Discovery medicine
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Review
Promise and pitfalls of immune checkpoint inhibitors in hepato-pancreato-biliary malignancies.
A growing understanding of the immune system and its anti-tumor functions has been imperative for the comprehension of malignant processes and beneficial in the pursuit of effective cancer treatments. To defend the body, immune cells must be able to differentiate between self and foreign cells using checkpoints, allowing the immune cells to attack foreign cells. Among the different types of immune target therapies recently developed, checkpoint inhibitors have come to the forefront in cancer treatment, encouraging their study in numerous different types of cancer, including hepato-pancreato-biliary malignancies (HPB). ⋯ Two classes of checkpoint inhibitors being extensively studied are inhibitors of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) ligand and programmed cell death protein 1 and its ligand (PD-1 and PD-L1). Checkpoint inhibitors have an advantage over other types of immunotherapies, such as cell-based therapies, in that they are commercially available and can be given to patients with a range of pathologies and regardless of HLA status. Herein, we will discuss the application of immune checkpoint inhibitors to HPB malignancies as well as the limitations of these medications in these cancers.
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The combined incidence and the extended disease course of breast and prostate cancer is a major challenge for health care systems. The solution for society requires an economically viable treatment strategy to maintain individuals disease free and productive, so as to avoid the fracture of the family unit. Forty years ago, translational research using the antiestrogen tamoxifen was targeted to estrogen receptor (ER) positive micrometastatic tumor cells and established the long-term antihormone adjuvant treatment strategy used universally today. ⋯ Targeted strategies to neutralize cell survival pathways are now required to amplify and enhance sex steroid induced apoptosis. Successful blockade of the critical pathways for cell survival will introduce an inexpensive targeted therapy to maintain breast and prostate cancer patients indefinitely. Rotating anti-hormonal and sex steroid targeted cocktails could maintain patients at a microscopic tumor burden to enhance the quality of life, enhance survival, and maintain the family as a self-supporting and economically productive unit within society.
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Review Case Reports
Pathological complete response with anti-PD-1 therapy in a patient with microsatellite instable high, BRAF mutant metastatic colon cancer: a case report and review of literature.
Mismatch repair (MMR) and BRAF mutation status are established independent prognostic factors for colorectal cancer (CRC). MMR deficient tumors are considered to have better prognosis whereas BRAF mutation is associated with poor prognosis. Studies evaluating the combined effect of BRAF and MMR status suggest MSI-high and BRAF mutant patients have a poorer prognosis as compared to MSI-high and BRAF wild type patients. Emerging evidence suggests MMR status predicts the immune response to anti-PD-1 therapy in CRC patients; however little is known about combined MMR and BRAF mutation status in this context. Therefore, it is important to identify whether there is a differential response to anti-PD-1 therapy based on BRAF status in the subset of MSI-high CRC patients. ⋯ The case presented illustrates that anti-PD-1 therapy can be effectively used to treat CRC patients with MSI-high and BRAF mutant status which is usually considered a poor prognostic category as opposed to MSI-high and BRAF wild type tumors. Future studies with anti-PD-1 therapy distinguishing these molecular subgroups will improve our knowledge of whether BRAF status can add to MMR status as a predictive biomarker for anti-PD-1 therapy in patients with metastatic CRC.
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Mitochondrial disorders are now well recognized as an important cause of genetic disease. They exhibit remarkable phenotypic, biochemical, and molecular heterogeneity, and frequently involve multiple organ systems. Their complexity partly relates to the dual expression of mitochondrial proteins by both mitochondrial and nuclear genomic DNA. ⋯ Recent advancements in DNA analysis using next generation sequencing technology have provided an unprecedented expansion in the depth of knowledge concerning both molecular mechanisms and biological pathways which underpin many mitochondrial diseases. This understanding has led to the emergence of many potential targets and treatment strategies for these disorders for which there is currently no cure. This review highlights the challenges to therapy development and clinical trial design and outlines the approaches currently being investigated to treat this diverse group of disorders.
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Review
Discovery of the drivers of inflammation induced chronic low back pain: from bacteria to diabetes.
The intervertebral disc is a unique avascular organ that supports axial skeleton flexion and rotation. The high proteoglycan content of the nucleus pulposus tissue, present at the center of the disc, is pivotal for its mechanical function, distribution of compressive loads. Chronic low back pain, a prevalent and costly condition, is strongly associated with disc degeneration. ⋯ Despite the promise and novelty of this theory, there are other possible inflammatory mediators that need careful consideration. The metabolic environment associated with diabetes and atypical matrix degradation products also have the ability to activate many of the same inflammatory pathways as seen during microbial infection. It is therefore imperative that the research community must investigate the contribution of all possible drivers of inflammation to address the wide spread problem of discogenic chronic low back pain.