The activity of anti-CD19 CAR T cell therapy in chronic lymphocytic leukemia (CLL) with Richter's transformation (RT) to aggressive large B cell lymphoma (LBCL) is largely unknown. In a multicenter ...retrospective study, we report the safety and efficacy of CAR T cell therapy in patients with RT (n=30) compared to patients with aggressive B cell lymphoma (n=283) and patients with transformed indolent Non-Hodgkins Lymphoma (iNHL) (n=141) between April 2016 and January 2023. Two-thirds of patients received prior therapy for CLL before RT and 89% of them received B-cell receptor and B-cell lymphoma 2 (BCL-2) inhibitors. Toxicities of CAR T cell therapy in RT were similar to other lymphomas, with no fatalities related to cytokine release syndrome or immune effector-cell associated neurotoxicity synderome. The 100-day overall response rate and complete response rates in patients with RT were 57% and 47%, respectively. With a median follow up of 19 months, the median overall survival (OS) was 9.9 months in patients with RT compared to 18 months in de-novo LBCL and not reached in patients with transformed iNHL. The OS at 12 months was 45% in patients with RT compared with 62% and 75% in patients with de novo LBCL and transformed iNHL, respectively. In a multivariate analysis, worse OS was associated with RT histology, elevated LDH, and more prior lines of therapy. CAR T cell therapy can salvage a proportion of patients with CLL and RT exposed to prior targeted agents; however, efficacy in RT is inferior compared to de novo LBCL and transformed iNHL
המחקר הנוכחי מהווה נדבך נוסף בחקר אמפירי של צדק בספרת החינוך ומתבסס על מחקרם של רנדול ומיולר (1995, Mueller & Randall (הבודק, כיצד הערכות צדק בזיקה למשאבים שונים משפיעות על אפקטיביות העובד, שביעות ...רצונו מן הארגון ומחויבותו כלפיו. אם עד עתה עיקר מחקרי הצדק בתחום החינוך התמקד בתפיסות הצדק של תלמידים, הרי שהמחקר הנוכחי בוחן את תפיסות הצדק של המורים והשפעתן על הקשר שבין השתייכות למגזר, המוגדר כהבדלי מעמדות ותרבות בין מורים יהודים וערבים בישראל, לבין עמדות כלפי העבודה, דהיינו: שביעות רצון ומחויבות ארגונית. במחקר הנוכחי נבחנים שני מודלים. המודל הראשון בוחן את העדפת כללי החלוקה ביחס להקצאת משאבים שונים (שכר, ביטחון תעסוקתי, מעמד, הגשמה עצמית, יחסים חברתיים ואלטרואיזם-עזרה לאחר) על-פי השתייכות המורה למגזר מן ההקשר הישראלי. המודל השני הוא מודל תיווך, הבוחן את הקשר שבין השתייכות המורה למגזר לבין עמדות כלפי העבודה, ובאיזו מידה הערכות הצדק השונות מתווכות בקשר זה. בבסיסו של המחקר הנוכחי עומדות שלוש הנחות מרכזיות. הנחה ראשונה, היא שהשתייכותו של המורה למגזר נתון (יהודי או ערבי) מעצבת באופן שונה את תפיסות הצדק של המורה במיוחד לאור ההקשר הישראלי הנבדק, המאופיין על-ידי כך שהאוכלוסייה הערבית מדגישה את חוסר השוויון בינה לבין האוכלוסייה היהודית ונאבקת על מנת לשנות מצב זה (סמוחה, 2001 .(הנחה שנייה היא שמורים אינם מעדיפים כלל חלוקה יחיד במצב של הקצאת משאבים שונים, אלא שביחס למצבי חלוקה שונים וביחס לסוג התגמול המחולק, נוטים אנשים להעדיף עקרונות שונים (1983, Walzer ,(המשרתים את האינטרסים האישיים שלהם (1988, Törnblom; 1975, Deutsch .(ההנחה השלישית, הנגזרת מן ההנחה השנייה היא שמורים, כפועל יוצא מהשתייכותם המגזרית והשפעתה על שיפוטי הצדק שלהם, נוטים לתת משקל יחסי שונה להערכת הצדק ביחס למשאבים שונים ומעבר להם, והערכה זו היא שמשפיעה על שביעות רצונם ומחויבותם הארגונית.כמסגרת תיאורטית למחקר הנוכחי מתואר מחקר הצדק החלוקתי תוך התמקדות בשני מרכיביו העיקריים: העדפת כללי חלוקה (preference rule (והערכת צדק (evaluation justice (בזיקה למשאבים שונים (שכר, מעמד, הגשמה עצמית ויחסים חברתיים). כללי חלוקה הם העקרונות על פיהם מתבצעת החלוקה, והערכת הצדק מתייחסת לתוצאות החלוקה האם הן הוגנות בעייני הפרט או לא. בנוסף לכך, מוצגת במחקר זה גישת הצדק הפרוצדוראלי המתייחסת להוגנות התהליכים או הפרוצדורות, אשר באמצעותם נערכת החלוקה. שלושת מרכיבי צדק אלה מהווים גם את השקפת הצדק הכללית וגם את הערכות הצדק הספציפיות ביחס לסוג המשאב של מורים מהמגזר הערבי והמגזר היהודי ואת ההשוואה ביניהם. כמו כן, מוצגים הפערים בין תפיסות הצדק של מורי המגזר הערבי לעמיתיהם המלמדים במגזר היהודי והבדלי המעמדות והתרבות ביניהם. בנוסף מוצגות הגדרות שונות לגבי עמדות כלפי העבודה: שביעות רצון ומחויבות ארגונית. ממצאי המחקר עולה, כי קיימים הבדלים בהעדפת כללי החלוקה בין מורי המגזר היהודי לבין מורי המגזר הערבי ביחס למשאבים "יחסים חברתיים" ו"עזרה לאחר", כך שבמגזר הערבי קיימת יותר העדפה לדיפרנציאציה (מתן לגיטימציה לאי שוויון בכללי החלוקה) בכל הקשור להקצאתם. בנוסף נמצא שככל שהמשאב הינו יותר אוניברסאליסטי (למשל, שכר), קיימת יותר העדפה לדיפרנציאציה, וככל שהמשאב יותר פרטיקולריסטי (למשל, יחסים חברתיים) קיימת נטייה לפחות דיפרנציאציה. ביחס להערכות הצדק נראה, כי אין הבדלים בין מורי המגזרים השונים ביחס להערכת הצדק החלוקתי הכללי שמעבר למשאבים ובהערכת הצדק הפרוצדוראלי. אך, כאשר נבדקת הערכת הצדק בהשוואה למגזר האחר מתגלה, כי מורי המגזר הערבי חשים מקופחים הרבה יותר ממורי המגזר היהודי, כפי שמשתקף גם במציאות הישראלית ומשועתק ממנה . בחינת הערכות הצדק החלוקתי ביחס למשאבים שונים (שכר, מעמד, הגשמה עצמית ויחסים חברתיים) נמצא, כי לסוג המשאב המחולק יש השפעה על הערכת הצדק, וכי תחושות הקיפוח של מורי המגזר היהודי ביחס למשאב "מעמד" גבוהות יותר מאלו של מורי המגזר הערבי, בעוד שבקרב מורי המגזר הערבי תחושות הקיפוח סביב המשאב "יחסים חברתיים" גבוהות יותר מאילו של מורי המגזר היהודי.
The study by Clara Sabbagh and Hila Malka reported in this chapter examines justice perceptions with respect to different kinds of resources that are distributed to teachers. The authors ask to what ...extent resource-specific justice perceptions vary across two national groups of teachers (Jewish and Arab) in the Israeli population and educational system. Their findings indicate that Israeli teachers across sectors prefer differentiation (favoring equity over equality/need) and perceive more injustice when universalistic, rather than particularistic resources are at stake. At the same time, justice perceptions were found to vary across sectorial/cultural lines. For instance, Israeli-Arab teachers preferred differentiation of particularistic resources more strongly than their Israeli-Jewish counterparts. Sabbagh and Malka suggest that cross-cultural and cross-sectional research may provide a clearer understanding of patterns of convergence and divergence in the meanings assigned to social resources and of the corresponding distribution rules.
In-situ tumor ablation provides the immune system with the appropriate antigens to induce anti-tumor immunity. Here, we present an innovative technique for generating anti-tumor immunity by ...delivering exogenous ultra-high concentration (> 10,000 ppm) gaseous nitric oxide (UHCgNO) intratumorally.
The capability of UHCgNO to induce apoptosis was tested in vitro in mouse colon (CT26), breast (4T1) and Lewis lung carcinoma (LLC-1) cancer cell lines. In vivo, UHCgNO was studied by treating CT26 tumor-bearing mice in-situ and assessing the immune response using a Challenge assay.
Exposing CT26, 4T1 and LLC-1 cell lines to UHCgNO for 10 s-2.5 min induced cellular apoptosis 24 h after exposure. Treating CT26 tumors in-situ with UHCgNO followed by surgical resection 14 days later resulted in a significant secondary anti-tumor effect in vivo. 100% of tumor-bearing mice treated with 50,000 ppm UHCgNO and 64% of mice treated with 20,000 ppm UHCgNO rejected a second tumor inoculation, compared to 0% in the naive control for 70 days. Additionally, more dendrocytes infiltrated the tumor 14 days post UHCgNO treatment versus the nitrogen control. Moreover, T-cell penetration into the primary tumor was observed in a dose-dependent manner. Systemic increases in T- and B-cells were seen in UHCgNO-treated mice compared to nitrogen control. Furthermore, polymorphonuclear-myeloid-derived suppressor cells were downregulated in the spleen in the UHCgNO-treated groups.
Taken together, our data demonstrate that UHCgNO followed by the surgical removal of the primary tumor 14 days later induces a strong and potent anti-tumor response.
We established a molecular method for quantifying ultraviolet (UV) disinfection efficacy using total bacterial DNA in a water sample. To evaluate UV damage to the DNA, we developed the “DNA damage” ...factor, which is a novel cultivation-independent approach that reveals UV-exposure efficiency by applying a simple PCR amplification method. The study's goal was to prove the feasibility of this method for demonstrating the efficiency of UV systems in the field using flow-through UV reactors. In laboratory-based experiments using seeded bacteria, the DNA damage tests demonstrated a good correlation between PCR products and UV dose. In the field, natural groundwater sampled before and after being subjected to the full-scale UV reactors was filtered, and the DNA extracted from the filtrate was subjected to PCR amplification for a 900-bp fragment of the 16S rRNA gene with initial DNA concentrations of 0.1 and 1 ng/μL. In both cases, the UV dose predicted and explained a significant proportion of the variance in the log inactivation ratio and DNA damage factor. Log inactivation ratio was very low, as expected in groundwater due to low initial bacterial counts, whereas the DNA damage factor was within the range of values obtained in the laboratory-based experiments. Consequently, the DNA damage factor reflected the true performance of the full-scale UV system during operational water flow by using the indigenous bacterial array present in a water sample. By applying this method, we were able to predict with high confidence, the UV reactor inactivation potential. For method validation, laboratory and field iterations are required to create a practical field calibration curve that can be used to determine the expected efficiency of the full-scale UV system in the field under actual operation.
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•Molecular method to quantify UV disinfection effectiveness in water was established.•PCR product reduction was correlated with UV dose.•DNA damage factor can be used when log inactivation may not be indicative.•The method challenges known validations.
Bacteria of the genus Legionella cause water-based infections resulting in severe pneumonia. Here we analyze and compare the bacterial microbiome of sputum samples from pneumonia patients in relation ...to the presence and abundance of the genus Legionella. The prevalence of Legionella species was determined by culture, PCR, and Next Generation Sequencing (NGS). Nine sputum samples out of the 133 analyzed were PCR-positive using Legionella genus-specific primers. Only one sample was positive by culture. Illumina MiSeq 16S rRNA gene sequencing analyses of Legionella-positive and Legionella-negative sputum samples, confirmed that indeed, Legionella was present in the PCR-positive sputum samples. This approach allowed the identification of the sputum microbiome at the genus level, and for Legionella genus at the species and sub-species level. 42% of the sputum samples were dominated by Streptococcus. Legionella was never the dominating genus and was always accompanied by other respiratory pathogens. Interestingly, sputum samples that were Legionella positive were inhabited by aquatic bacteria that have been observed in an association with amoeba, indicating that amoeba might have transferred Legionella from the drinking water together with its microbiome. This is the first study that demonstrates the sputum major bacterial commensals and pathogens profiles with regard to Legionella presence.
causes waterborne infections resulting in severe pneumonia. High-resolution genotyping of
isolates can be achieved by multiple-locus variable-number tandem-repeat analysis (MLVA). Recently, we found ...that different MLVA genotypes of
dominated different sites in a small drinking-water network, with a genotype-related temperature and abundance regime. The present study focuses on understanding the temperature-dependent growth kinetics of the genotypes that dominated the water network. Our aim was to model mathematically the influence of temperature on the growth kinetics of different environmental and clinical
genotypes and to compare it with the influence of their ecological niches. Environmental strains showed a distinct temperature preference, with significant differences among the growth kinetics of the three studied genotypes (Gt4, Gt6, and Gt15). Gt4 strains exhibited superior growth at lower temperatures (25 and 30°C), while Gt15 strains appeared to be best adapted to relatively higher temperatures (42 and 45°C). The temperature-dependent growth traits of the environmental genotypes were consistent with their distribution and temperature preferences in the water network. Clinical isolates exhibited significantly higher growth rates and reached higher maximal cell densities at 37°C and 42°C than the environmental strains. Further research on the growth preferences of
clinical and environmental genotypes will result in a better understanding of their ecological niches in drinking-water systems as well as in the human body.
is a waterborne pathogen that threatens humans in developed countries. The bacteria inhabit natural and man-made freshwater environments. Here we demonstrate that different environmental
genotypes have different temperature-dependent growth kinetics. Moreover,
strains that belong to the same species but were isolated from environmental and clinical sources possess adaptations for growth at different temperatures. These growth preferences may influence the bacterial colonization at specific ecological niches within the drinking-water network. Adaptations for growth at human body temperatures may facilitate the abilities of some
strains to infect and cause illness in humans. Our findings may be used as a tool to improve
monitoring in drinking-water networks. Risk assessment models for predicting the risk of legionellosis should take into account not only
concentrations but also the temperature-dependent growth kinetics of the isolates.
Background: Immune checkpoint inhibitors have transformed clinical oncology. However, their use is limited as response is observed in only ~20–50% of patients. Previously, we demonstrated that ...treating CT26 tumor-bearing mice with ultra-high-concentration gaseous nitric oxide (UNO) followed by tumor resection stimulated antitumor immune responses. Accordingly, UNO may improve tumor response to immune checkpoint inhibitors. Here, we investigated the ability of UNO to improve the efficacy of a programmed cell death protein-1 (PD-1) antibody in vitro and in treating CT26 tumor-bearing mice. Methods: CT26 cells were injected into the flank of Balb/c mice (n = 15–16 per group). On day 6, CT26 cells were injected into the contralateral flank, and anti-mPD-1 injections commenced. Primary tumors were treated with intratumoral UNO on day 8. Tumor volume, response rates, toxicity, and survival were monitored. Results: (1) Short exposure to 25,000–100,000 parts per million (ppm) UNO in vitro resulted in significant upregulation of PD-L1 expression on CT26 cells. (2) UNO treatment in vivo consistently reduced cell viability in CT26 tumors. (3) Treatment reduced regulatory T-cell (Treg) levels in the tumor and increased levels of systemic M1 macrophages. UNO responders had increased CD8+ T-cell tumor infiltration. (4) Nine days after treatment, primary tumor growth was significantly lower in the combination arm vs. anti-mPD-1 alone (p = 0.0005). (5) Complete tumor regression occurred in 8/15 (53%) of mice treated with a combination of 10 min UNO and anti-mPD-1, 100 days post-treatment, compared to 4/16 (25%) of controls treated with anti-mPD-1 alone (p = 0.1489). (6) There was no toxicity associated with UNO treatment. (7) Combination treatment showed a trend toward increased survival 100 days post-treatment compared to anti-mPD-1 alone (p = 0.0653). Conclusion: Combining high-concentration NO and immune checkpoint inhibitors warrants further assessment especially in tumors resistant to checkpoint inhibitor therapy.
Abstract
Background: Metastases are responsible for a significant portion of the morbidity and mortality in cancer patients. In situ destruction of tumor mass has been reported to provide the immune ...system with an antigen source for the induction of antitumor immunity, which can then attack distant metastases. Nitric oxide (NO) acts as a signaling molecule in multiple disease states, including cancer. NO has been shown to activate innate and adaptive responses of the immune system against tumors. In a previous Beyond Air study, 89% of CT26 tumor bearing mice treated with 50,000 parts per million (ppm) gaseous NO (gNO), rejected a secondary tumor induction. Here, we assessed the effects of a single intra-tumoral injection of gNO at concentrations of 20,000-50,000 ppm on immune cell recruitment in the tumor, spleen, and blood.
Methods: Mouse colon carcinoma (CT26) tumor bearing Balb/c mice underwent a single intra-tumoral treatment with 20,000 (n=3) or 50,000 (n=4) ppm gNO for 5 minutes. Mice treated with N2 (n=3), under the same conditions, served as a control. Tumors were removed 14 days post treatment and were histologically analyzed to test for immune cell penetration, inflammation, and necrosis. Immune cells from the spleen and blood were harvested 21 days post treatment and assessed via flow cytometry.
Results: 1. Treatment with 50,000 ppm gNO resulted in higher levels of inflammation, lymphocytes and T-cell infiltration, and necrosis within the tumor compared to both N2 and 20,000 ppm NO, as viewed histologically. 2. Flow cytometry analysis of immune cells from the spleen revealed a 1.3-fold increase of both B cells and IFN-γ expressing T cells with 50,000 NO treatment, and a 1.3-fold increase of B cells and 1.1-fold increase of IFN-γ expressing T cells with 20,000 NO treatment, compared to N2. 3. A 29% reduction of myeloid-derived suppressor cells (MDSCs) was detected in spleens of mice treated with 50,000 ppm gNO, and 40% for 20,000 ppm, compared to mice treated with N2.
Conclusion: Intra-tumoral injection of ultra-high doses of NO at 20,000 and 50,000 ppm gNO led to an increased recruitment and concentration of T and B cells. Additionally, 50,000 ppm NO led to an increase of lymphocyte infiltration to the tumor. Taken together, the data suggest that the increase in lymphocyte infiltration, B and T cell population, and the reduction of MDSCs, are indicative of an adaptive immune response that results in rejection of secondary tumors in gNO-treated mice.
Citation Format: Hila Confino, Matan Goldshtein, Yakir Levi, Lidor Malka, Amir Avniel, Steve Lisi, Ido Wolf. Single intra-tumoral injection of gaseous nitric oxide induces an adaptive immune response in a mouse CT-26 solid tumor model abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1283.
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