scholarly journals In Situ Vaccination with Combination of Class B and Class C Toll-like Receptor 9 Agonist CpG Immune Adjuvant Nanoparticles to Induce a Systemic Anti-Lymphoma Response

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2265-2265
Author(s):  
Adam Yuh Lin ◽  
Jonathan Scott Rink ◽  
Colby Shad Thaxton ◽  
Leo I. Gordon
Keyword(s):  
Treatment Group ◽  
Tumor Growth ◽  
Advanced Disease ◽  
Growth Curves ◽  
Lymphoma Cells ◽  
Treatment Groups ◽  
Untreated Tumor ◽  
Class B ◽  
Class C

Abstract Introduction: Treatment of relapsed and refractory aggressive B cell lymphomas is challenging, especially after autologous stem cell transplant or chimeric antigen receptor T cell therapy. CpG oligodeoxynucleotides (CpGs) mimic bacterial DNA and bind to toll-like receptor 9 (TLR9). TLR9 is expressed in the endosomes of innate immune cells and B lymphocytes as well as B cell lymphomas. CpG binding to TLR9 in these cells leads to a pro-inflammatory response and induces apoptosis of lymphoma cells by altering NF-kB activation. However, clinical utility of CpGs is limited due to difficulties delivering the DNA directly to the innate immune cells and lymphoma cells, and these DNA strands are easily degraded in biological fluids. Therefore, we designed a nano-carrier to deliver two classes of CpGs to improve clinical efficacy of CpGs in treating lymphoma. Class B CpGs (B-CpGs) mainly stimulate B cells while class C CpGs (C-CpGs) act on both B cells and plasmacytoid dendritic cells. Though C-CpGs are the focus of current clinical trials, B-CpGs may have a special a role in the treatment of lymphoma due to their more potent, direct cytotoxic effect on the malignant lymphoma cells. Here, we evaluated the anti-lymphoma effect of the combination of B-CpG nanoparticles (BNP) and C-CpG nanoparticles (CNP) by optimizing lymphoma cell death and immune stimulation. Methods: BNP and CNP were synthesized by surface-functionalizing gold nanoparticles with modified B-CpGs and C-CpGs, followed by purification via centrifugation. We used a dual flank tumor murine lymphoma model to evaluate the local and systemic anti-lymphoma efficacy of the CpG NPs and screen for the most effective formulation. A20 lymphoma tumors were implanted on both flanks of Balb/c mice. When the tumors were 5-7mm in diameter, various treatments were injected intratumorally on days 1, 4, and 8 on the side with the larger tumor. Treatment groups include PBS, B-CpG, C-CpG, B+C-CpG, BNP, CNP, BNP+CNP. Free CpGs were injected at 50ug/ml in 50ul (2.5ug CpG per injection) and nanoparticles at 100nM (equivalent to 50ug/ml CpGs) in 50ul. Tumor growth were measured every other day. Event is defined as tumor volume > 3cm 3. Second, we used an advanced disease lymphoma model to evaluate intravenous delivery of combination NPs. We implanted A20 lymphoma cells on a flank tumor (on day -14), then we injected A20 cells intravenously to mimic advanced disease (on day -7). We treated the mice with intravenous (tail vein) injections of PBS, B+C-CpG, or BNP+CNP on days 1, 4, and 8. Results: We found that the combination of BNP and CNPs had the most significant reduction in total tumor volume (TTV) (treated + untreated tumor size) (393mm 3 on day 22). The PBS group demonstrated rapid tumor growth (TTV 3516mm 3). The experimental treatment groups, B-CpG (TTV 949mm 3),, C-CpG (TTV 2230mm 3), B+C-CpGs (TTV 1680mm 3), BNP (TTV 1224mm 3), and CNP (1894mm 3) had similar TTV growth curves. Separating the treated tumor and untreated tumor growth curves, we found that B-CpG and BNP along with combination of BNP+CNP had the best tumor suppression on the treated side. This is not surprising as B-CpG sequences are more directly cytotoxic to lymphoma cells versus C-CpGs. Interestingly, combination nanoparticle treatment (BNP+CNP) was the only group that had significantly reduced tumor growth of the untreated tumor compared with all other conditions (p<0.03) where no statistical difference was measured when the PBS treatment group with the other groups. The BNP+CNP treatment group also had significantly prolonged event free survival compared with all other treatment groups. Furthermore, in the advanced disease model, when BNP and CNP were both injected intravenously, the flank tumor was notably smaller (149mm 3) compared with the other two groups (B+C-CpG 1310mm 3 or PBS 1555mm 3). Importantly, there were no visible lymphoma nodules on liver in the nanoparticle treatment group while there are obvious nodules for both the PBS and the free CpG groups. Conclusions: Overall, the combination of class B and class C CpG nanoparticles can generate a strong in situ anti-lymphoma vaccination response, presumably through the combination of by combining the superior cytotoxicity of BNPs with the enhanced immune stimulation effect of the CNPs. Further evaluation of the combined mechanism of action of this dual CpG nanoparticle approach and toxicity studies are in progress. Disclosures Thaxton: Zylem biosciences: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding.

Reproductive performance of group-synchronized Merino d'Arles and Romanov crossbred ewes. 1. A note on the effects of lactation on fecundity

1977 ◽  
Vol 24 (1) ◽  
pp. 113-116 ◽  
Author(s):  
F. J. Galindez ◽  
M. Prud'hon ◽  
G. Reboul
Keyword(s):  
Treatment Group ◽  
Reproductive Performance ◽  
The Other ◽  
Fertility Level ◽  
Homogeneous Groups ◽  
Treatment Groups ◽  
Significant Superiority

SUMMARYFifty-six Merino d'Aries and 56 Romanov × Merino crossbred lactating ewes were divided into two treatment groups, one (T1) with a ewe-to-ram ratio of 48: 1 (24 Merino and 24 crossbred) and the other (T2) of 64: 1 (32 Merino and 32 crossbred).Intravaginal sponges with 40 mg FGA (Searle) were inserted in two subgroups at 8-day intervals and withdrawn after 12 and 16 days in situ, in four equal groups at 4-day intervals. A dose of 400 IU pregnant mare's serum gonadotrophin (PMSG) was applied at sponge withdrawal.Fertility after two oestrous cycles was equally satisfactory in both treatments, though it was lower in treatment group T2. This could be due to the significantly low (P<0·01) number of Merino ewes raddled by the T2 ram (0·33 Merino against 0·92 crossbred) suggesting preferential behaviour by the ram in this treatment.Comparisons between breeds show a slight superiority in the fertility of crossbred ewes and a highly significant superiority in prolificacy These results suggest that using the described method, 2% of rams seems more than adequate to mate with progestagen-synchronized ewes with a satisfactory fertility level. It is, however, recommended to use homogeneous groups of ewes.

scholarly journals The role of oxygen in avascular tumor growth

2015 ◽  
Author(s):  
David Robert Grimes ◽  
Pavitra Kannan ◽  
Alan McIntyre ◽  
Anthony Kavanagh ◽  
Abul Siddiky ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Growth Curves ◽  
Mechanistic Explanation ◽  
Treatment Prognosis ◽  
Sigmoidal Growth ◽  
Oxygen Dynamics ◽  
Local Oxygen ◽  
Avascular Tumor

AbstractThe oxygen status of a tumor has significant clinical implications for treatment prognosis, with well-oxygenated subvolumes responding markedly better to radiotherapy than poorly supplied regions. Oxygen is essential for tumor growth, yet estimation of local oxygen distribution can be difficult to ascertain in situ, due to chaotic patterns of vasculature. It is possible to avoid this confounding influence by using avascular tumor models, such as tumor spheroids, a much better approximation of realistic tumor dynamics than monolayers, where oxygen supply can be described by diffusion alone. Similar to in situ tumours, spheroids exhibit an approximately sigmoidal growth curve, often approximated and fitted by logistic and Gompertzian sigmoid functions. These describe the basic rate of growth well, but do not offer an explicitly mechanistic explanation. This work examines the oxygen dynamics of spheroids and demonstrates that this growth can be derived mechanistically with cellular doubling time and oxygen consumption rate (OCR) being key parameters. The model is fitted to growth curves for a range of cell lines and derived values of OCR are validated using clinical measurement. Finally, we illustrate how changes in OCR due to gemcitabine treatment can be directly inferred using this model.

Engineering CpG Deoxynucleotide-Conjugated Gold Nanoparticles for Enhanced Anti-Lymphoma Effects in an Immune Competent Lymphoma Model

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1577-1577
Author(s):  
Adam Yuh Lin ◽  
Jonathan Rink ◽  
Reem Karmali ◽  
Colby Shad Thaxton ◽  
Leo I. Gordon
Keyword(s):  
Gold Nanoparticles ◽  
Dendritic Cells ◽  
Tumor Growth ◽  
B Cell ◽  
Research Funding ◽  
Annexin V ◽  
Advisory Board ◽  
Class B ◽  
Class C

Introduction: Aggressive B cell lymphomas are clinically challenging, especially in the relapsed/refractory setting. Synthetic DNAs containing the unmethylated cytosine-phosphate-guanine (CpG) deoxynucleotides motif are potent stimulants of the innate immune system. CpGs bind to toll-like receptor 9 (TLR9) in the endosomes. Activation of TLR9 leads to G1-phase arrest of lymphoma cells and induces apoptosis via the Fas ligand pathway. Class B CpGs are linear single stranded DNA that stimulate B cells, while class C CpGs form a duplex secondary structure and act on both B cells and dendritic cells. Witzig et al. (Am J Hematol 2013) used class B CpGs in combination with radioimmunotherapy for B cell lymphomas and had an overall response rate of 93% with 63% complete responses. More recently, Frank et al. (Cancer Discovery 2018) used class C CpGs in combination with radiation to treat advanced stage indolent lymphoma and found that both treated and untreated sites had significant lymph node shrinkage. However, only 7 of 29 qualified for partial response. We have previously shown that CpG conjugated gold nanoparticles (NPs) improve macrophage stimulation. Therefore, we hypothesize that CpG-conjugated gold NPs can enhance the CpG's anti-lymphoma effects though direct and immune mediated mechanisms (Figure 1A). Material and Methods: Using a previously verified triethylene glycol modified CpG (tmCpG) design, we synthesized class B tmCpG NPs (1826 for mice, 2006 for human) and class C tmCpG NPs (2395). Lymphoma cell lines (SUDHL4, Ramos, A20) and bone marrow derived dendritic cells (JAWSII) were used in in vitro and in vivo assays. Viability was measured by MTS and apoptosis by annexin V-PI flow cytometry. For dual tumor studies, A20 lymphoma cells were injected subcutaneously in both flanks of BALB/c mice. The side with the larger tumor was treated with either PBS, free CpG, or tmCpG NPs intratumorally on days 1, 4, and 8. Tumors were monitored for growth and, when either tumor reached 2 cm3, the mice were euthanized. Results: Changing the CpG sequence did not alter the monolayer formation on the nanoparticles, and 1nM of tmCpG NPs are equivalent to 0.5ug/ml of CpGs. Class C tmCpG NPs (2395) tend to form aggregates during washing and collection phases but could be sonicated back into suspension. Both class B (1826 and 2006) and class C (2395) tmCpG NPs significantly reduced viability of SUDHL4, Ramos, and A20 cells, compared with free CpGs, while having no effect on the viability of JAWSII cells. tmCpG NPs induced lymphoma cell death by apoptosis as measured by annexin V-PI. In in vivo studies, both class B free CpG and class B tmCpG NP groups had reduced tumor growth and improved survival compared with PBS controls. Nine of 15 mice (60%) in the tmCpG NP group had no detectable tumor on the treated side, while only 4 of 15 mice (27%) in the free CpG group had no tumors. On the untreated side, there was no difference in tumor growth between the three groups. In another dual tumor study, the class C tmCpG NPs trended towards a reduction of tumor growth in both the treated and untreated tumors by comparison to free CpG or PBS but the sample size was too small (n=4) to achieve statistical significance. One of the 4 mice in the class C tmCpG NP group had complete resolution of both treated and untreated tumors, while all of the PBS and free CpG mice died before day 28, suggesting that there was an abscopal effect generated by using the nanoparticle construct (Figure 1B). Conclusions: The tmCpG NP design significantly improved cytotoxicity of CpGs toward lymphoma compared with free CpGs. Class B tmCpG NPs had stronger direct cytotoxic effects at the treated tumor site compared with free CpG, while class C tmCpG NPs had immune effects at the distant untreated sites. Future studies should focus on re-engineering the platform to stabilize and optimize tmCpG NPs for improved anti lymphoma activity. Disclosures Karmali: Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution; Astrazeneca: Speakers Bureau. Thaxton:Zylem: Other: Co-founder of the biotech company Zylem. Gordon:Juno/Celgene: Other: Advisory Board, Research Funding; Gilead: Other: Advisory Board; Zylem LLC: Other: co-founder; research in nanoparticles in cancer; Bayer: Other: Advisory Board.

scholarly journals Tumorous-head (tuh-1; tuh-3) modulates Abd-B bithorax-complex functions in Drosophila melanogaster.

Genetics ◽  
1993 ◽  
Vol 133 (3) ◽  
pp. 593-604
Author(s):  
D T Kuhn ◽  
J A Mack ◽  
C Duan ◽  
G Packert
Keyword(s):  
Maternal Effect ◽  
Bithorax Complex ◽  
Class A ◽  
Complex Functions ◽  
Class B ◽  
In Trans ◽  
Class C ◽  
Specific Cluster ◽  
R Functions

Abstract Abdominal-B (Abd-B) mutants of the bithorax-complex (BX-C) were studied in trans with tuh-3 to evaluate their interactions with this homeotic mutant and the maternal effect locus (tuh-1) controlling tuh-3 expression. Head defects occur in tuh-3 offspring from tuh-1h homozygous mothers, while genital defects occur in homozygous tuh-3 offspring from mothers carrying the tuh-1g allele. The influence exerted by the tuh-1 maternal effects on tuh-3 Abd-B transcript distribution was evaluated by whole mount in situ hybridization. Results demonstrated that: (1) of the 21 Abd-B mutants tested, head defects were produced by SGA62, I127B, I127O and tuh-3, with I127B and tuh-3 as the only mutants to require the head defect maternal effect for expression; (2) one specific cluster of regulatory (r) mutants, Uab1, 65 and I127B, enhanced penetrance and expressivity of tuh-3 head defects; (3) the most profound suppression of head defect penetrance occurred when Abd-B mutants eliminated the morphogenetic (m) and r functions; (4) genital defects increased in frequency in tuh-3/Abd-B mutant trans-heterozygotes with loss of r function; (5) Abd-B transcription (class A, class B, class C) appears normal in tuh-3 embryos when their mothers pass on the tuh-1h head defect maternal effect, whereas the regulatory transcripts (class B and class C) are reduced when tuh-3 mothers pass on the tuh-1g genital disc maternal effect; (5) tuh eye-antennal imaginal discs express ABD-B protein; and (6) tuh-3 misregulates both m and r function of Abd-B.

Evaluation of unconventional poultry feed in broilers

2019 ◽  
Vol 17 (1) ◽  
Keyword(s):  
Body Weight ◽  
Treatment Group ◽  
Blood Meal ◽  
Feed Consumption ◽  
Trial Period ◽  
Feed Ingredients ◽  
Treatment Groups ◽  
Broiler Production ◽  
Group I ◽  
Unconventional Feed

Background: Commercial broiler is a rapidly growing sector in Bangladesh. The broilers are supplied with the balanced ration prepared from a number of ingredients which are not available uniformly throughout the years. On the other hands, manufactured feeds are costly and inconvenient for the rural farmers. This study is undertaken to use unconventional feed ingredients aiming to decrease the broiler production cost. Method: A total of ninety-nine day- old broiler chicks (Hubbard) of either sex were used in this study in 3 treatment groups to assess processed unconventional feed item (shoti, blood meal, poultry dropping and molasses) on growth and profitability upon rearing for 60 days. Broilers were reared in dip litter system and were fed ad libitum on conventional and unconventional diet dividing into 3 treatment diets namely, treatment diet 1 (T1: Conventional as control), treatment diet 2 (T2: unconventional with blood meal and shoti), and treatment diet 3 (T3: unconventional with blood meal, shoti, poultry droppings and molasses) throughout the trial period. Treatment group 1 (T1) was used as control. Results: Broilers fed on control diet (conventional feed) achieved higher (P<0.01) body weight, while the broilers offered diets with the highest amount of unconventional feed had the lowest body weight. Increased (P<0.01) feed intake was observed during 21days and 49 days of age when broilers fed diets with the supplementation, but no significant differences were found among the groups in terms of feed consumption during 33 day of age. FCR differed significantly (P<.01) throughout the trial period with the broilers fed diets without supplementation of unconventional feed item had the superior FCR than the others. Mortality rate was 6.06%,9.09%, and 9.09% in treatment group I, treatment group II, and treatment group III respectively while live weights, feed conversion and feed consumption was unaffected by all the dietary groups with/without incorporation of unconventional feed item up to day 60 days of age. Statistically significant (P<0.01) decreased live weight was observed among the treatment groups in 60-day-old birds. Productivity and cost-benefit analysis were performed. Conclusion: Use of unconventional feed ingredients in broiler production greatly reduces the feed cost with little hampering the growth rate and hence, it is profitable for the farmers.

TERATOGENIK EKSTRAK ETANOL UWI BANGGAI UNGU (Dioscorea alata L.) PADA MENCIT BETINA (Mus musculus)

2020 ◽  
Vol 5 (2) ◽  
pp. 309-318
Author(s):  
Ihwan Ihwan ◽  
◽  
Rahmatia Rahmatia ◽  
Khildah Khaerati ◽  
Keyword(s):  
Treatment Group ◽  
Embryo Development ◽  
Mus Musculus ◽  
Birth Defect ◽  
Abnormal Development ◽  
Dioscorea Alata ◽  
Treatment Groups ◽  
Study Results ◽  
Pregnant Mice ◽  
Ethanol Extracts

Teratogenic is an abnormal development on embryo and is the cause of congenital defect or birth defect. This study aims to determine the effect of the addition of Dioscorea alata L. ethanol extracts to the embryo development on pregnant mice whose given orally to 24 mice which divided to 4 treatment groups, they are the normal group (NG) with NaCMC 0.5%; 28 mg/KgBB treatment group; 35 mg/KgBB; 42 mg/Kg BB. The addition of Dioscorea alata L ethanol extracts was done on the sixth day until the 15th day of pregnancy. On the 18th day of pregnancy, Laparaktomi was done to the pregnant mice and the embryo was taken out of the uterus. The observation was done to the fetus numbers, weight weighing of the fetus's body, dan length measurement of the fetus's body. Another observation is the observation of the external organ defect of the embryo. The study results that the addition of Dioscorea alata L ethanol extracts with various doses have no significant effect (P>0.5) to the mice external fetus development. On the examination of the fetus, we can conclude that Dioscorea alata L ethanol extracts don’t give any effect that may cause the defect of the fetus’ external organ.

scholarly journals Differences in the Effectiveness of Long-Acting Injection and Orally Administered Antipsychotics in Reducing Rehospitalization among Patients with Schizophrenia Receiving Home Care Services

2019 ◽  
Vol 8 (6) ◽  
pp. 823
Author(s):  
Hsiao-Fen Hsu ◽  
Chia-Chan Kao ◽  
Ti Lu ◽  
Jeremy C. Ying ◽  
Sheng-Yu Lee
Keyword(s):  
Treatment Group ◽  
Home Care ◽  
Second Generation ◽  
Home Care Services ◽  
Rehospitalization Rate ◽  
Treatment Groups ◽  
Psychiatric Rehospitalization ◽  
Care Services ◽  
Long Acting

The current study explored the differences in the effectiveness of first and second generation long-acting injections and orally administered antipsychotics in reducing the rehospitalization rate among patients with schizophrenia receiving home care services in a medical center in Southern Taiwan. Longitudinal data between 1 January 2006, and 31 December 2015, were collected retrospectively. Patients were classified into three treatment groups: First generation antipsychotic (FGA) long-acting injection (LAI), second generation antipsychotic long-acting injection (SGA) (LAI), and oral antipsychotics. The primary outcomes were the rehospitalization rate and the follow-up time (duration of receiving home care services) until psychiatric rehospitalization. A total of 78 patients with schizophrenia were recruited. The average observation time was about 40 months. The oral treatment group tended to be older with a higher number of female patients and a lower level of education. The FGA treatment group tended to have a higher frequency and duration of hospitalization before receiving home care services. We found no significant differences in the follow-up time or psychiatric rehospitalization rate after receiving home care services among the three treatment groups. We propose that oral and LAI antipsychotics were equally effective when patients received home care services. Our results can serve as a reference for the choice of treatment for patients with schizophrenia in a home care program.

Effects of Buserelin on day of service or 12 days post service on farrowing rate and litter size to first service in outdoor sows and gilts

1999 ◽  
Vol 1999 ◽  
pp. 176-176
Author(s):  
A.R. Peters ◽  
L.A. Dwyer ◽  
A. Dawson ◽  
P.A. Canham ◽  
J.D. Mackinnon
Keyword(s):  
Treatment Group ◽  
Litter Size ◽  
East Anglia ◽  
Treatment Groups ◽  
Prolonged Weaning ◽  
Breeding Herd ◽  
Commercial Breeding ◽  
Buserelin Treatment ◽  
Seasonal Infertility ◽  
Farrowing Rate

The problem of seasonal infertility in pigs has been recognised for many years. The infertility complex can may be manifested by increased returns to service, prolonged weaning to oestrus intervals and decreased litter size. The purpose of this trial was to evaluate the effects of Buserelin treatment on fertility in sows and gilts during the seasonally infertile period.A total of 1231 mixed parity sows and gilts from five outdoor herds in East Anglia were randomly assigned to one of three treatment groups. Any sows not presented for service at first post weaning oestrus were excluded. All sows and gilts judged to be in adequate health and condition to be kept in a commercial breeding herd were included. Group C sows and gilts were given no treatment. Group R1 sows and gilts were injected i.m. with 8μg Buserelin (2.0ml Receptal; Hoechst Roussel Vet UK Ltd) on the day of service.

scholarly journals Some kinematics of halo coronal mass ejections

2020 ◽  
Vol 29 (1) ◽  
pp. 81-88
Author(s):  
Virendra Kumar Verma ◽  
Nishant Mittal ◽  
Ramesh Chandra
Keyword(s):  
Coronal Mass Ejections ◽  
Solar Flares ◽  
Coronal Holes ◽  
Geomagnetic Disturbances ◽  
Class A ◽  
Heliospheric Physics ◽  
Class B ◽  
The Mean ◽  
Class C

AbstractWe present an investigation of halo coronal mass ejections (HCMEs) kinematics and other facts about the HCMEs. The study of HCMEs is very important because HCMEs are regarded as the main causes of heliospheric and geomagnetic disturbances. In this study, we have investigated 313 HCMEs observed during 1996-2012 by LASCO, coronal holes, and solar flares. We find that HCMEs are of two types: accelerated HCMEs and decelerated HCMEs. The mean space speed of HCMEs is 1283 km/s while the mean speed of decelerated HCMEs and accelerated HCMEs is 1349 km/s and 1174 km/s, respectively. The investigation shows that 1 (0.3%) HCME was associated with class A SXR, 14 (4.7%) HCMEs were associated with class B SXR-flares, 87 (29.4%) HCMEs were associated with class C SXR-flares, 125 (42.2%) HCMEs were associated with class M SXR-flares and 69 (23.3%) HCMEs were associated with class X SXR-flares. The speed of HCMEs increases with the importance of solar SXR-flares. The various results obtained in the present analysis are discussed in the light of the existing scenario of heliospheric physics.

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