scholarly journals Evaluation of IL-1 blockade as an adjunct to linezolid therapy for tuberculosis in mice and macaques

2019 ◽  
Author(s):  
Caylin G. Winchell ◽  
Bibhuti B. Mishra ◽  
Jia Yao Phuah ◽  
Mohd Saqib ◽  
Samantha J. Nelson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Treatment Time ◽  
Treatment Strategies ◽  
Conclusive Evidence ◽  
Bone Marrow Suppression ◽  
Bone Marrow Toxicity ◽  
Susceptible Mouse ◽  
Erythroid Progenitor ◽  
Resistant Tuberculosis ◽  
New Treatment

AbstractIn 2017 over 550,000 estimated new cases of multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) occurred, emphasizing a need for new treatment strategies. Linezolid (LZD) is a potent antibiotic for drug-resistant Gram-positive infections and is an effective treatment for TB. However, extended LZD use can lead to LZD-associated host toxicities, most commonly bone marrow suppression. LZD toxicities may be mediated by IL-1, an inflammatory pathway important for early immunity during M. tuberculosis infection. However, IL-1 can contribute to pathology and disease severity late in TB progression. Since IL-1 may contribute to LZD toxicity and does influence TB pathology, we targeted this pathway with a potential host-directed therapy (HDT). We hypothesized LZD efficacy could be enhanced by modulation of IL-1 pathway to reduce bone marrow toxicity and TB associated-inflammation. We used two animal models of TB to test our hypothesis, a TB-susceptible mouse model and clinically relevant cynomolgus macaques. Antagonizing IL-1 in mice with established infection reduced lung neutrophil numbers and partially restored the erythroid progenitor populations that are depleted by LZD. In macaques, we found no conclusive evidence of bone marrow suppression associated with LZD, indicating our treatment time may have been short enough to avoid the toxicities observed in humans. Though treatment was only 4 weeks (the FDA approved regimen at the time of study), we observed sterilization of the majority of granulomas regardless of co-administration of the FDA-approved IL-1 receptor antagonist (IL-1Rn), also known as Anakinra. However total lung inflammation was significantly reduced in macaques treated with IL-1Rn and LZD compared to LZD alone. Importantly, IL-1Rn administration did not impair the host response against Mtb or LZD efficacy in either animal model. Together, our data support that inhibition of IL-1 in combination with LZD has potential to be an effective HDT for TB and the need for further research in this area.

scholarly journals Accelerating development of high-risk neuroblastoma patient-derived xenograft models for preclinical testing and personalised therapy

2020 ◽  
Vol 122 (5) ◽  
pp. 680-691 ◽  
Author(s):  
Alvin Kamili ◽  
Andrew J. Gifford ◽  
Nancy Li ◽  
Chelsea Mayoh ◽  
Shu-Oi Chow ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Pleural Fluid ◽  
Personalised Medicine ◽  
Model Development ◽  
Treatment Strategies ◽  
Nsg Mice ◽  
Patient Derived Xenograft ◽  
New Treatment ◽  
Pdx Models

Abstract Background Predictive preclinical models play an important role in the assessment of new treatment strategies and as avatar models for personalised medicine; however, reliable and timely model generation is challenging. We investigated the feasibility of establishing patient-derived xenograft (PDX) models of high-risk neuroblastoma from a range of tumour-bearing patient materials and assessed approaches to improve engraftment efficiency. Methods PDX model development was attempted in NSG mice by using tumour materials from 12 patients, including primary and metastatic solid tumour samples, bone marrow, pleural fluid and residual cells from cytogenetic analysis. Subcutaneous, intramuscular and orthotopic engraftment were directly compared for three patients. Results PDX models were established for 44% (4/9) of patients at diagnosis and 100% (5/5) at relapse. In one case, attempted engraftment from pleural fluid resulted in an EBV-associated atypical lymphoid proliferation. Xenogeneic graft versus host disease was observed with attempted engraftment from lymph node and bone marrow tumour samples but could be prevented by T-cell depletion. Orthotopic engraftment was more efficient than subcutaneous or intramuscular engraftment. Conclusions High-risk neuroblastoma PDX models can be reliably established from diverse sample types. Orthotopic implantation allows more rapid model development, increasing the likelihood of developing an avatar model within a clinically useful timeframe.

scholarly journals Influence of metformin on HIF-1 pathway in multiple myeloma

2020 ◽  
Vol 72 (5) ◽  
pp. 1407-1417
Author(s):  
Kinga A. Kocemba-Pilarczyk ◽  
Sonia Trojan ◽  
Barbara Ostrowska ◽  
Małgorzata Lasota ◽  
Paulina Dudzik ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Treatment Strategies ◽  
Annexin V ◽  
Growth And Survival ◽  
Hypoxic Conditions ◽  
New Treatment ◽  
First Time ◽  
Pcr Techniques

Abstract Background Multiple myeloma (MM) is defined as plasma cells malignancy, developing in the bone marrow. At the beginning of the disease, the malignant plasma cells are dependent on bone marrow microenvironment, providing growth and survival factors. Importantly, the recent studies pointed hypoxia as an important factor promoting progression of MM. In particular, hypoxia-triggered HIF-1 signaling was shown to promote chemoresistance, angiogenesis, invasiveness and induction of immature phenotype, suggesting that strategies targeting HIF-1 may contribute to improvement of anti-myeloma therapies. Methods The Western Blot and RT-PCR techniques were applied to analyze the influence of metformin on HIF-1 pathway in MM cells. To evaluate the effect of metformin on the growth of MM cell lines in normoxic and hypoxic conditions the MTT assay was used. The apoptosis induction in metformin treated hypoxic and normoxic cells was verified by Annexin V/PI staining followed by FACS analysis. Results Our results showed, for the first time, that metformin inhibits HIF-1 signaling in MM cells. Moreover, we demonstrated the effect of metformin to be mainly oxygen dependent, since the HIF-1 pathway was not significantly affected by metformin in anoxic conditions as well as after application of hypoxic mimicking compound, CoCl2. Our data also revealed that metformin triggers the growth arrest without inducing apoptosis in either normoxic or hypoxic conditions. Conclusions Taken together, our study indicates metformin as a promising candidate for developing new treatment strategies exploiting HIF-1 signaling inhibition to enhance the overall anti-MM effect of currently used therapies, that may considerably benefit MM patients.

Progress in global rollout of new multidrug-resistant tuberculosis treatments

2019 ◽  
Vol 23 (9) ◽  
pp. 996-999 ◽  
Author(s):  
K. Held ◽  
S. McAnaw ◽  
C-Y. Chiang ◽  
A. Trebucq ◽  
C. R. Horsburgh
Keyword(s):  
Treatment Strategies ◽  
Multidrug Resistant ◽  
New Drugs ◽  
Internet Survey ◽  
Treatment Regimens ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Global Increase ◽  
New Treatment

SETTING: The global multidrug-resistant tuberculosis (MDR-TB) epidemic has grown over the past decade and continues to be difficult to manage. In response, new drugs and treatment regimens have been recommended.OBJECTIVE: In 2017 and again in 2018, the International Union Against Tuberculosis and Lung Disease (The Union) drug-resistant (DR) TB Working Group collaborated with RESIST-TB to implement an internet survey to members of The Union around the world to assess access to these new treatment strategies.DESIGN: A nine-question survey was developed using SurveyMonkey®. The survey was open for participation to all members of The Union registered under the TB Section. Two reminders were sent during each survey. The responses were analyzed taking into account the WHO Region to which the respondent belonged.RESULTS: The 2018 survey showed a global increase in implementation of the shorter (9-month) MDR-TB regimen (from 33% to 56% of respondents, P < 0.001) and an increase in the use of bedaquiline and/or delamanid (from 25% to 41% of respondents, P < 0.001) compared to 2017. There were substantial variations in roll-out between WHO regions.CONCLUSION: These results demonstrate improvement in global implementation of the new treatment strategies over a 1-year period.

Humoral Immunity in Heart Failure

2019 ◽  
Vol 19 (1) ◽  
pp. 14-18 ◽  
Author(s):  
Amrita Sarkar ◽  
Khadija Rafiq
Keyword(s):  
Heart Failure ◽  
Humoral Immunity ◽  
Treatment Strategies ◽  
Pathophysiological Mechanism ◽  
Peripheral Vascular ◽  
Cardiac Inflammation ◽  
Humoral Immune ◽  
Humoral Immune System ◽  
New Treatment ◽  
Immunity Function

Cardiovascular Disease (CVD) is a class of diseases that involve disorders of heart and blood vessels, including hypertension, coronary heart disease, cerebrovascular disease, peripheral vascular disease, which finally lead to Heart Failure (HF). There are several treatments available all over the world, but still, CVD and heart failure became the number one problem causing death every year worldwide. Both experimental and clinical studies have shown a role for inflammation in the pathogenesis of heart failure. This seems related to an imbalance between pro-inflammatory and anti-inflammatory cytokines. Cardiac inflammation is a major pathophysiological mechanism operating in the failing heart, regardless of HF aetiology. Disturbances of the cellular and humoral immune system are frequently observed in heart failure. This review describes how B-cells play a specific role in the heart failure states. There is an urgent need to identify novel therapeutic targets and develop advanced therapeutic strategies to combat the syndrome of HF. Understanding and describing the elements of the humoral immunity function are essential and may suggest potential new treatment strategies.

scholarly journals Severe bone marrow suppression due to methotrexate toxicity following aceclofenac-induced acute kidney injury

2018 ◽  
pp. bcr-2018-224722 ◽  
Author(s):  
Robin George Manappallil ◽  
Durga Prasan ◽  
Jayameena Peringat ◽  
Illolil Kuniyil Biju
Keyword(s):  
Bone Marrow ◽  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Bone Marrow Suppression ◽  
Methotrexate Toxicity

Bone marrow toxicity induced by oral benzo[a]pyrene: Protection resides at the level of the intestine and liver

1983 ◽  
Vol 70 (3) ◽  
pp. 390-401 ◽  
Author(s):  
Catherine Legraverend ◽  
David E. Harrison ◽  
Francis W. Ruscetti ◽  
Daniel W. Nebert
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Toxicity

scholarly journals Emerging Natural-Product-Based Treatments for the Management of Osteoarthritis

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 265
Author(s):  
Maria-Luisa Pérez-Lozano ◽  
Annabelle Cesaro ◽  
Marija Mazor ◽  
Eric Esteve ◽  
Sabine Berteina-Raboin ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Natural Product ◽  
Treatment Strategies ◽  
Cartilage Degradation ◽  
Therapeutic Strategies ◽  
Clinical Models ◽  
Osteoarthritic Joint ◽  
Dietary Components ◽  
New Treatment ◽  
Review Current

Osteoarthritis (OA) is a complex degenerative disease in which joint homeostasis is disrupted, leading to synovial inflammation, cartilage degradation, subchondral bone remodeling, and resulting in pain and joint disability. Yet, the development of new treatment strategies to restore the equilibrium of the osteoarthritic joint remains a challenge. Numerous studies have revealed that dietary components and/or natural products have anti-inflammatory, antioxidant, anti-bone-resorption, and anabolic potential and have received much attention toward the development of new therapeutic strategies for OA treatment. In the present review, we provide an overview of current and emerging natural-product-based research treatments for OA management by drawing attention to experimental, pre-clinical, and clinical models. Herein, we review current and emerging natural-product-based research treatments for OA management.

scholarly journals The Optimal First-Line Therapy ofHelicobacter pyloriInfection in Year 2012

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Chao-Hung Kuo ◽  
Fu-Chen Kuo ◽  
Huang-Ming Hu ◽  
Chung-Jung Liu ◽  
Sophie S. W. Wang ◽  
...  
Keyword(s):  
Rescue Therapy ◽  
Treatment Strategies ◽  
Sequential Therapy ◽  
Antibiotics Resistance ◽  
First Line ◽  
First Line Therapy ◽  
Metronidazole Resistance ◽  
Rescue Treatment ◽  
New Treatment ◽  
H Pylori

This paper reviews the literature about first-line therapies forH. pyloriinfection in recent years. First-line therapies are facing a challenge because of increasing treatment failure due to elevated antibiotics resistance. Several new treatment strategies that recently emerged to overcome antibiotic resistance have been surveyed. Alternative first-line therapies include bismuth-containing quadruple therapy, sequential therapy, concomitant therapy, and hybrid therapy. Levofloxacin-based therapy shows impressive efficacy but might be employed as rescue treatment due to rapidly raising resistance. Rifabutin-based therapy is also regarded as a rescue therapy. Several factors including antibiotics resistance, patient compliance, and CYP 2C19 genotypes could influence the outcome. Clinicians should use antibiotics according to local reports. It is recommended that triple therapy should not be used in areas with high clarithromycin resistance or dual clarithromycin and metronidazole resistance.

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