Targeted and systemic insights into the crosstalk between DNA-dependent protein kinase catalytic subunit and receptors of estrogen, progesterone and epidermal growth factor in the context of cancer.

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has emerged as a regulator of carcinogenesis. Increased expression of DNA-PKcs correlates with metastatic cancers. Here we review recently reported crosstalk of DNA-PKcs with estrogen (ER), progesterone (PR) and epidermal growth factor (EGFR) receptors. The reports show an extensive network of functional and direct interactions. Targeted studies focused on specific molecular mechanisms, and a systems biology network analysis shows unbiasedly engagement of various cellular functions. Feedforward regulation between expression and activities of DNA-PKcs and ER, DNA-PKcs-dependent phosphorylation of PR and an impact on PR-dependent transcription, and DNA-PKcs-promoted EGFR-dependent aggressiveness and metastases are examples of the results of targeted studies. Systems biology approach extracted many more genes and proteins engaged by DNA-PKcs in interaction with ER, PR, and EGFR. Examples are such regulators and predictors of breast tumorigenesis as BRCA1, TP53, and 18 genes of the MammaPrint signature. Reviewed here data suggest that the diagnostic value of DNA-PKcs in the context of ER, PR and EGFR signaling is defined by a network signature rather than by single markers. This review summarizes mechanisms of DNA-PKcs interaction with ER, PR, and EGFR, highlights tumor suppressors and oncogenes engaged by DNA-PKcs, and emphasizes the importance of diagnostic network-based signatures.

Endogenous Purulent Pericarditis Due to Klebsiella aerogenes in a Patient With Traumatic Chest Injury: A Case Report.

Purulent pericarditis is a rare but serious medical condition caused by an infection that spreads to the pericardial space surrounding the heart. Gram-positive organisms are the most common pathogens associated with purulent pericarditis. However, there has been a shift in recent years toward gram-negative bacteria. Klebsiella aerogenes is a rare pathogen that has never been linked to purulent pericarditis. In this report, we describe the case of a 40-year-old male patient with chronic bronchiectasis who, two months after suffering an injury, developed purulent pericarditis due to an uncommon organism, K. aerogenes. During his stay in the hospital, the patient developed several infections caused by K. aerogenes. These included bacteremia and ventilator-associated pneumonia (VAP). Beta-lactamase-inducible K. aerogenes was grown in pericardial fluid culture following an emergency pericardiocentesis. The organism was resistant to carbapenems in a sputum culture, even though it was sensitive to meropenem in a blood culture. The patient had hypotension, requiring inotropes, and continued persistent bacteremia due to K. aerogenes. The patient had a heart attack with no pulse or electrical activity and died despite getting the best care possible. In light of this example, it is crucial to think about K. aerogenes and other rare organisms as possible pathogens in purulent pericarditis, especially in people who do not normally have known risk factors for this condition. Multidrug resistance patterns can make treatment more complicated, and aggressive care may be necessary in critically ill patients with chronic bacteremia.

The characteristics of CALR mutations in myeloproliferative neoplasms: a clinical experience from a tertiary care center in Qatar and a literature review.

BACKGROUND: Myeloproliferative neoplasms (MPNs) are hematological disorders characterized by abnormal production of myeloid cells due to genetic mutations. Since 2013, researchers have identified somatic mutations in the Calreticulin (CALR) gene, primarily insertions or deletions, in two Philadelphia chromosome-negative MPNs; essential thrombocytosis (ET) and primary myelofibrosis (PMF), and occasionally in chronic myelomonocytic leukemia (CMML). This study aims to identify the various types of CALR mutations and their impact on CALR-positive MPN patients' clinical manifestations and outcomes. METHODS: A single-center retrospective study was conducted. The data was collected from pre-existing records. The study was carried out on Philadelphia-negative MPN patients who were being followed up on at the NCCCR (National Center for Cancer Care and Research) to assess the clinical manifestation and outcome of disease treatment. All patients included, were followed in our center between January 1, 2008, and November 20, 2021. RESULTS: A total of 50 patients with CALR-positive MPN were reviewed with a median follow-up of three years (1-11). This cohort included 31 (62%) patients with ET, 10 (20%) patients with PMF, and 9 (18%) patients with prefibrotic myelofibrosis (pre-MF). The study involved 38 (76%) male and 12 (24%) female patients. There were 16 (32%) patients diagnosed before the age of 40, 24 (48%) patients diagnosed between the ages of 40 and 60; and 10 (20%) patients diagnosed after the age of 60. Molecular analysis showed 24 (48%) patients with CALR type 1, 21 (42%) patients with CALR type 2, and 5 (10%) patients with none Type 1, none Type 2 CALR mutations. Two patients have double mutations; 1(2%) with none Type 1, none Type 2 CALR and JAK2 mutations, and 1(2%) with CALR type 1 and MPL mutations. The thrombotic events were 3 (6%) venous thromboembolisms, 3 (6%) abdominal veins thromboses, 2 (4%) strokes, and 4 (8%) ischemic cardiac events. Only 4 (8%) patients progressed to Myelofibrosis and were carrying CALR 1 mutations, and 1 (2%) patient progressed to AML with CALR 2 mutation. CONCLUSION: The data shows a significant rise in CALR-positive MPN diagnoses in younger people, emphasizing the need for a better assessment tool to improve disease management and reduce complications.

Linezolid-Induced Pancreatitis Associated with Lactic Acidosis and Relative Hypoglycemia: A Rare Case Report.

Background: Linezolid is known to cause side effects, including nausea, diarrhea, and headaches of short duration. As extended use of linezolid is becoming more common, additional rare side effects should be considered. Case Presentation: A 68-year-old man hospitalized for osteomyelitis developed severe abdominal pain and altered mental status following five weeks of linezolid therapy. Laboratory studies showed very high lipase levels, lactic acidosis not responding to resuscitation, and relative hypoglycemia. All common causes of pancreatitis were ruled out, and a trial of linezolid withdrawal was done resulting in drastic improvement in the patient's clinical status. Conclusions: For patients on extended course of linezolid who develop abdominal pain, drug-induced pancreatitis should be considered as a side effect, and a trial of withdrawal of linezolid should be undertaken. LEARNING POINTS: Linezolid can be associated with a rare but serious triad of adverse effects of pancreatitis, hypoglycemia, and lactic acidosis.Possible risk factors include a prolonged course of linezolid, renal dysfunction, and sepsis.

Prevalence and global trends of polypharmacy in patients with chronic liver disease: A systematic review and meta-analysis.

BACKGROUND: Despite its central role in drug metabolism, the exact prevalence estimates and factors affecting global trends of polypharmacy in patients with chronic liver disease (CLD) have remained unexamined. The aim of this systematic review and meta-analysis is to estimate the prevalence of polypharmacy in patients with CLD and to comprehensively synthesize the socio-demographic factors that drive this. METHODS: We conducted a comprehensive search of relevant databases (PubMed, EMBASE, Science citation index, Cochrane Database of Systematic Reviews, and database of abstracts of reviews of effectiveness) for studies published from inception to May 30, 2022 that reported on prevalence estimates of polypharmacy in patients with CLD. The risk of bias was conducted utilizing Loney criteria. The primary outcome was the pooled prevalence of polypharmacy in patients with CLD. We subsequently performed a systematic review and weighted meta-analysis to ascertain the exact pooled prevalence of polypharmacy among patients with CLD. RESULTS: We identified approximately 50 studies from the initial literature search, of which 7 (enrolling N = 521,435 patients) with CLD met the inclusion criteria; of these, 58.7% were male, with a mean age of 53.9 (SD ±â€…12.2) years. The overall pooled prevalence of polypharmacy among patients with CLD was 31% (95% confidence interval [CI]: 4%-66%, I2 = 100%, τ2 ≤ 0.001, P ≤ .0001). We found higher pooled prevalence estimates among patients aged 50 years and older compared to their younger cohorts (42%, [CI 10-77]; I2 = 100%, P = <.001 vs 21%, [CI 0-70]; I2 = 100%, P = <.001). CONCLUSION: In an examination of multiple community- and hospital-based databases of patients with CLD, we found a pooled prevalence estimate of polypharmacy of approximately 31%. This represents a case burden within the range reported in the general population and will likely respond to mitigation strategies employed thus far for patients in that population.