Statins inhibit the synthesis of mevalonate, a precursor isoprenoid molecule to geranylgeraniol that is necessary for the post-translational modification of several small GTPase oncogenes. Despite numerous preclinical studies suggesting that statins can be effective anticancer agents, prospective clinical trials have failed to demonstrate any clinical benefit in patients with cancer. We previously demonstrated that geranylgeraniol suppresses the activity of statins in cell culture studies, and that pitavastatin can cause regression of ovarian cancer xenografts in mice if the animals' diet is modified to avoid the inclusion of geranylgeraniol. Dietary sources of geranylgeraniol may consequently limit the activity of statins in cancer clinical trials. The present study tested several foods to identify those that affected the cytotoxic activity of pitavastatin towards ovarian cancer cells. Solvent extracts of several foods were tested for their ability to suppress the effects of pitavastatin in cell growth assays. The results revealed that pitavastatin induced cell death in ovarian cancer cells (IC 50 =5.2 µM) and this was blocked by geranylgeraniol whereas other products of the mevalonate pathway (coenzyme Q, dolichol or cholesterol) had no effect on the activity of pitavastatin in cell growth assays. Solvent extracts from several foods, especially oils (apart from rapeseed), also blocked the cytotoxic activity of pitavastatin. Several extracts from a range of fruit, vegetables and carbohydrate-rich foods also did not block the activity of pitavastatin. However, extracts from beans, lettuce, oats, eggs and various nuts reduced the activity of pitavastatin. These data identified foods that patients could eat to potentially improve the outcome of clinical trials of pitavastatin in cancer.

Context Many cancer patients who initially respond to chemotherapy eventually develop chemoresistance, and to address this, we previously conducted a RNAi screen to identify genes contributing to resistance. One of the hits from the screen was branched-chain α-keto acid dehydrogenase kinase (BCKDK). BCKDK controls the metabolism of branched-chain amino acids (BCAAs) through phosphorylation and inactivation of the branched-chain α-keto acid dehydrogenase complex (BCKDH), thereby inhibiting catabolism of BCAAs. Methods We measured the impact on paclitaxel sensitivity of inhibiting BCKDK in ovarian and breast cancer cell lines. Results Inhibition of BCKDK using siRNA or two chemical inhibitors (BCKDKi) was synergistic with paclitaxel in both breast and ovarian cancer cells. BCKDKi reduced levels of BCAA and the addition of exogenous BCAA suppressed this synergy. BCKDKi inactivated the mTORC1-Aurora pathway, allowing cells to overcame M-phase arrest induced by paclitaxel. In some cases, cells almost completed cytokinesis, then reverted to a single cell, resulting in multinucleate cells. Conclusion BCKDK is an attractive target to augment the sensitivity of cancer cells to paclitaxel.

Electrolyte disturbances are common in ill patients. Several conditions in the intensive care unit (ICU) might be responsible for developing electrolyte disorders, and medications may also contribute to these disturbances. The current study aimed to determine the frequency of electrolyte disturbances and assess the pattern of electrolyte imbalance in hospitalized patients, determining the possible effects of these electrolyte disorders. This cross-sectional study included patients admitted to the intensive care unit, respiratory care unit (RCU), and coronary care unit (CCU) at the Al-Sadar teaching hospital, Najaf, Iraq, from November 2020 to April 2021. The study collected data from two hundred patients regarding demographics, categories of ICUs at admission, comorbidities, and laboratory values at admission. Also, electrolyte levels at ICU admission and during hospitalization were collected from the medical database record. In addition, the patient's age, sex, fasting blood sugar (FBS), body mass index (BMI), B.urea, and creatinine were matched. Na+, K+, ionized Ca++, and Cl serum levels were significantly different during hospitalization. Comorbidities with predominant hypokalemia were found in 80.5%, hypochloremia in 73%, hypocalcaemia in 72%, and hyponatremia in 56.7% of hospitalized patients. Studying the effect of co-morbidities indicated a higher percentage (44%) of admitted patients with ischemic heart diseases, 38 (19%) with digestive diseases, 21 (10.5%) with orthopedic surgery in an emergency, 14 (7%) with pneumonia and lung diseases, 12 (6%) with diabetics, 18 (9%) with sepsis, and 9(4.5%) with seizure. Hospitalized patients may be at higher risk of developing combined electrolytes disorder associated with decreased serum levels of K+, Na+, Ca++, and Cl-. Thus, doctors and clinicians are recommended to observe electrolyte changes and correct them as they seem to negatively impact the outcome and prognosis.

Estrogen hormone is one of the steroid hormones has a critical role in breast cancer etiology. It has been implicated in proliferation and differentiation of cells through its action promoting binding of its receptor to DNA, changing transcriptional expression of target genes. In addition to the classical DNA binding mechanism, estrogen can also regulate gene expression through a nongenomic mechanism associated with activation a variety of signal transduction pathways (e.g. PI3`K/AKT, ERK/MAPK, PLC/PKCs , p38/MAPK). Dysregulation of the balance between pro-apoptotic and anti-apoptotic members of the Bcl-2 family, would result in apoptosis inhibition and tumorigenesis. Also, poor responses towards hormonal therapy, radiotherapy, and chemotherapy and treatment resistance are likely caused by dysregulation of apoptosis. Importantly, E2 has been shown to prevent apoptosis, first through its action in activation of anti-apoptotic proteins like Bcl-xl and Bcl-2 in breast cells like MCF-7, T47D and ZR-75-1 or due to its metabolites independently of ER. Estrogen metabolism includes several very important pathways that can possibly induce de novo DNA mutation. These pathways include:2, &4-hydroxylation, 16 α hydroxylation and 4 hydroxyestradiol-quinone-adenine/guanine adduct depurination, which subsequently participate in DNA damage that can lead to breast cancer. Endocrine resistance is considered one of the most permanent problems that can reduce the benefits of breast cancer treatment. Alteration of microRNAs expression, polymorphisms occuring in tamoxifen metabolism, and using reduntant alternative signaling pathways, resulting in poor treatment responses of breast cancer patients and induction of endocrine resistance.Thus, most proposed therapeutic strategies will be based on a combination of drugs targeting various pathways alongside endocrine therapy that may improve the outcomes of endocrine responses in resistant breast cancer cells.