysosomal proteolytic enzymes belonging to the cysteine protease family. Elevated cathepsin levels and decreased concentration of their endogenous inhibitors have been demonstrated in a variety of tumors, suggesting a contribution to invasion and metastasis. The situation for prostate cancer was so far unknown. Using fluorimetric assays, catalytic activities of the cathepsins B, H, L were measured in prostatic tissue samples obtained from different groups of patients, in primary cell cultures established from human prostate and in the immortalized cell lines LNCaP, PC3 and DU145. Inhibitory activities of cysteine protease inhibitors (CPI) were tested against purified cathepsin B. Comparing matched pairs of normal and cancerous tissue samples from the prostate, significantly decreased levels of CB and CL were found in malignant samples. In contrast, primary cell cultures from malignant tissue showed elevated levels of all three cathepsins and increased ratios of cathepsins to CPI when compared to cell cultures from non-malignant prostate. The permanent cell lines showed a similiar distribution of cathepsin levels, DU145 with the highest activity, followed by LNCaP and PC3. These results suggest that elevated cathepsin activities and increased ratios of cathepsins to CPI in malignant cell cultures compared to non-malignant samples may be an indication for a cellular proteolytic imbalance in prostatic cancer cells. Regarding different results, determinations in primary cell cultures should be preferred to tissue samples
Is mindful partnering associated with physiological reactivity to marital conflict?
No full textHuman Development and Family Studies
co-author: Dr. Rachel Lucas-Thompson.2021 Fall.Research suggests that high physiological reactivity to marital conflict may serve as a source of chronic stress that leads to negative health outcomes (Wanic & Kulik, 2011), as well as divorce and lower marital quality (Gottman, 2014). Mindful partnering, a newly conceptualized construct to measure interpersonal mindfulness in the relationship with one's intimate partner, may be associated with lesser physiological reactivity to marital conflict, and we hypothesized such an association in this research. Seventeen couple pairs (N= 34) visited the laboratory to complete several tasks, including questionnaires and a conflict discussion in which they discussed the largest areas of conflict in their relationship. Participants had their Respiratory Sinus Arrythmia (RSA), a measure of nervous system activation, measured during the baseline period and conflict discussion. Participants completed the Mindful Partnering Measure (MPM) to measure the extent to which one demonstrates mindful partnering in their relationship with their romantic partner. Regression analyses suggested that MPM-Mindful Awareness significantly predicted partner’s greater RSA, indicating that 9% of the variance in RSA-R was accounted for by partner’s MPM- mindful awareness (a small effect), suggesting greater relaxation and a less pronounced stress response. These results suggest that when one’s partner is fully present and attentive, it may relieve the potential stress of marital disagreement. Being present with full attention in this way may soothe a partner's nervous system by creating a feeling of being fully listened to and understood in the context of conflict
Babycurus subpunctatus Borelli 1925
No full textBabycurus subpunctatus Borelli, 1925 (Figures 56–57, 62–63, 66, 78–86, 103–123, Table 2) Babycurus subpunctatus Borelli, 1925: 318; Kovařík, 1998: 104; Fet & Lowe, 2000: 79; Kovařík, 2000: 256; Kovařík, 2003: 134. TYPE LOCALITY AND TYPE DEPOSITORY. Somalia, Cuban Cubu; MCSN. MATERIAL EXAMINED. Ethiopia, Somali State, Liben region, between Filtu and Dolo Odo, 04°50'07.5"N 40°55'13.5"E, 912 m a.s.l. (Fig. 120, locality No. 14 EI), 1♂ 1♀ (Figs. 110–122), 20.XI.2014, leg. F. Kovařík, FKCP. Somalia, Cuban Cubu, IX.1923, 1♀ (holotype, Figs. 80–82, 103–109), leg. S. Patrizi, MCSN. DIAGNOSIS. Total length 22.5 mm (male) – 32.25 mm (females). Coloration yellowish brown to orange. Chelicerae yellow without reticulation. Pedipalp movable fingers with 6 principal rows of denticles and apical row of four denticles. Last row has one external and no internal granule. Pectines with 16–17 teeth in both sexes. First metasomal segment has 10 carinae, second through fourth segments have eight carinae. Telson setose, smooth, with subaculear tooth short and pointed. Vesicle elongate, ellipsoidal. Aculeus curved, slightly shorter than vesicle. Sexual dimorphism minor, adult males with chela slightly narrower in males (ratio chela length manus width 5.1 in male and 4.3– 4.6 in females); there is no difference in length and width of metasomal segments (ratio metasomal segment V length to width 2.44–2.9 in both sexes); posterior margin of sternite V without smooth median patch in both sexes; fingers of pedipalps almost straight in both sexes. COMMENTS ON LOCALITY. The both specimens were collected under stones along a road on the locality 14EI (Fig. 120) during a day (temperature 34.6 ºC and 38% humidity). Apart from B. subpunctatus, the first author (FK) recorded Hottentotta trilineatus, Parabuthus cf. liosoma (Ehrenberg, 1828), Uroplectes sp., and two very common species of Pandinus sp. at this locality.Published as part of Kovařík, František, Lowe, Graeme, Seiter, Michael, Plíšková, Jana & Šťáhlavský, František, 2015, Scorpions of Ethiopia (Arachnida: Scorpiones). Part II. Genus Babycurus Karsch, 1886 (Buthidae), with description of two new species, pp. 1-31 in Euscorpius 196 on page 3
Josef Pieper and the Danger of Sophistry
No full textThis thesis explores Josef Pieper’s writings on sophistry and their contemporary relevance. It has three goals: to show the relevance of sophistry, to clarify the meaning of the concept, and to explore its consequences for the individual and society. I think of these three goals as responses to three questions: Why is sophistry relevant? What is it? Why is it worth exposing and opposing? In the introduction I give a brief biography of Josef Pieper and a survey of his work. Then, the first chapter answers the first question; the second chapter responds to the second question; and the third chapter to the third question. Key to the second chapter is Pieper’s text Abuse of Language, Abuse of Power, where, I maintain, he characterizes sophistry in five ways: as a disposition, an art, a corruption, a weapon, and a danger. Since the first of these - sophistry as a disposition - is the most important, the third chapter presents Pieper’s metaphysics, which is deeply rooted in Plato, Aristotle, and Thomas Aquinas, to whom I refer liberally. This gives deeper insight into the sophistical disposition and its ultimate consequence: unhappiness. Finally, the conclusion offers a few remedies for the sophistical worldview
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