Immune checkpoint inhibitors are immune stimulatory drugs used to treat many types of cancer. These drugs are antibodies against inhibitory proteins, such as CTLA-4 and PD-1/PD-L1, that are expressed on immune cells. When bound, they allow for increased stimulation of T cells to fight tumor cells. However, immune checkpoint inhibitors have several immune-related adverse effects. Many cases have come to light recently of cardiotoxicity as a result of treatment with these drugs. Cardiotoxicity from immune checkpoint inhibitors is unique due to its rarity and high mortality rate. Patients with this toxicity may present with myocarditis, pericarditis, Takotsubo cardiomyopathy, conduction disorders, and others within just a few weeks of starting immune checkpoint inhibitors. We present here a review of the current research on immune checkpoint inhibitors, their associated cardiotoxicities, the timing of presentation of these conditions, lab tests and histology for each condition, and finally the treatment of patients with cardiotoxicity. We observe a positive skew in the onset of presentation, which is significant for the treating physician.
This case report describes the occurrence of hyperbilirubinemia as a complication of metastatic melanoma. A 72-year-old male patient was diagnosed with BRAF V600E-mutated melanoma with metastases in the liver, lymph nodes, lungs, pancreas, and stomach. Due to a lack of clinical data and specific guidelines for the treatment of mutated metastatic melanoma patients with hyperbilirubinemia, a conference of specialists debated between initiating treatment or providing supportive care. Ultimately, the patient was started on the combination therapy of dabrafenib and trametinib. This treatment resulted in a significant therapeutic response via normalization of bilirubin levels and an impressive radiological response of metastases just one month post-treatment initiation.
In the following report, we describe a case of alkaline phosphatase (ALP) elevation occurring during treatment with alectinib (Alecensa™), which was administered for anaplastic lymphoma kinase (ALK) mutated metastatic non-small cell lung cancer (mNSCLC). A 51 year-old female with widespread metastatic disease exhibited a rapid and significant response within a very short period to alectinib therapy, accompanied by a rapid increase of ALP to more than six times the upper limit of normal (grade 3) ALP, decreasing to within normal limits within 3 weeks after initiation of therapy without any dose modification.
MicroRNAs (miRNAs) are oligonucleotides involved in various processes in the cell, including gene expression regulation. MicroRNA‐106a is involved in transcription regulation of the gene coding for interleukin 10 (IL‐10), an anti‐inflammatory cytokine, and has been implicated in asthma exacerbation in mice. However, despite the well‐known sex differences in human asthma incidence, no studies have been done evaluating sex differences on the impact of miR‐106a in asthma. In this study, we hypothesized that there are sex differences in miR‐106a expression in the lungs of asthmatic mice, under normal conditions and in response to air pollution challenge. To test this hypothesis, both male and female mice were exposed to house dust mites (HDM) or phosphate‐buffered saline (control) for 5 weeks to trigger the asthma phenotype. Mice were subsequently subjected to ozone challenge (2ppm, 3 hours) to model asthma exacerbations. The asthma phenotype was confirmed by lung histology, lung function testing using a rodent ventilator, and expression of inflammatory markers by Real Time PCR. To measure miRNA expression, lungs were harvested, total RNA was extracted and converted to cDNA. We performed Real Time PCR with specific primers for miR‐106a and the small RNA U6 (normalization control) using the miRCURY LNA® RT® kit. Our results show sex differences in expression of miR‐106a upon HDM and ozone challenge. Ozone exposure increased miR‐106a expression in non‐asthmatic females and asthmatic males when compared to filtered air exposed mice (p<0.0001 and p<0.05, respectively). Male asthmatic mice had higher miR‐106a expression than non‐asthmatic male mice (p<0.0001). However, the interaction between ozone exposure and sex was significant in non‐asthmatic mice only. We conclude that the observed differences in miR‐106a expression may be a result of different lung immune cells recruited to the male and female asthmatic lung. Understanding the mechanisms behind these sex differences may lead to future development of novel treatments for asthma.Support or Funding InformationThanks to the American Physiological Society Undergraduate Summer Research Fellowship for allowing me to do this research and to the NIH grants HL133520 and HL141618 for supporting this work.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The influence of the cytochrome P450 enzymes, specifically a polymorphism of the CYP1A2 genotype, following caffeine ingestion has been shown to influence aerobic endurance; however, the effect on short‐term anaerobic performance is inconclusive. Individuals with the AA variant are responders to caffeine and those with the AC/CC variant are non‐responders.PURPOSETo examine the effects of caffeine and specific CYP1A2 genotype on anaerobic performance.METHODS10 subjects completed two 30 second Wingate Anaerobic Tests (WAnT30) (resistance = 0.075 kg•BW−1) on the Velotron that were separated by 2 to 7 days. Relative peak power (PP) and relative mean power (MP) were computed by the Velotron software. An oral bolus of caffeine (CAF), 5mg•kg−1, or placebo (PLA), maltodextrin, was given in a randomized and counterbalanced design 60 min prior to testing. Buccal epithelial cells were collected via a mouth rinse of 0.9% NaCl. Genomic extraction was obtained using QiAmp Mini spin columns and cell lysing with proteinase k, followed by PCR amplification with Fast Taq. The restriction enzyme (ApaI) was used to cut fragments. Cut and uncut samples underwent electrophoresis in 1% agarose gel and ultraviolet light photography identified genotype. The data was analyzed using a 2 (condition) × 2 (CYP) ANOVA with repeated measures (p>0.05).RESULTS5 people were AA and 5 people were AC/CC. The results revealed that CAF elicited no ergogenic effects. The main effect of condition, PLA versus CAF, showed no significant difference for PP or MP (p = 0.49). The main effect of CYP1A2, AA or AC/CC, did not reveal power differences for PP or MP (p = 0.96). Follow‐up pairwise comparisons between PLA to CAF for PP (W•kg−1) showed non‐significant D's of 1.17% in AA (10.3 and 10.42) and −0.38% for AC/CC (10.36 and 10.46, respectively). Likewise, MP resulted in non‐significant D's of 3.66% for AA (8.2 and 8.5 W•kg−1, respectively) and 2.24% for AC/CC (8.3 and 8.5, W•kg−1 respectively).CONCLUSIONCaffeine did not produce an ergogenic effect for anaerobic exercise, regardless of an individual's CYP1A2 variant. However, the larger percent increases, specifically in MP, suggest that further research should be conducted, such as increasing sample size and identifying confounding variables such as other receptor sites that may interact with caffeine.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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