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Results for “acquired resistance”

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At least 19 recordsLinked to original sources

PubMed1977

Kinetics and maintenance of acquired resistance in mice to Listeria monocytogenes.

In the mouse system, acquired resistance to Listeria monocytogenes can only be demonstrated after immunization with viable microorganisms. A successful state of immunity cannot be elicited with formalin-killed organisms or bacterial cell-derived products. Viable, serologically cross-reactive organisms (not mouse pathogenic) do not induce a state of immunity as measured by acquired resistance. The duration of immunity, once established, is dose independent, and the absolute interval of its existence is not extended by secondary challenge with large numbers of viable organisms. The decline of immunity in actively immunized animals is not altered by antigenic challenge with formalin-killed cells or cell products. This indicates that the cellular requirements for the development of host resistance are similar for induction as well as maintenance. In vitro measurements of cellular immunity by migration inhibition indicate that formalin-killed organisms as well as cell products were recognized by actively sensitized lymphocytes obtained from immune animals.

Animals↗

PubMed2026

Landscape of acquired resistance alterations in gastrointestinal malignancies after genomically targeted therapy.

BACKGROUND: Targeted therapies directed at specific genomic alterations have transformed the management of gastrointestinal (GI) cancers; however, acquired resistance remains inevitable. Circulating tumor DNA (ctDNA) analysis via liquid biopsy provides a non-invasive approach to characterize genomic mechanisms of resistance. We therefore evaluated patterns of acquired genomic resistance in patients with GI cancers treated with targeted therapies. METHODS: Patients with GI cancers treated with standard of care or investigational therapies targeting EGFR, HER2, FGFR, MET, KRAS, BRAF for at least 60 days who underwent both baseline comprehensive genomic profiling and post-progression ctDNA sequencing were retrospectively evaluated. RESULTS: Of 106 patients meeting inclusion criteria, 45 had biliary tract cancer (BTC), 42 colorectal cancer (CRC), and 19 other GI malignancies. At least one putative resistance-associated alteration was detected in ctDNA in 53% of cases. Resistance patterns were heterogeneous with 47% showing no detectable alterations and 33% harboring ≥2 resistance alterations. Among 164 total alterations, the majority were single nucleotide variants (82%), followed by amplifications (17%). Overall, 48% were classified as 'bypass' alterations-activating alternative oncogenic pathways, most commonly MAPK signaling-while 52% were 'on-target' alterations involving secondary changes within the drug target. RAS alterations represented a key mechanism of bypass resistance, accounting for 28% of all resistance alterations. Interestingly, in CRC, bypass alterations predominated (69%), whereas in BTCs, on-target alterations were more frequent (61%). CONCLUSIONS: Liquid biopsies frequently identify acquired resistance following targeted therapy across GI cancers, often revealing multiple concurrent alterations. Patterns of resistance varied by tumor type, with both on-target and bypass mechanisms observed. These findings highlight common themes of resistance and support the growing clinical role of ctDNA analysis in defining resistance and guiding management in GI malignancies.

Gastrointestinal malignancies↗

PubMed1979

Penetrability of the outer membrane of Neisseria gonorrhoeae in relation to acquired resistance to penicillin and other antibiotics.

Acquired antibiotic resistance in Neisseria gonorrhoeae is principally associated with three genetic markers, penA, mtr, and penB. penA is a specific marker for penicillin resistance, whereas mtr and penB are nonspecific in conferring resistance to penicillin and several other antibiotics as well. It has been suggested that the nonspecific markers may cause a general decrease in the penetrability of the gonococcal outer membrane. To investigate this, antibiotic penetration of the outer membrane was studied in two isogenic strains-FA19 (susceptible parent) and FA140 (containing penA, mtr, and penB)-and also in a clinical isolate with multiple resistance. The method involved brief treatment of exponential cells with ethylenediaminetetraacetic acid at 5 degrees C to disrupt the outer membrane barrier. The 50% inhibitory concentrations of antibiotics for treated and normal cells were measured turbidimetrically, and from their ratios outer membrane penetration barriers were calculated. Small barriers were observed for actinomycin D and benzylpenicillin, and these were very similar in the susceptible and resistant strains. Also, in FA140 no significant barriers for rifampin, erythromycin, and tetracycline were detected. These results suggest that mechanism(s) other than reduced outer membrane penetrability underlie acquired resistance due to penA, mtr, and penB.

Anti-Bacterial Agents↗

PubMedDate not supplied

Natural resistance to Marek's disease at hatching in chickens lacking maternal antibody, and relationship between this early resistance and resistance acquired with age.

Chickens of lines 6 and N, selected for resistance to Marek's disease (MD) and lacking maternal antibody, were resistant to MD mortality when exposed to pathogenic MD virus (MDV) at 1 day old. This finding indicated that natural resistance to MD is well developed at hatching in certain lines and is not dependent upon increasing age. Evidence obtained for lesion regression in early resistance and for possible genetic control of resistance acquired with age indicated that resistance at hatching and that acquired with age may be similar in character and may represent early and late manifestations of common natural resistance, possibly mediated through similar mechanisms.

Age Factors↗

PubMed1978

Acquired resistance in turkey poults to Pasteurella multocida (P-1059 strain) during aflatoxin consumption.

The potential for impairment by aflatoxin of the development of acquired immunity to fowl cholera in 8 week old turkey poults from a commercial flock was investigated by challenge of vaccinated poults at 10, 12, and 16 weeks of age. Sixty poults were allotted to 4 groups: A) aflatoxin fed, nonvaccinated; B) aflatoxin fed, vaccinated; C) control fed, nonvaccinated; and D) control fed, vaccinated. Aflatoxin B-1 (.5 ppm) was added to the control ration of groups A and B from 49 to 70 days of age. The avirulent CU (Clemson University) strain of Pasteurella multocida drinking water vaccine was given for one day to groups B and C. Challenge (5 poults from each group) was by administration of the virulent (P-1059) strain of P. multocida in the drinking water for 4 consecutive days. The presence of aflatoxin B-1 (.5 ppm) in the feed during oral vaccination with the avirulent strain of P. multocida did not impair the development of acquired resistance to later challenge with the virulent strain. Results indicate that age of poults and method of vaccination may be important factors in the development of acquired resistance to fowl cholera when aflatoxin is present in the diet.

Administration, Oral↗

PubMed2024

L3MBTL1, a polycomb protein, promotes Osimertinib acquired resistance through epigenetic regulation of DNA damage response in lung adenocarcinoma.

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI) approved for patients with EGFR T790M resistance mutations as first- or second-line treatment of EGFR-positive patients. Resistance to Osimertinib will inevitably develop, and the underlying mechanisms are largely unknown. In this study, we discovered that acquired resistance to Osimertinib is associated with abnormal DNA damage response (DDR) in lung adenocarcinoma cells. We discovered that the polycomb protein Lethal(3) Malignant Brain Tumor-Like Protein 1 (L3MBTL1) regulates chromatin structure, thereby contributing to DDR and Osimertinib resistance. EGFR oncogene inhibition reduced L3MBTL1 ubiquitination while stabilizing its expression in Osimertinib-resistant cells. L3MBTL1 reduction and treatment with Osimertinib significantly inhibited DDR and proliferation of Osimertinib-resistant lung cancer cells in vitro and in vivo. L3MBTL1 binds throughout the genome and plays an important role in EGFR-TKI resistance. It also competes with 53BP1 for H4K20Me2 and inhibits the development of drug resistance in Osimertinib-resistant lung cancer cells in vitro and in vivo. Our findings suggest that L3MBTL1 inhibition is a novel approach to overcoming EGFR-TKI-acquired resistance.

Humans↗

PubMed1979

The kinetics and quality of acquired resistance in self-healing and metastatic leishmaniasis.

Quantitative methods for enumerating viable L. enriettii in tissues have been used to determine the course of cutaneous leishmaniasis in guinea-pigs. The development and kinetics of acquired resistance have been evaluated in self-healing and chronic metastatic forms of the disease. It is revealed that 3 weeks after a primary local infection, a standard challenge infection is totally eliminated within 7 days. This resistance is as strong in animals with a current infection as it is in those that have fully recovered from such an infection. Animals developing metastatic disease also develop resistance to the standard challenge. This is initially as strong as in animals with only localized disease, but wanes with the progression of the infection. Although the quality of resistance becomes poorer in animals with metastatic infection, it is not lost completely. The relationship between acquired resistance and the resolution of the primary infection is discussed.

Animals↗

PubMed1976

Acquired resistance against Listeria monocytogenes in red mice and CF1 mice immunized with strains of BCG or Mycobacterium tuberculosis.

Groups of red mice and CF1 mice immunized intravenously with varying doses of a weak or a strong strain of BCG or a strain of Mycobacterium tuberculosis were challenged 3 weeks after immunization with 0.1 or 0.2 ml 10(-2) Listeria monocytogenes injected intravenously, simultaneously with a non-immunized control group. The acquired resistance was determined on the basis of the number of survivors and the survival times of the animals that died spontaneously. In the red mice, the strong BCG strain induced a definitely higher resistance than the weak strain, and the M. tuberculosis strain a slightly higher resistance than the BCG strains. As in red mice, the resistance of CF1 mice was higher in animals immunized with M. tuberculosis than in those immunized with the BCG strains. However, the difference in the survival times of mice immunized with the two strains of BCG was much less than in red mice, and was only clearly significant as regards one of the doses used. The relationship between the virulence of a mycobacterial strain and its ability to induce acquired resistance against an infection with listeria or against an infection with virulent tubercle bacilli is discussed. It is concluded that red mice are more suitable than CF1 mice for evaluation of the protective potency of a BCG strain.

Animals↗

PubMed1976

Parameters of acquired resistance and their role in the evaluation of new chemotherapeutic drugs.

Acquired resistance can be defined as a qualitative alteration of the genetic material of a cell which is phenotypically correlated with a measurable decrease of the cell's sensitivity against one or several chemotherapeutic agents. There are two basic genetic mechanisms which can lead to the emergence of resistance: mutation and the acquisition of additional genetic material from another cell. Both forms of resistance play an important role in clinical situations: the emergence of resistance by mutation occurs in tumor cells and can also lead to therapeutic problems in antimicrobial chemotherapy. In bacteria, however, acquisition of resistance plasmids represents the dominating mechanism which is responsible for most therapeutic problems in the clinical environment. The different genetic mechanisms involved in the emergence of resistance are paralleled -- at least in bacteria -- by two principally different groups of biochemical mechanisms implementing resistance. Mutations lead to alterations of single cell constituents such as the cell membrane or cellular receptors necessary for the binding of the antimicrobial agent. This form of resistance is biochemically characterized by the inaccessibility of the cell interior for a particular compound or by the modification of an intracellular binding site which loses its affinity for the chemotherapeutic agent. Resistance plasmids on the other hand code for enzymes which inactivate the antibiotic (beta-lactamases, aminoglycosideinactivating enzymes, chloramphenicol-acetyltransferase); In some cases, they direct the synthesis of proteins which affect cell permeability (tetracycline) or isoenzymes which have a lower affinity for the inhibitor (trimethoprim). Resistance against antibiotics can be inducible; In these cases the regulatory mechanisms involved are stable genetical traits as resistance itself; Using chloramphenicol, beta-lactam-antibiotics and aminoglycosides as examples, it is demonstrated that resistance data gathered early in the development of a new drug are of little value in estimating the clinical potential of a new compound. Information on the rate at which resistance develops, on the pattern according to which it emerges ("single step" or "multi step") and on cross-resistance patterns is important in the characterization of a new drug but is often invalidated by later findings obtained in the clinical environment; The problem appears somewhat simpler if a new drug is a member of an already known class of compounds, e.g. a beta-lactam or an aminoglycoside. In such cases our knowledge of frequent enzymatic inactivation mechanisms provides a basis not only for the evaluation of an existing drug, but also for the synthesis of new derivatives.

Anti-Bacterial Agents↗

PubMed1977

Mechanisms of acquired resistance to Pasteurella multocida infection: a review.

Pasteurella multocida is an animal parasite of considerable economic and veterinary importance. The organism produces both capsular polysaccharide and somatic (lipopolysaccharide) antigens used to serotype the organisms. Correlations exist between antigenic structure, host susceptibility and strain virulence. The host response seems to be predominantly polymorphonuclear in nature, with little evidence of a mononuclear component in the host response to infection. In the absence of specific opsonins, phagocytosis rates are very slow, the organisms multiplying freely in an essentially extracellular environment. Passive transfer studies indicate that acquired resistance is humorally modiated, presumably by promoting phagocytosis withing the peritoneal cavity. There is, however, no sign of early increased local bactericidal action within the peritoneal cavity; protection seems rather to be due to an inhibition of the rapid spread by the organisms to the bloodstream and other reticuloendothelial organs. Viable attenuated oral vaccines are effective for chicken and turkey poults, both experimentally and under field conditions. The nature of the protective immunoglobulins and their mode of action against an orally induced infection has not been widely examined as yet. Effective protection can be achieved in birds, cattle and experimental animals with a variety of killed vaccines (especially when presented in a suitable adjuvant). The lack of quantitative growth data in suitably vaccinated animals and the absence of definitive studies of the bactericidal mechanisms involved in the expression of this acquired resistance continue to limit our present understanding of defense against this important animal disease.

Animals↗

PubMed1977

[Extrachromosomal antibiotic resistance of the intestinal bacterial flora. II. The role of resistance acquired by endogenous intestinal bacterial flora (author's transl)].

In a previous paper, we have shown that multiple resistant bacteria in the human gut flora may have two origins: firstly, through food which carries resistant bacteria and secondly, our present study, resident intestinal bacteria which become resistant to antibiotics, either because they are chromosomic mutant or because they acquire resistance plasmid from an exogen strain. In all cases these resistant bacteria can implant and multiply in the gut only if there are disorders in the normal bacterial equilibrium. Antibiotherapy can create this inbalance and especially if it is not carefully followed up: it selects resistant bacteria, allows their implantation, and promotes plasmid R transfer. The resistant bacteria are able, in some cases, to spread out from the intestinal tract and give rise to further infections.

Anti-Bacterial Agents↗

PubMed1976

Acquired resistance to Schistosoma haematobium in the baboon (Papio anubis) after cercarial exposure and adult worm transplantation.

Observations were made on the development of acquired resistance to Schistosoma haematobium in the baboon following immunization with cercariae by the percutaneous route and by the transplantation of adult worms into the mesenteric veins. In the first experiment six baboons were immunized with 1000 S. haematobium cercariae given percutaneously. They were challenged with 10 000 cercariae given 73 weeks later and the results were compared with a similar infection in non-immunized animals. The results showed that the baboon can develop a strong resistance to reinfection with S. haematobium. The manifestations of the immunity were (i) the absence of any increase in egg output after challenge (ii) the substantially lower level of adult worms and eggs in the tissues of the immunized baboons compared with the challenge control animals (iii) a reduction in the egg laying capacity of the residual worms and (iv) the virtual absence of gross pathology and the mild lesions seen in the tissue sections of all the immunized animals. The depression in egg laying of the worms was confirmed by transplanting them into non-immune baboons. This experiment indicated that the non-egg-laying worms in the immune baboons were not irreversibly damaged since they survived, some even migrating to the vesical and ureteric vessels, and egg-laying was rapidly resumed after transplantation. A further experiment was designed to see if a similar degree of immunity could be produced by an adult worm infection without previous exposure to cercariae or schistosomula. The immunization dose consisted of 50-100 S. haematobium worm pairs which were transplanted into the mesenteric veins of each of six baboons and the animals were challenged percutaneously with 7000 cercariae 35-55 weeks later. There was little difference in the worm burdens of the immunized and control animals but the worms in the immunized baboons produced fewer eggs and the pathology seen in these animals was much milder than in the challenge control animals suggesting that some degree of resistance to reinfection was produced by the transplanted worms.

Animals↗

PubMed2025

Artificial intelligence-powered spatial analysis of tumor microenvironment in patients with non-small cell lung cancer with acquired resistance to EGFR tyrosine kinase inhibitor.

PURPOSE: This study evaluated the dynamic changes in the tumor microenvironment (TME) in patients with non-small cell lung cancer (NSCLC) and acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) using an artificial intelligence (AI)-powered spatial TME analyzer. We then assessed the predictive efficacy of immune-checkpoint inhibitors (ICIs)-based treatment. EXPERIMENTAL DESIGN: An AI-powered whole-slide image analyzer was used to segment cancer areas (CAs) and cancer stroma and to identify tumor-infiltrating lymphocytes (TILs), tertiary lymphoid structures, fibroblasts, and endothelial cells (ECs) in the tumor tissue. We analyzed 143 NSCLC samples after resistance to EGFR-TKIs from two cohorts: (1) 89 patients treated with ICI monotherapy and (2) 54 patients from the ATTLAS phase III trial comparing atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP) versus pemetrexed plus carboplatin. RESULTS: Post-TKI samples showed reduced TILs in the CA (p=0.045) and increased ECs in the CA (p=0.005) compared with pre-TKI samples. These changes differed according to EGFR mutation subtype. Higher TILs in CA were associated with a better overall response rate (ORR) and progression-free survival (PFS). Similarly, higher EC levels in CA correlated with improved ORR and PFS. In the ATTLAS cohort, these factors were associated with clinical benefits from ABCP, with a significant association with TILs and a marginal association with ECs. CONCLUSION: Our findings suggest that EGFR-TKIs affect the immune landscape of patients with EGFR-mutated NSCLC. Higher TILs or ECs in the CA were significantly associated with a favorable response to subsequent ICI-based treatment. TRIAL REGISTRATION NUMBER: NCT03991403.

Aged↗

PubMed1979

The effect of iron and protein deficiency on the development of acquired resistance to reinfection with Nippostrongylus brasiliensis in rats.

Iron and protein deficiency delays the immunological rejection of Nippostrongylus brasiliensis from the small intestine of rats undergoing a primary infection with the parasite. In the present study, iron and protein deficiency significantly reduced acquired resistance to reinfection with N. brasiliensis. Repletion of deficient animals with iron and protein restored their capacity to mount an effective immune response to a secondary infection with the parasite. These results suggest that chemotherapy of helminthiasis should be integrated with nutritional supplementation.

Animals↗

PubMed1979

The effect of age, acquired resistance, pregnancy and lactation on some reactions of cattle to infection with Ostertagia ostertagi.

An experiment is described in which the effects of age, previous infection, pregnancy and lactation on some reactions of cattle to infection with Ostertagia ostertagi were studied. It was found that an acquired resistance to the establishment of worms developed more rapidly in 20-month-old heifers than in calves, that it was unaffected by pregnancy of the host but that it was largely lost by heifers in early lactation. The rate at which populations were turned over, i.e. the mean life-span of worms through the late 4th and 5th stages was unaffected by the factors studied. Although, in the conditions of the experiment, development of the worms was not arrested in susceptible calves, both age of the host and its previous experience of infection were significant causes of arrest, and in previously infected 20-month-old cattle 86% of the worms of a challenge infection were arrested. Pregnancy did not affect the proportion of worms that was arrested but in lactating heifers only marginally more worms were arrested than in calves. Worms that were not arrested grew more rapidly in calves and in lactating heifers than in empty heifers or those in mid-pregnancy.

Age Factors↗

PubMed2026

RAS-GTP Inhibition Overcomes Acquired Resistance to KRASG12C Inhibitors Mediated by Oncogenic and Wild-Type RAS Activation in Non-Small Cell Lung Cancer.

UNLABELLED: Small-molecule KRASG12C(OFF) inhibitors that bind to the inactive GDP-bound state of KRAS have demonstrated efficacy in patients with KRASG12C-mutant tumors, yet responses tend to be transient because of emergence of on-treatment resistance. Recently, RAS(ON) G12C-selective inhibitors, which bind to the active GTP-bound state of RAS, were described, and elironrasib is undergoing evaluation in multiple clinical trials. In this study, we generated resistant cell lines and patient-derived xenograft models to KRASG12C(OFF) and RAS(ON) G12C-selective inhibitors and interrogated resistance mechanisms using a multiomics strategy consisting of phosphoproteomics, whole-exome sequencing, and RNA sequencing combined with functional testing using small-molecule and CRISPR screens and RAS(ON) inhibitors being evaluated in clinical trials. Two models reactivated RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and were vulnerable to dual inhibition by RAS(ON) G12C-selective and RAS(ON) multiselective inhibitors, RMC-4998 and RMC-7977. Two models, which lacked any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity and were sensitive to RAS-GTP inhibition by RMC-7977. Finally, one model displayed epithelial-mesenchymal transition, loss of RAS dependence, and acquired reliance on cell-cycle kinases and proteins associated with DNA damage response. This work highlights KRASG12C-selective inhibitor resistant states that parallel and complement clinical findings and demonstrate that a large subset could be overcome with a RAS(ON) multi-selective inhibitor as a stand-alone agent or in combination with other therapies. SIGNIFICANCE: Multi-omic characterization of resistance mechanisms to KRASG12C-selective inhibitors in non-small cell lung cancer provides insights that could inform precision medicine-based therapeutic approaches for improving the treatment of KRASG12C mutant tumors. See related article by Stern et al., p. 485.

Humans↗

PubMed1979

The effect of route of infection on acquired resistance to Fasciola hepatica in the rat and sheep.

Rats and sheep were infected with Fasciola hepatica by subcutaneous, intramuscular or oral (intraruminal--sheep) inoculation with encysted metacercariae and the development of flukes from these primary infections assessed. Additional rats and sheep similarly infected were challenged with encysted metacercariae orally (rats), or intraruminally (sheep) to assess the level of acquired resistance generated by previous infection by each of the three routes of administration. In both rats and sheep 0--5 per cent, 0--5 per cent and 20--25 per cent of metacercariae given by the subcutaneous, intramuscular or oral (intraruminal--sheep) routes were recovered as flukes in the liver four and 12 weeks after infection of rats, or 17 weeks after infection of sheep. Primary infection of rats with F hepatica by each of the three routes generated strong protection against oral challenge whereas no protection was generated in sheep, irrespective of route of infection.

Administration, Oral↗

PubMed1976

A comparison of the acquired resistance to Dipetalonema viteae stimulated in hamsters by trickle versus tertiary infections.

Two groups of hamsters were hyperinfected with Dipetalonema viteae. Each of the 15 hamsters in the first group received a total of 900 larvae given in three equal doses on days 0, 150 and 250 from the start of the experiment (tertiary-infection group). Each of the 20 hamsters in the second group received a total of 900 larvae given in 18 equal doses (50 larvae per dose) at 14 day intervals. Thus the final dose was given on day 238 from the start of the experiment (trickle-infection group). About half of the hamsters in each group were killed 100 days after the last sensitizing infection and their adult worm burdens and subcutaneous nodules were counted. The tertiary-infection group had a higher average number of adult worms per hamster, but fewer subcutaneous nodules than the trickle infection group. However, when the number of adult worms and subcutaneous nodules were added together, the sums from both groups were similar. The remaining hamsters of the above two groups, along with a group of nine previously uninfected hamsters, were given a challenge infection of 500 larvae per animal. Necropsy data taken 70-80 days after the challenge infection indicated inhibition and/or destruction of developing larval stages in the trickle + challenge-infection group, but no such acquired resistance phenomenon in the tertiary + challenge-infection or challenge-infection groups. While the mechanism remains unknown, it is clear that prior exposure to repeated small infections over an extended period stimulated a protective response to D. viteae in hamsters. This response was not seen in animals given three large infections over a similar time period.

Animals↗