Genetics of Immune Dysregulation and Cancer Predisposition: Two Sides of the Same Coin

Approximately 10% of cancers have a hereditary predisposition. However, no genetic diagnosis is available in 60%-80% of familial cancers. In some of these families, immune dysregulation-mediated disease is frequent. The immune system plays a critical role in identifying and eliminating tumors; thus, dysregulation of the immune system can increase the risk of developing cancer. This review focuses on some of the genes involved in immune dysregulation the promote the risk for cancer. Genetic counseling for patients with cancer currently focuses on known genes that raise the risk of cancer. In missing hereditary familial cases, the history family of immune dysregulation should be recorded, and genes related to the immune system should be analyzed in relevant families. On the other hand, patients with immune disorders diagnosed with a pathogenic mutation in an immune regulatory gene may have an increased risk of cancer. Therefore, those patients need to be under surveillance for cancer. Gene panel and exome sequencing are currently standard methods for genetic diagnosis, providing an excellent opportunity to jointly test cancer and immune genes.     

Phosphorylation of Ribosomal Protein S6 Mediates Mammalian Target of Rapamycin Complex 1–Induced Parathyroid Cell Proliferation in Secondary Hyperparathyroidism

Secondary hyperparathyroidism is characterized by increased serum parathyroid hormone (PTH) level and parathyroid cell proliferation. However, the molecular pathways mediating the increased parathyroid cell proliferation remain undefined. Here, we found that the mTOR pathway was activated in the parathyroid of rats with secondary hyperparathyroidism induced by either chronic hypocalcemia or uremia, which was measured by increased phosphorylation of ribosomal protein S6 (rpS6), a downstream target of the mTOR pathway. This activation correlated with increased parathyroid cell proliferation. Inhibition of mTOR complex 1 by rapamycin decreased or prevented parathyroid cell proliferation in secondary hyperparathyroidism rats and in vitro in uremic rat parathyroid glands in organ culture. Knockin rpS6^p−/− mice, in which rpS6 cannot be phosphorylated because of substitution of all five phosphorylatable serines with alanines, had impaired PTH secretion after experimental uremia- or folic acid–induced AKI. Uremic rpS6^p−/− mice had no increase in parathyroid cell proliferation compared with a marked increase in uremic wild–type mice. These results underscore the importance of mTOR activation and rpS6 phosphorylation for the pathogenesis of secondary hyperparathyroidism and indicate that mTORC1 is a significant regulator of parathyroid cell proliferation through rpS6.     

Wide Local Excision as an Alternative Treatment for Periampullary Carcinoma

Wide excision of periampullary carcinoma is associated with low operative morbidity and mortality, but its effect on long-term survival, compared with that of pancreaticoduodenal resection, is controversial. Five patients with periampullary carcinoma were treated with wide local excision as a definitive procedure. There was no operative death, and four patients survived for two or more years following the operation. These patients are presented and the literature is reviewed.     

Insulin‐like growth factor‐1 in psoriatic plaques treated with PUVA and methotrexate

Background The pathogenesis of psoriasis is thought to depend on the activation of immune cells and their secreted cytokines, chemokines and growth factors like IGF‐1 which may contribute to the epidermal hyperplasia of psoriasis. Treatment of psoriasis with PUVA and methotrexate are associated with clinical improvement and decrease in epidermal hyperplasia. Objective To examine the effects of PUVA and methotrexate therapy on IGF‐1 expression in psoriatic plaques and whether this change correlates with clinical response. Methods For 24 psoriatic patients, the PASI score and levels of lesional IGF‐1 and its mRNA were determined by RT‐PCR before and after treatment with either methotrexate or PUVA. Skin biopsies from 12 healthy volunteers served as control for IGF‐1 levels in normal skin. Results Lesional skin of psoriatic patients showed a statistically significant elevation in IGF‐1 and its mRNA levels in comparison to control (P = 0.0001). Both methotrexate and PUVA treatment were associated with a significant decrease in both PASI scores and lesional IGF‐1 after 10 month treatment. Conclusion Both methotrexate and PUVA therapy for psoriasis are associated with a decrease in PASI score and IGF‐1. The IGF‐1 down‐regulation may possibly be a consequence of the decrease in cytokines and inflammatory cellular infiltrate that occur following treatment with either modalities or due to their effect on local fibroblast activity and proliferation.     

Successful delivery following myocardial ischemia during the second trimester of pregnancy

Acute myocardial infarction during pregnancy is considered to be associated with approximately 50% mortality of both mother and fetus. However, there are not enough data regarding the role of acute myocardial ischemia. We present a 36-year-old, pregnant, white female who was admitted twice at 18 and 20 weeks of gestation with acute myocardial ischemia. Cardiac catheterization revealed 70–80% stenosis of the mid left anterior descending artery (LAD) with normal antegrade flow and very good retrograde filling of the LAD from distal collaterals of the right coronary artery. Therefore, due to angiographic suggestion of protected LAD territory, we recommended medical therapy and scheduled a vaginal delivery that was successfully completed without cardiovascular complications. A stress thallium test performed 6 months later was normal, supporting our clinical judgment. In conclusion, every case of a pregnant woman with coronary insufficiency should be treated according to individual coronary anatomy and blood supply to the territory of the diseased artery, and should not be based on the old data in the literature. The decision for revascularization prior to delivery versus medical therapy, or Caesarean section versus natural delivery, should be made by a team of a cardiologist and an obstetrician.     

L-Cysteine Increases Glucose Uptake in Mouse Soleus Muscle and SH-SY5Y Cells

Previous investigation demonstrated the potential of L-cysteine (L-Cys) at high concentrations to cause hypoglycemia in mice totally deprived of insulin. For further elucidation of the glucose-lowering mechanism, glucose uptake and quantity of glucose transporters (GLUTs 3 and 4) in mouse soleus muscle and C2C12 muscle cells, as well as in human SH-SY5Y neuroblastoma cells, were investigated. A marked enhancement of glucose uptake was demonstrated, peaking at 5.0 mM L-Cys in soleus muscle (P < 0.05) and SH-SY5Y cells (P < 0.001), respectively. In contrast, glucose uptake was not affected in the C2C12 muscle cells. Kinetic analysis of the SH-SY5Y glucose uptake showed a 2.5-fold increase in maximum transport velocity compared with controls (P < 0.001). In addition, both GLUT3 and GLUT4 levels were increased following exposure to L-Cys. Our findings point to a possible hypoglycemic effect of L-Cys.