Cell-Cycle Position of Single MYC-Driven Cancer Cells Dictates Their Susceptibility to a Chemotherapeutic Drug.

While many tumors initially respond to chemotherapy, regrowth of surviving cells compromises treatment efficacy in the long term. The cell-biological basis of this regrowth is not understood. Here, we characterize the response of individual, patient-derived neuroblastoma cells driven by the prominent oncogene MYC to the first-line chemotherapy, doxorubicin. Combining live-cell imaging, cell-cycle-resolved transcriptomics, and mathematical modeling, we demonstrate that a cell's treatment response is dictated by its expression level of MYC and its cell-cycle position prior to treatment. All low-MYC cells enter therapy-induced senescence. High-MYC cells, by contrast, disable their cell-cycle checkpoints, forcing renewed proliferation despite treatment-induced DNA damage. After treatment, the viability of high-MYC cells depends on their cell-cycle position during treatment: newborn cells promptly halt in G1 phase, repair DNA damage, and form re-growing clones; all other cells show protracted DNA repair and ultimately die. These findings demonstrate that fast-proliferating tumor cells may resist cytotoxic treatment non-genetically, by arresting within a favorable window of the cell cycle.

Hypochloremia in cats - prevalence and associated diseases.

OBJECTIVE: To describe the prevalence and possible causes of hypochloremia in the local hospital cat population. MATERIAL AND METHODS: Retrospective study consisting of two parts. Data were collected from the local electronic medical records database using the search terms "chloride" and "cats" (part A), and "blood gas analysis" and "cats" (part B). The medical records of the hypochloremic cats were then reviewed to determine prior treatment or infusions and to identify major underlying disease processes. Part A included an age and gender matched non-hypochloremic control group, whereas in part B acid-base status was assessed. RESULTS: Hypochloremia was detected in 367 (27%) of 1363 blood samples. The application of a correction formula to adjust for free water changes decreased the number of hypochloremic cats to 253 (19%). Only a minority had received glucocorticoids or loop diuretics and the prevalence of vomiting was 44%. Common associated disorders were gastrointestinal and respiratory diseases, as well as azotemia and diabetes mellitus. Polyuria/polydipsia, dehydration, prednisolone or furosemide pretreatment, azotemia and diabetes mellitus increased, whereas fluid therapy and the diagnosis of neoplasia decreased the prevalence of hypochloremia. An inverse correlation was found between corrected chloride and standardized base excess (rs = -0.597, p = 0.001) as well as anion gap (rs = -0.4, p = 0.026). 99% of the hypochloremic cats had derangements of acid-base balance. CONCLUSION: Hypochloremia is a common electrolyte disorder in the local cat population. The correction formula is necessary to adjust for changes in plasma osmolality. Although associated with metabolic alkalosis, most of the hypochloremic cats have a normal or decreased pH. The inverse correlation of chloride and anion gap als well as the high proportion of azotemic or diabetic animals support the concept of compensatory acidosis induced hypochloremia. CLINICAL RELEVANCE: Hypochloremia should prompt the clinician to performe blood-gas analysis. Diabetes mellitus (especially ketoacidosis) and renal disease should be included in current algorithms for the evaluation of hypochloremic patients.