Calcium-Sensing Receptor and Regulation of WNK Kinases in the Kidney.

The kidney is essential for systemic calcium homeostasis. Urinary calcium excretion can be viewed as an integrative renal response to endocrine and local stimuli. The extracellular calcium-sensing receptor (CaSR) elicits a number of adaptive reactions to increased plasma Ca2+ levels including the control of parathyroid hormone release and regulation of the renal calcium handling. Calcium reabsorption in the distal nephron of the kidney is functionally coupled to sodium transport. Apart from Ca2+ transport systems, CaSR signaling affects relevant distal Na+-(K+)-2Cl- cotransporters, NKCC2 and NCC. NKCC2 and NCC are activated by a kinase cascade comprising with-no-lysine [K] kinases (WNKs) and two homologous Ste20-related kinases, SPAK and OSR1. Gain-of-function mutations within the WNK-SPAK/OSR1-NKCC2/NCC pathway lead to renal salt retention and hypertension, whereas loss-of-function mutations have been associated with salt-losing tubulopathies such as Bartter or Gitelman syndromes. A Bartter-like syndrome has been also described in patients carrying gain-of-function mutations in the CaSR gene. Recent work suggested that CaSR signals via the WNK-SPAK/OSR1 cascade to modulate salt reabsorption along the distal nephron. The review presented here summarizes the latest progress in understanding of functional interactions between CaSR and WNKs and their potential impact on the renal salt handling and blood pressure.

Increased Pain Sensitivity in Obese Patients After Lung Cancer Surgery.

Background: Obesity and cancer are recognized worldwide health threats. While there is no reported causal relationship, the increasing frequency of both conditions results in a higher incidence of obese patients who are being treated for cancer. Physiological data indicate that there is a relationship between obesity and susceptibility to pain; however, currently, there are no specific pharmacological interventions. Objective: To evaluate the self-reported intensity of postoperative pain in obese and nonobese lung cancer who receive either thoracotomy or video-assisted thoracic surgery (VATS) surgical therapy. Material and Methods: In 50 obese [mean body mass index (BMI) of 34.1 ± 3.2 kg/m2] and 62 nonobese (mean BMI of 24.9 ± 3 kg/m2) lung cancer patients, the intensity of pain was estimated every 4 h using a visual analog scale (VAS, 0 indicating no pain and 10 indicating "worst imaginable pain") beginning shortly after surgery (Day O) and continuing until the day of discharge (Day D). Results: The self-reported pain was more severe in obese than in nonobese patients, both at the time of the operation [Day O (4.5 ± 1.2 vs 3.4 ± 1.1; p < 0.0001)] and at the day of discharge [Day D (3.9 ± 1.4 vs 2.6 ± 0.9, p < 0.0001)]. This finding was consistent both in the patients after thoracotomy and after video-assisted thoracic surgery (VATS, p < 0.0001). The patients with severe pain shortly after surgery (VAS score >4) had significantly higher BMI (31.8 ± 5.6 kg/m2 vs 28.8 ± 5.2 kg/m2, p < 0.01) and were hospitalized longer than the remaining patients (13.0 ± 13.6 days vs 9.5 ± 3.6 days, p < 0.05). Conclusion: The reported perception of pain in obese lung cancer patients is greater than in nonobese patients undergoing the same thoracic surgery. In obese patients, severe pain persisted longer. Pain management is an important consideration in the postoperative care of lung cancer patients, even more so with obese patients.

How Cancer Cells Resist Chemotherapy: Design and Development of Drugs Targeting Protein-Protein Interactions.

BACKGROUND: Resistance toward chemotherapeutics is one of the main obstacles on the way to effective cancer treatment. Personalization of chemotherapy could improve clinical outcome. However, despite preclinical significance, most of the potential markers have failed to reach clinical practice partially due to the inability of numerous studies to estimate the marker's impact on resistance properly. OBJECTIVE: The analysis of drug resistance mechanisms to chemotherapy in cancer cells, and the proposal of study design to identify bona fide markers. METHODS: A review of relevant papers in the field. A PubMed search with relevant keywords was used to gather the data. An example of a search request: drug resistance AND cancer AND paclitaxel. RESULTS: We have described a number of drug resistance mechanisms to various chemotherapeutics, as well as markers to underlie the phenomenon. We also proposed a model of a rational-designed study, which could be useful in determining the most promising potential biomarkers. CONCLUSION: Taking into account the most reasonable biomarkers should dramatically improve clinical outcome by choosing the suitable treatment regimens. However, determining the leading biomarkers, as well as validating of the model, is a work for further investigations.