scholarly journals TUBERCULOSIS OF RABBITS INDUCED BY DROPLET NUCLEI INFECTION

1948 ◽  
Vol 87 (6) ◽  
pp. 585-594 ◽  
Author(s):  
H. L. Ratcliffe ◽  
W. F. Wells
Keyword(s):  
Inflammatory Response ◽  
Linear Relationship ◽  
Normal Control ◽  
Acquired Resistance ◽  
Single Exposure ◽  
Initial Infection ◽  
Development Of Resistance ◽  
Droplet Nuclei ◽  
Initial Lesions

At intervals from 2 to 11 weeks after normal rabbits had inhaled small numbers of virulent bovine tubercle bacilli as separated cells in droplet nuclei, groups of these animals received a single exposure to reinfection during which each animal inhaled about 20,000 separated bacilli. Normal control rabbits which inhaled this large number of bacilli died within 4 weeks thereafter. Their deaths were attributed to destruction of the lungs by developing initial tubercles. Eleven of 12 rabbits which were reinfected within 4 weeks after initial infection seemed to respond as normal animals. Their lungs were largely replaced by developing reinfection tubercles when they died or were killed within 32 days after reinfection. The inflammatory response of the reinfection tubercles was not consistently different from that of initial tubercles, although reinfection tubercles contained fewer bacilli than initial lesions of the same age. Within 5 weeks after initial infection rabbits apparently had developed immunity to reinfection with virulent bovine tubercle bacilli inhaled as separated cells in droplet nuclei. In some of them, however, exposure to massive inhaled reinfection seemed to stimulate the progress of initial infection. It is suggested that in rabbits the development of resistance to tubercle bacilli does not bear a linear relationship to time, but progresses in steps and within 5 weeks after small initial infection by inhalation is adequate to prevent the growth of separated bacilli when these are deposited upon alveolar walls. It is suggested also that the basic effect of acquired resistance of rabbits to tubercle bacilli is inhibition of multiplication of the bacilli.

Resistance by cattle to cattle tick, Boophilus microplus. III. The development of resistance to experimental infestations by purebred Sahiwal and Australian Illawarra Shorthorn cattle

1971 ◽  
Vol 22 (2) ◽  
pp. 331 ◽  
Author(s):  
RW Hewetson
Keyword(s):  
Adult Female ◽  
Acquired Resistance ◽  
Boophilus Microplus ◽  
Cattle Tick ◽  
Control Group ◽  
The Third ◽  
Development Of Resistance ◽  
Significant Difference ◽  
Sahiwal Cattle ◽  
Males And Females

Purebred Sahiwal cattle acquired resistance to Boophilus microplus in a similar manner to crossbred Sahiwal cattle as previously reported. The purebred entire males and females were more resistant than a control group of crossbred steers because they dropped significantly fewer replete ticks than the crossbreds at the third and fourth, but not at the first and second infestations. Adult female ticks dropped by purebred animals were significantly lighter than those dropped by crossbred animals at the fourth infestation only. There was no significant difference in the numbers of eggs laid and hatched from ticks dropped by purebred and crossbred animals. Australian Illawarra Shorthorn steers developed resistance at a second and third infestation which waned at a fourth infestation, but individual steers displayed developing resistance throughout the four infestations. Day of modal drop of replete female ticks appeared to be affected by breed, and developing resistance or season.

scholarly journals Parthenolide as Cooperating Agent for Anti-Cancer Treatment of Various Malignancies

2020 ◽  
Vol 13 (8) ◽  
pp. 194 ◽  
Author(s):  
Malgorzata Sztiller-Sikorska ◽  
Malgorzata Czyz
Keyword(s):  
Cancer Cells ◽  
Nuclear Factor Kappa B ◽  
Acquired Resistance ◽  
Complementary Therapy ◽  
Mechanisms Of Action ◽  
Nuclear Factor ◽  
Development Of Resistance ◽  
Current State ◽  
Anti Cancer ◽  
Survival Signaling

Primary and acquired resistance of cancer to therapy is often associated with activation of nuclear factor kappa B (NF-κB). Parthenolide (PN) has been shown to inhibit NF-κB signaling and other pro-survival signaling pathways, induce apoptosis and reduce a subpopulation of cancer stem-like cells in several cancers. Multimodal therapies that include PN or its derivatives seem to be promising approaches enhancing sensitivity of cancer cells to therapy and diminishing development of resistance. A number of studies have demonstrated that several drugs with various targets and mechanisms of action can cooperate with PN to eliminate cancer cells or inhibit their proliferation. This review summarizes the current state of knowledge on PN activity and its potential utility as complementary therapy against different cancers.

scholarly journals Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 142 ◽  
Author(s):  
Mariusz L. Hartman ◽  
Malgorzata Sztiller-Sikorska ◽  
Anna Gajos-Michniewicz ◽  
Malgorzata Czyz
Keyword(s):  
Phenotypic Plasticity ◽  
Cell Lines ◽  
Mapk Pathway ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Genetic Alterations ◽  
Resistant Cell ◽  
Cross Resistance ◽  
Preclinical Model ◽  
Development Of Resistance

The clinical benefit of MAPK pathway inhibition in BRAF-mutant melanoma patients is limited by the development of acquired resistance. Using drug-naïve cell lines derived from tumor specimens, we established a preclinical model of melanoma resistance to vemurafenib or trametinib to provide insight into resistance mechanisms. Dissecting the mechanisms accompanying the development of resistance, we have shown that (i) most of genetic and non-genetic alterations are triggered in a cell line- and/or drug-specific manner; (ii) several changes previously assigned to the development of resistance are induced as the immediate response to the extent measurable at the bulk levels; (iii) reprogramming observed in cross-resistance experiments and growth factor-dependence restricted by the drug presence indicate that phenotypic plasticity of melanoma cells largely contributes to the sustained resistance. Whole-exome sequencing revealed novel genetic alterations, including a frameshift variant of RBMX found exclusively in phospho-AKThigh resistant cell lines. There was no similar pattern of phenotypic alterations among eleven resistant cell lines, including expression/activity of crucial regulators, such as MITF, AXL, SOX, and NGFR, which suggests that patient-to-patient variability is richer and more nuanced than previously described. This diversity should be considered during the development of new strategies to circumvent the acquired resistance to targeted therapies.

Therapeutic implications for acquired resistance and heart toxicity using targeted therapy to erbB2

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3084-3084 ◽  
Author(s):  
S. S. Bacus ◽  
J. Hill ◽  
N. Spector
Keyword(s):  
Kinase Inhibitors ◽  
Cardiac Toxicity ◽  
Acquired Resistance ◽  
Breast Cancers ◽  
Therapeutic Implications ◽  
Development Of Resistance ◽  
Attractive Therapeutic Target ◽  
Er Positive ◽  
Similar Phenotype ◽  
Clinical Responses

3084 Background: ErbB2 overexpression predicts for a poor prognosis in breast cancer making it an attractive therapeutic target. Molecules such as EGFR/ErbB2 tyrosine kinase inhibitors (TKI’s), lapatinib/GW2974 and antibodies such as trastuzumab are currently used in clinical trials. Clinical responses to TKI’s have been observed, but are short-lived. Our data elucidates the pathway of acquired resistance to TKI’s and the underlying pathway associated with cardiac toxicity after trastuzumab treatment. Finally, we show the clinical implications and the therapeutic approaches to overcome this. Methods: Immunostaining and Western Blot were performed for HER2, EGFR, ER, PR, Bcl-2, FOXO3a, ERRα, ERR, PGC-1α, p-AKT and pERK. AU565, MCF7, BT-474, MCF7/HER2 and AU/BCL2 were treated with ß-estradiol, tamoxifen citrate, GW2974 and trastuzumab. Results: We show that upregulation of ERα and ER-regulated genes contribute to the resistance to HER1/HER2 inhibitors. Although the ErbB2 pathway is inhibited by lapatinib, the dependence of tumor cell survival in resistant cancer cells switches from ErbB2 to ER pathway. By inhibiting ErbB2/P13/AKT signaling, the inhibitors upregulate FOXO3a, which upregulates ER and ER-regulated genes, such as BCL2, contributing to cellular resistance. We also show that this occurs in patients with ErbB2/EGFR overexpressing ER positive cancers treated with lapatinib. By combining EGFR/HER2 inhibitors or antibodies with interventions that down regulate ER activity or estrogen deprivation, we were able to delay ER-mediated resistance. In addition, we have shown that the genes associated with the fatty acid metabolic pathway are upregulated by trastuzumab, but not lapatinib. Conclusion: Our results show that activation of ER and ER-regulated genes (BCL2) that contributed to the development of resistance to ErbB inhibitors in AU and BT474 cells also occurred in patients treated by lapatinib whose breast cancers expressed a similar phenotype. Identifying the mechanisms involved in the development of resistance and toxicities to ErbB inhibitors will lead to rational therapeutic strategies and improve their efficacy. In addition, less cardiac toxicity is anticipated in patients treated with lapatinib. No significant financial relationships to disclose.

Effects of prednisolone on murine strongyloidiasis

Parasitology ◽  
1981 ◽  
Vol 83 (2) ◽  
pp. 401-409 ◽  
Author(s):  
D. I. Grove ◽  
H. J. S. Dawkins
Keyword(s):  
Small Intestine ◽  
Rapid Development ◽  
Acquired Resistance ◽  
Acquired Immunity ◽  
Development Of Resistance ◽  
Prednisolone Treatment ◽  
Secondary Infections ◽  
Spontaneous Expulsion ◽  
C3h Mice ◽  
Resistance To Infection

SUMMARYThe effects of prednisolone were investigated in C57B1/6 mice infected with Strongyloides ratti. In primary infections, the numbers of adult worms in the small intestine and larvae in the stools were increased and there was a slight delay in the spontaneous expulsion of worms. In secondary infections, there was an initial suppression of acquired resistance, with larvae appearing normally in the stools on the 5th day after infection. This was followed, however, by a rapid development of resistance and expulsion of worms over the next few days. Prednisolone treatment did not alter fecundity in primary or secondary infections. There was no evidence of autoinfection in control or corticosteroid-treated animals. Prednisolone abrogated innate resistance to infection in C3H mice. It is concluded that prednisolone probably facilitated infection by non-specific mechanisms as well as by suppressing specific acquired immunity.

Use of cortisone derivatives to inhibit resistance to Nippostrongylus brasiliensis and to study the fate of parasites in resistant hosts

Parasitology ◽  
1965 ◽  
Vol 55 (4) ◽  
pp. 723-730 ◽  
Author(s):  
Bridget M. Ogilvie
Keyword(s):  
Cellular Response ◽  
Marked Effect ◽  
Trichinella Spiralis ◽  
Early Stage ◽  
Acquired Resistance ◽  
Challenge Infection ◽  
Cortisone Acetate ◽  
Nippostrongylus Brasiliensis ◽  
Initial Infection ◽  
Nematode Parasites

Acquired resistance to some nematode parasites can be suppressed by daily administration of cortisone acetate to the host. Cortisone treatment completely suppressed previously acquired resistance of mice to Trichinella spiralis (Coker, 1956) and suppressed, at least partially, the acquisition of resistance to T. spiralis by rats during initial infection (Markell & Lewis, 1957).A previous report (Weinstein, 1955) suggested cortisone acetate treatment was less effective in the suppression of acquired resistance of rats to Nippostrongylus brasiliensis. Weinstein showed that daily treatment with 2 mg cortisone acetate throughout five immunizing infections and continued during the challenge infection increased the number of worms in the intestine and had a marked effect on the cellular response in the skin and lungs. However, there was no significant effect when daily cortisone treatment commenced only on the fifth day before the challenge infection. This result suggested that acquisition of immunity to N. brasiliensis was partially overcome by cortisone treatment, but the same level of drug treatment had no effect on immunity already acquired.In the experiments reported here, previously acquired resistance to N. brasiliensis was suppressed completely and the initiation of immunity stopped, either completely or at a very early stage, by treatment with the cortisone derivatives prednisolone or betamethasone. The complete suspension of all manifestations of acquired resistance obtained by treatment with these drugs was used to investigate the fate of larvae migrating in an immune host.The rats and strain of parasite, and the methods of handling them, have been described previously (Ogilvie, 1965).

Type of progression in patients treated with imatinib for advanced gastrointestinal stromal tumor (GIST): A study based on the EORTC-ISG-AGITG trial 62005

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10536-10536
Author(s):  
M. M. Van Glabbeke ◽  
J. Verweij ◽  
P. Casali ◽  
J. Zalcberg ◽  
A. Le Cesne ◽  
...  
Keyword(s):  
Phase Iii ◽  
Phase Iii Trial ◽  
Development Of Resistance ◽  
Biological Event ◽  
Baseline Factors ◽  
Exon 9 ◽  
M 12 ◽  
Exon 11 ◽  
The Impact ◽  
Initial Lesions

10536 Background: Development of resistance in GIST patients responding to targeted agents is heterogeneous, and different types of mutations may be observed in different lesions of the same patient. Progressive disease (PD) is defined as increase in size of initial lesions, occurrence of new lesions, or both (RECIST): mixed progression (MXPD), were new lesions develop when old lesions are still responding could represent a different type of biological event. We evaluated the impact of progression type and time to first PD (TTP) on survival after progression (SAP) in a randomized phase III trial comparing two doses of imatinib as first line treatment of GIST in 946 patients. Methods: PD was classified into 5 categories: PD in old lesion without new lesions (PD-), and new lesions associated with CR (CR+), PR (PR+), NC (NC+) and finally PD (PD+); MXPD was defined as CR+ or PR+. We investigated the correlations between type of PD, baseline patients’ characteristics, imatinib dose, TTP and SAP with univariate (UVA) and multivariate (MVA) analysis. Results: Currently, 516 patients with PD have been radiologically documented. PD-, CR+, PR+, NC+, and PD+ were observed respectively in 47%, 2%, 10%, 8%, and 33% of the cases. MXPD was more frequent in patients without prior chemotherapy (15% vs 8%), or with a long TTP (0–6 m: 1%; 6–12 m: 8%; 12–24 m: 12%; 24–60 m: 19%; 60+ m: 25%). MXPD was less frequent in KIT exon 9 mutants (7%) and wild types (4%) than in KIT exon 11 mutants (17%) (UVA), but this is entirely explained by their shorter TTP (MVA). No other correlation was found with imatinib dose or baseline factors. SAP was shown to increases with TTP (P<0.0001), and was independently (and adversely) affected by PD of old lesions and development of new lesions: when compared to PD- patients, TTP adjusted SAP hazard ratio for patients with new lesions were 0.28 (CR+), 1.07 (PR+), 1.32 (NC+) and 1.61 (PD+). SAP was longer after MXPD (UVA), but this is explained by their longer TTP (MVA). Conclusions: In GIST patients treated with imatinib, survival after first progression increases with time to progression and decreases with “severity” of progression. Mixed progressions occur later than other types of progression, and therefore lead to a longer further survival. [Table: see text]

The relationship between pathology and resistance to reinfection with Schistosoma mansoni in mice: a causal mechanism of resistance in chronic infections

Parasitology ◽  
1987 ◽  
Vol 94 (1) ◽  
pp. 81-91 ◽  
Author(s):  
S. M. McHugh ◽  
Patricia S. Coulson ◽  
R. A. Wilson
Keyword(s):  
Schistosoma Mansoni ◽  
Acquired Resistance ◽  
Causal Mechanism ◽  
Injection Technique ◽  
Strong Correlations ◽  
Chronic Infections ◽  
Development Of Resistance ◽  
Time Post Infection ◽  
Hepatic Portal ◽  
Collateral Vessels

SUMMARYThe development of resistance in mice to reinfection with Schistosoma mansoni was recorded during an early chronic infection, and compared with hepatic portal pathological and vascular changes. The latter were assessed using a microsphere injection technique. The degree of acquired resistance was directly dependent on the patent worm burden and the time post-infection. Strong correlations were noted between the development of resistance and the appearance of parasite eggs in the lungs and spleens of infected hosts. Weaker associations were present between resistance and other aspects of the disease pathology, such as portal hypertension and organ weights. The appearance of injected microspheres in the lungs and spleens correlated well with the appearance of eggs in those organs and with the development of resistance. The levels of resistance had risen and microspheres were detected in the lungs, before the development of major extra-hepatic, porta-systemic collateral vessels. It is concluded that intra-hepatic vascular alterations may be a causal factor in the development of resistance, preventing the sequestration of migrating schistosomula in the liver. It is estimated that as much as 70–75% of the recorded resistance can be attributed to this immunologically non-specific mechanism.

Worm burdens, acquired resistance and live weight gains in lambs during prolonged daily infections with Trichostrongylus colubriformis (Giles, 1892) Loos, 1905

Parasitology ◽  
1974 ◽  
Vol 69 (3) ◽  
pp. 315-327 ◽  
Author(s):  
S. N. Chiejina ◽  
M. M. H. Sewell
Keyword(s):  
Worm Burden ◽  
Clinical Symptoms ◽  
Acquired Resistance ◽  
Live Weight ◽  
Trichostrongylus Colubriformis ◽  
Irreversible Damage ◽  
Cure Reaction ◽  
Development Of Resistance ◽  
Weight Gains ◽  
Faecal Egg Counts

Three groups of lambs, aged 3, 5 and 6 months respectively, were infected daily with 5000 infective larvae of Trichostrongylus colubriformis for periods of 15–20 weeks. Some of the lambs also received a single challenge infection at the end of week 16. The course of the infections was monitored by means of faecal egg counts, measurement of live-weight gains and regular post mortem worm counts.There was an initial rapid increase in egg counts soon after patency, which was followed by an exponential fall in the counts in most lambs. This fall seemed to precede the expulsion of worms by a few weeks and was associated with reduced fecundity in the female worms. Furthermore, although the trend of the egg counts of some lambs suggested that a self-cure reaction had taken place, in a number of these lambs the low faecal egg counts did not reflect the size of their worm burden.Heavy worm burdens were usually associated with clinical symptoms of trichostrongylosis, including anorexia, diarrhoea and loss of weight. As the lambs developed resistance to reinfection and expelled their worm burden a rapid clinical recovery occurred, except in a few lambs which appeared to have suffered irreversible damage from the earlier heavy worm burden.The worm burden in most lambs appeared to be cumulative during the first 4–8 weeks before they developed a strong resistance to reinfection. There was considerable loss of the adult worm burden by 8–15 weeks after initial infection and some evidence of stunting in the remaining parasites.The immunological control of T. colubriformis infections in these lambs was achieved by means of the development of resistance to reinfection, inhibition of the ovulation of the female worms, stunting of adult worms and expulsion of adult worms by resistant lambs. These may be separate immune phenomena requiring different thresholds of parasitic material in individual animals, depending on their age, the rate and duration of infection and their innate ability to develop resistance to the parasite.

Acquired Resistance to Experimental Heterakis Infections in Chickens and Turkeys: Effect on the Transmission of Histomonas meleagridis

1967 ◽  
Vol 41 (1) ◽  
pp. 55-62 ◽  
Author(s):  
Everett E. Lund
Keyword(s):  
Acquired Resistance ◽  
Slight Reduction ◽  
Initial Infection

Attempts were made to induce increased resistance to caecal worm infections in chickens and turkeys by giving 5-week-old birds embryonated Heterakis eggs. To test for such resistance, the birds were challenged 28 days later by feeding comparable numbers of embryonated eggs. To study the possible influence of any response on the transmission of blackhead, some of the birds received Heterakis eggs from worms grown in birds that had blackhead.In blackhead-free chickens there was only a slight reduction in the number of worms recoveied from the initial infection as a result of the superimposed second infection. However, there were 37% fewer worms from the second feeding of eggs than were present in the control birds that had had no previous Heterakis infection. In blackhead-free turkeys, the immunized birds had fewer worms from both doses than did the controls. These reductions averaged about 40% in both instances.

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