Autosomal dominant distal renal tubular acidosis in two pediatric patients with mutations in the SLC4A1 gene. Can the maximum urinary pCO2 test be normal?

Primary distal renal tubular acidosis (dRTA) is a rare tubulopathy characterised by the presence of hyperchloremic metabolic acidosis. It is caused by the existence of a defect in the function of the H+ -ATPase located on the luminal side of the α-intercalated cells or the Cl - HCO3- (AE1) anion exchanger located on the basolateral side. Patients do not acidify the urine after acid overload (NH4Cl) or after stimulating H+ secretion by obtaining a high intratubular concentration of an anion such as chlorine (pH is measured) or HCO3- (urinary pCO2 is measured). We present a family with autosomal dominant dRTA produced by a heterozygous mutation in the SLC4A1 gene in which the two paediatric members showed a test of normal maximum urinary pCO2. Our hypothesis is that since the H + -ATPase is intact, at least initially, the stimulation induced by intratubular electronegativity to secrete H + could be effective, which would allow the maximum urinary pCO2 to be paradoxically normal, which could explain the onset, moderate presentation of symptoms and late diagnosis in patients with this mutation. This is the first documented case of a dominant dRTA in Mexico.

Clinical Findings and Genetic Analysis of Nine Mexican Families with Bartter Syndrome.

BACKGROUND: Bartter's syndrome (BS) is a group of salt-wasting tubulopathies characterized by hypokalemia, metabolic alkalosis, hypercalciuria, secondary hyperaldosteronism, and low or normal blood pressure. Loss-of-function variants in genes encoding for five proteins expressed in the thick ascending limb of Henle in the nephron, produced different genetic types of BS. AIM: Clinical and genetic analysis of families with Antenatal Bartter syndrome (ABS) and with Classic Bartter syndrome (CBS). METHODS: Nine patients from unrelated non-consanguineous Mexican families were studied. Massive parallel sequencing of a gene panel or whole-exome sequencing was used to identify the causative gene. RESULTS: Proband 1 was homozygous for the pathogenic variant p.Arg302Gln in the SLC12A1 gene encoding for the sodium-potassium-chloride NKCC2 cotransporter. Proband 3 was homozygous for the nonsense variant p.Cys308* in the KCNJ1 gene encoding for the ROMK potassium channel. Probands 7, 8, and 9 showed variants in the CLCKNB gene encoding the chloride channel ClC-Kb: proband 7 was compound heterozygous for the deletion of the entire gene and the missense change p.Arg438Cys; proband 8 presented a homozygous deletion of the whole gene and proband 9 was homozygous for the nonsense mutation p.Arg595*. A heterozygous variant of unknown significance was detected in the SLC12A1 gene in proband 2, and no variants were found in SLC12A1, KCNJ1, BSND, CLCNKA, CLCNKB, and MAGED2 genes in probands 4, 5, and 6. CONCLUSIONS: Genetic analysis identified loss-of-function variants in the SLC12A1, KCNJ1, and CLCNKB genes in four patients with ABS and in the CLCNKB gene in two patients with CBS.

Prospective feasibility study of a mindfulness-based program for breast cancer patients in the southeastern US.

BACKGROUND: Mindfulness interventions can improve psychological distress and quality of life (QoL) in cancer survivors. Few mindfulness programs for cancer recovery exist in Southeastern U.S. The primary objective of this study was to assess the feasibility of a modified mindfulness-based stress reduction (MBSR) program for breast cancer patients in Birmingham, Alabama. The secondary objective was to explore potential program effects on mindfulness skills and QoL. METHODS: This study was a prospective, quasi-experimental feasibility study conducted over 10 months at a university hospital. Feasibility was achieved if 80% of eligible patients screened enrolled in the study and 70% of enrolled patients attended all 8 program sessions. Effectiveness was estimated by changes in mindfulness and QoL indicators measured with validated scales administered at 3 time points and assessed with a non-parametric Friedman test. Sessions included meditation, yoga, and an attention practice called body scan. There were 3 groups of 2-5 patients. RESULTS: The sample totaled 12 patients. Forty-four percent (12/27) of eligible patients enrolled in the study, and two out of 12 enrolled patients completed 8 program sessions, resulting in 16.7% (2/12) retention. However, more than half (66.7%) of participants completed at least 7 sessions. Between baseline and 8-week follow-up, patients demonstrated statistically significant improvements in distress, general wellbeing, and fatigue-related QoL. CONCLUSIONS: Feasibility objectives were not achieved. However, a majority of participants (66.7%) completed 7 of 8 program sessions. Program effects were promising for distress, fatigue, and wellbeing. Results warrant further research on MBSR-like programs for breast cancer patients in Alabama.

Metabolic acidosis and hyperkalemia differentially regulate cation HCN3 channel in the rat nephron.

The kidney controls body fluids, electrolyte and acid-base balance. Previously, we demonstrated that hyperpolarization-activated and cyclic nucleotide-gated (HCN) cation channels participate in ammonium excretion in the rat kidney. Since acid-base balance is closely linked to potassium metabolism, in the present work we aim to determine the effect of chronic metabolic acidosis (CMA) and hyperkalemia (HK) on protein abundance and localization of HCN3 in the rat kidney. CMA increased HCN3 protein level only in the outer medulla (2.74 ± 0.31) according to immunoblot analysis. However, immunofluorescence assays showed that HCN3 augmented in cortical proximal tubules (1.45 ± 0.11) and medullary thick ascending limb of Henle's loop (4.48 ± 0.45) from the inner stripe of outer medulla. HCN3 was detected in brush border membranes (BBM) and mitochondria of the proximal tubule by immunogold electron and confocal microscopy in control conditions. Acidosis did not alter HCN3 levels in BBM and mitochondria but augmented them in lysosomes. HCN3 was also immuno-detected in mitoautophagosomes. In the distal nephron, HCN3 was expressed in principal and intercalated cells from cortical to medullary collecting ducts. CMA did not change HCN3 abundance in these nephron segments. In contrast, HK doubled HCN3 level in cortical collecting ducts and favored its basolateral localization in principal cells from the inner medullary collecting ducts. These findings further support HCN channels contribution to renal acid-base and potassium balance.

Patient perspectives on primary care and oncology care coordination in the context of multiple chronic conditions: A systematic review.

BACKGROUND: Patients' views on the optimal model for care coordination between primary care providers (PCPs) and oncologists in the context of cancer and multiple chronic conditions (MCC) are unclear. Thus, the purpose of this systematic review is to evaluate the perceptions of patients with both cancer and MCC regarding their care coordination needs. METHODS: Following PRISMA guidelines, the literature was systematically searched through PubMed, CINAHL, and PsycINFO for articles pertaining to patients' perspectives, experiences, and needs regarding care coordination between PCPs and oncologists during the cancer care continuum, in the context of patients with cancer and MCC. English-language articles were included if they met the following criteria: 1) published between 2008 and 2018; 2) peer-reviewed study; 3) patients aged 18 years or older diagnosed with any type or stage of cancer; 4) patients have one or more chronic comorbid condition; 5) inclusion of patient perceptions, experiences, or needs related to care coordination between PCPs and oncologists; and 6) ability to extract results. Data extraction was performed with a standardized form, and themes were developed through qualitative synthesis. A grounded theory approach was used to qualitatively evaluate data extracted from articles and create a framework for providers to consider when developing patient-centered care coordination strategies for these complex patients. Risk of bias within each study was assessed independently by two authors using the Mixed Methods Appraisal Tool. RESULTS: A total of 22 articles were retained, representing the perspectives of 8,114 patients with cancer and MCC. Studies were heterogeneous in the patients' respective phases of cancer care and study design. From qualitative synthesis, four themes emerged regarding patients' needs for cancer care coordination and were included as constructs to develop the Patient-centered Care Coordination among Patients with Multiple Chronic Conditions and Cancer (PCP-MC) framework. Constructs included: 1) Communication; 2) Defining provider care roles; 3) Information access; and 4) Individualized patient care. Care navigators served as a communication bridge between providers and patients. CONCLUSIONS: Findings highlight the importance that patients with both cancer and MCC place on communication with and between providers, efficient access to understandable care information, defined provider care roles, and care tailored to their individual needs and circumstances. Providers and policymakers may consider the developed PCP-MC framework when designing, implementing, and evaluating patient-centered care coordination strategies for patients with both cancer and MCC.

Influences of diet and the gut microbiome on epigenetic modulation in cancer and other diseases.

Epigenetic modulation of gene activity occurs in response to non-genetic factors such as body weight status, physical activity, dietary factors, and environmental toxins. In addition, each of these factors is thought to affect and be affected by the gut microbiome. A primary mechanism that links these various factors together in mediating control of gene expression is the production of metabolites that serve as critical cofactors and allosteric regulators of epigenetic processes. Here, we review the involvement of the gut microbiota and its interactions with dietary factors, many of which have known cellular bioactivity, focusing on particular epigenetic processes affected and the influence they have on human health and disease, particularly cancer and response to treatment. Advances in DNA sequencing have expanded the capacity for studying the microbiome. Combining this with rapidly improving techniques to measure the metabolome provides opportunities to understand complex relationships that may underlie the development and progression of cancer as well as treatment-related sequelae. Given broad reaching and fundamental biology, both at the cellular and organismal levels, we propose that interactive research programs, which utilize a wide range of mutually informative experimental model systems-each one optimally suited for answering particular questions-provide the best path forward for breaking ground on new knowledge and ultimately understanding the epigenetic significance of the gut microbiome and its response to dietary factors in cancer prevention and therapy.

Cancer-Related Fatigue, Version 2.2015.

Cancer-related fatigue is defined as a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning. It is one of the most common side effects in patients with cancer. Fatigue has been shown to be a consequence of active treatment, but it may also persist into posttreatment periods. Furthermore, difficulties in end-of-life care can be compounded by fatigue. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Related Fatigue provide guidance on screening for fatigue and recommendations for interventions based on the stage of treatment. Interventions may include education and counseling, general strategies for the management of fatigue, and specific nonpharmacologic and pharmacologic interventions. Fatigue is a frequently underreported complication in patients with cancer and, when reported, is responsible for reduced quality of life. Therefore, routine screening to identify fatigue is an important component in improving the quality of life for patients living with cancer.

Peptide sr11a from Conus spurius is a novel peptide blocker for Kv1 potassium channels.

More than a hundred conotoxins are known today and from them, only seven conopeptides have been identified to target voltage-gated potassium channels (Kv). Conotoxin sr11a belongs to the I(2)-superfamily which is characterized by four disulfide bridges and provokes muscle stiffness when injected intracranially in mice. The aim of this work was to test the biological activity of sr11a on recombinant voltage-gated Kv1 potassium channels expressed in Xenopus laevis oocytes. Peptide sr11a was purified by high-performance liquid chromatography from the venom of the vermivorous Conus spurius. We found that peptide sr11a inhibits the delayed rectifiers Kv1.2 and Kv1.6 but had not effect on the slowly inactivating Kv1.3 channel. The functional dyad composed of a basic Lys and a hydrophobic amino acid residue is a crucial structural element, regarding the binding properties and blocking activities of more than a hundred K(+) channel toxins. Peptide sr11a does not contain Lys residues and then, it lacks the functional dyad. Molecular modeling of peptide sr11a reveals the presence of exposed basic residues of Arg and suggests that Arg17 and Arg29 are important on its biological activity.

Expression and immunolocalization of ERG1 potassium channels in the rat kidney.

Potassium (K(+)) channels participate in K(+) secretion, K(+) recycling, and cell volume regulation and help to maintain the resting potential in mammalian kidneys. Previously, we identified a set of voltage-gated K(+) channels (Kv1) in the inner medullary collecting duct of the rat kidney. In the present work, we identified the voltage-gated K(+) channel ether-à-go-go-related gene (ERG) in the rat kidney. mRNAs of ERG1a and its N-terminal splice-variant ERG1b were detected. Immunoblots of the cortex and medulla revealed two molecular mass proteins of 135 and 80 kDa, consistent in size with the nonglycosylated ERG1a and ERG1b isoforms, respectively. However, bands of 155 and 95 kDa, corresponding to mature glycosylated ERG1a and ERG1b, respectively, were also observed. In our immunohistochemical experiments, we could not differentiate the ERG1 isoforms because we used an antibody against a carboxy-terminal epitope. ERG1 was differentially localized in specific nephron segments: its localization was intracellular in the proximal tubule and medullary collecting ducts and in the apical membranes in the distal convoluted and connecting tubules. ERG1 was also abundant in glomerular arterioles and renal vessels. In summary, ERG1 displays a heterogeneous distribution in the rat kidney.

Effect of yeast-derived beta-glucan in conjunction with bevacizumab for the treatment of human lung adenocarcinoma in subcutaneous and orthotopic xenograft models.

Human lung cancer is the leading cause of cancer death worldwide. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), in combination with chemotherapy showed significant therapeutic efficacy in human lung cancer patients. However, increased adverse effects limit its clinical utilization. Previous studies demonstrated that polysaccharide beta-glucan significantly augments antitumor monoclonal antibody-mediated efficacy via stimulation of the innate effector neutrophil complement receptor 3. Here, we explored combined beta-glucan with bevacizumab therapy for human lung cancer using murine xenograft models. To that end, human lung adenocarcinomas were screened for membrane-bound VEGF expression. Both subcutaneous and orthotopic lung cancer xenograft models were used to evaluate the combination therapy. We found that PC14PE6 adenocarcinoma cells express membrane-bound VEGF both in vitro and in vivo. Bevacizumab bound to surface VEGF on PC14PE6 cells and activated complement. In the subcutaneous PC14PE6 tumor model, beta-glucan plus bevacizumab showed augmented efficacy in terms of tumor progression and long-term survival compared with bevacizumab-treated alone. These effects were accompanied with massive complement deposition and neutrophil infiltration within tumors. However, this effect was not observed in surface-bound VEGF-negative human lung tumors. Therapeutic efficacy of beta-glucan with bevacizumab was further demonstrated in an orthotopic lung cancer model. Thus, our data suggest that beta-glucan enhances bevacizumab-mediated efficacy and may provide therapeutic benefits for lung cancers with membrane-bound VEGF expression.

Yeast-derived beta-glucan augments the therapeutic efficacy mediated by anti-vascular endothelial growth factor monoclonal antibody in human carcinoma xenograft models.

PURPOSE: Bevacizumab is a recombinant IgG1 humanized monoclonal antibody against vascular endothelial growth factor (VEGF). Its proposed mechanism of action is independent of immune effector functions. Many human carcinomas not only secrete VEGF but also express membrane-bound VEGF. In addition, VEGF receptors are expressed on tumor cells. It is hypothesized that bevacizumab could bind membrane-bound VEGF or VEGF-VEGF receptor complexes on tumors, thereby initiating potential immunologic consequences. We previously showed that yeast-derived beta-glucan functions with antitumor antibodies that activate complement to recruit complement receptor 3-expressing leukocytes capable of mediating complement receptor 3-dependent cellular cytotoxicity of tumors opsonized with iC3b. In the current study, the therapeutic efficacy mediated by combining bevacizumab with yeast-derived beta-glucan was studied in human carcinoma xenograft models. EXPERIMENTAL DESIGN: Human tumor cell lines were screened for membrane-bound VEGF expression both in vitro and in vivo. Complement activation mediated by bevacizumab was examined. Tumor cell lines positive or negative for membrane-bound VEGF expression were implanted in severe combined immunodeficient mice to establish xenograft models. Tumor-bearing mice were treated with different regimens. Tumor regression and long-term survival were recorded. RESULTS: Human ovarian carcinoma SKOV-3 cells expressed membrane-bound VEGF both in vitro and in vivo. Bevacizumab was bound to membrane-bound VEGF, activated complement, and synergized with beta-glucan to elicit cellular cytotoxicity in vitro. In vivo study showed that beta-glucan could significantly augment the therapeutic efficacy mediated by bevacizumab. CONCLUSIONS: Yeast-derived beta-glucan can synergize with anti-VEGF monoclonal antibody bevacizumab for the treatment of cancer with membrane-bound VEGF expression.

A phase I study of thalidomide, capecitabine and temozolomide in advanced cancer.

AIM: To develop a novel oral antiangiogenic and immunomodulatory chemotherapy regimen against advanced cancers. METHODS: Patients were enrolled in cohorts of three or six in a standard phase I design. Thalidomide 100 mg was kept stable for all cohorts. If well tolerated after one week, capecitabine and temozolomide (TCT) fixed-dose were given daily without rest and escalated one at a time until dose limiting toxicity (DLT) occurred. If no DLT occurred within 28 days (1 cycle), the subsequent group was enrolled into the next dose level. RESULTS: Twenty-three adult patients with objective documentation of progressive metastatic cancer after a median of two therapies (range 0-4) received TCT in this study. Based on DLT within the first 28 days, the MTD of daily TCT therapy was thalidomide 100 mg, capecitabine 2000 mg and temozolomide 100 mg. With long-term treatment, majority of the patients required dose interruptions due to fatigue, hand-foot syndrome, and neutropenia. A dose level consisting of daily thalidomide and three-weeks-on one-week-off capecitabine and temozolomide was implemented and administered to six patients without DLT. Out of 23 subjects, four (17%) achieved a partial response (renal, gastric, prostate 2), and four patients (17%) had stable disease (renal, colon, pancreas 2), adding to a clinical benefit of 34%. CONCLUSIONS: TCT is an effective palliative oral chemo-immunotherapy for patients with advanced cancer. The recommended dose for phase II trial is thalidomide 100 mg daily without a break, capecitabine 2000 mg and temozolomide 100 mg daily three-weeks on and one-week off.