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Cancer Metastasis Reviews Jun 2019Cancer development is a complex process that follows an intricate scenario with a dynamic interplay of selective and adaptive steps and an extensive cast of molecules... (Review)
Review
Cancer development is a complex process that follows an intricate scenario with a dynamic interplay of selective and adaptive steps and an extensive cast of molecules and signaling pathways. Solid tumor initially grows as an avascular bulk of cells carrying oncogenic mutations until diffusion distances from the nearest functional blood vessels limit delivery of nutrients and oxygen on the one hand and removal of metabolic waste on the other one. These restrictions result in regional hypoxia and acidosis that select for adaptable tumor cells able to promote aberrant angiogenesis, remodel metabolism, acquire invasiveness and metastatic propensity, and gain therapeutic resistance. Tumor cells are thereby endowed with capability to survive and proliferate in hostile microenvironment, communicate with stroma, enter circulation, colonize secondary sites, and generate metastases. While the role of oncogenic mutations initializing and driving these processes is well established, a key contribution of non-genomic, landscaping molecular players is still less appreciated despite they can equally serve as viable targets of anticancer therapies. Carbonic anhydrase IX (CA IX) is one of these players: it is induced by hypoxia, functionally linked to acidosis, implicated in invasiveness, and correlated with therapeutic resistance. Here, we summarize the available experimental evidence supported by accumulating preclinical and clinical data that CA IX can contribute virtually to each step of cancer progression path via its enzyme activity and/or non-catalytic mechanisms. We also propose that targeting tumor cells that express CA IX may provide therapeutic benefits in various settings and combinations with both conventional and newly developed treatments.
Topics: Acidosis; Animals; Carbonic Anhydrase IX; Cell Hypoxia; Humans; Neoplasms
PubMed: 31076951
DOI: 10.1007/s10555-019-09799-0 -
Nephrology, Dialysis, Transplantation :... Jun 2022Metabolic acidosis is a complication of chronic kidney disease (CKD) that increases risk of CKD progression, and causes bone demineralization and muscle protein... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of veverimer on serum bicarbonate and physical function in diabetic patients with chronic kidney disease and metabolic acidosis: subgroup analysis from a randomized, controlled trial.
BACKGROUND
Metabolic acidosis is a complication of chronic kidney disease (CKD) that increases risk of CKD progression, and causes bone demineralization and muscle protein catabolism. Patients with diabetes are prone to metabolic acidosis and functional limitations that decrease quality of life. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis. This post hoc subgroup analysis evaluated effects of veverimer on metabolic acidosis and physical function among patients with diabetes.
METHODS
This was a Phase 3, multicenter, randomized, blinded, placebo-controlled trial in 196 patients with CKD (estimated glomerular filtration rate 20-40 mL/min/1.73 m2) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo.
RESULTS
At Week 52, veverimer-treated patients with diabetes (n = 70), had a significantly greater increase in mean serum bicarbonate than the placebo group (n = 57) (4.4 versus 2.9 mmol/L, P < 0.05). Patient-reported limitations of physical function on the Kidney Disease and Quality of Life-Physical Function Domain (e.g. walking several blocks and climbing a flight of stairs) improved significantly in the veverimer versus placebo group (+12.5 versus +0.3, respectively, P < 0.001) as did objective physical performance on the repeated chair stand test (P < 0.0001).
CONCLUSIONS
Few interventions for patients with diabetes and CKD have successfully improved quality of life or physical functioning. Our study demonstrated that veverimer effectively treated metabolic acidosis in patients with diabetes and CKD, and significantly improved how these patients felt and functioned.
Topics: Acidosis; Bicarbonates; Diabetes Mellitus; Humans; Polymers; Quality of Life; Renal Insufficiency, Chronic; Sodium Bicarbonate
PubMed: 34240198
DOI: 10.1093/ndt/gfab209 -
Journal of Dairy Science Jun 2007Ruminal acidosis continues to be a common ruminal digestive disorder in beef cattle and can lead to marked reductions in cattle performance. Ruminal acidosis or... (Review)
Review
Ruminal acidosis continues to be a common ruminal digestive disorder in beef cattle and can lead to marked reductions in cattle performance. Ruminal acidosis or increased accumulation of organic acids in the rumen reflects imbalance between microbial production, microbial utilization, and ruminal absorption of organic acids. The severity of acidosis, generally related to the amount, frequency, and duration of grain feeding, varies from acute acidosis due to lactic acid accumulation, to subacute acidosis due to accumulation of volatile fatty acids in the rumen. Ruminal microbial changes associated with acidosis are reflective of increased availability of fermentable substrates and subsequent accumulation of organic acids. Microbial changes in the rumen associated with acute acidosis have been well documented. Microbial changes in subacute acidosis resemble those observed during adaptation to grain feeding and have not been well documented. The decrease in ciliated protozoal population is a common feature of both forms of acidosis and may be a good microbial indicator of an acidotic rumen. Other microbial factors, such as endotoxin and histamine, are thought to contribute to the systemic effects of acidosis. Various models have been developed to assess the effects of variation in feed intake, dietary roughage amount and source, dietary grain amount and processing, step-up regimen, dietary addition of fibrous byproducts, and feed additives. Models have been developed to study effects of management considerations on acidosis in cattle previously adapted to grain-based diets. Although these models have provided useful information related to ruminal acidosis, many are inadequate for detecting responses to treatment due to inadequate replication, low feed intakes by the experimental cattle that can limit the expression of acidosis, and the feeding of cattle individually, which reduces experimental variation but limits the ability of researchers to extrapolate the data to cattle performing at industry standards. Optimal model systems for assessing effects of various management and nutritional strategies on ruminal acidosis will require technologies that allow feed intake patterns, ruminal conditions, and animal health and performance to be measured simultaneously in a large number of cattle managed under conditions similar to commercial feed yards. Such data could provide valuable insight into the true extent to which acidosis affects cattle performance.
Topics: Acidosis; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Cattle; Cattle Diseases; Digestion; Fatty Acids, Volatile; Female; Fermentation; Hydrogen-Ion Concentration; Lactic Acid; Rumen
PubMed: 17517750
DOI: 10.3168/jds.2006-478 -
International Journal of Molecular... May 2015Cancer cells preferentially utilize glycolysis, instead of oxidative phosphorylation, for metabolism even in the presence of oxygen. This phenomenon of aerobic... (Review)
Review
Cancer cells preferentially utilize glycolysis, instead of oxidative phosphorylation, for metabolism even in the presence of oxygen. This phenomenon of aerobic glycolysis, referred to as the "Warburg effect", commonly exists in a variety of tumors. Recent studies further demonstrate that both genetic factors such as oncogenes and tumor suppressors and microenvironmental factors such as spatial hypoxia and acidosis can regulate the glycolytic metabolism of cancer cells. Reciprocally, altered cancer cell metabolism can modulate the tumor microenvironment which plays important roles in cancer cell somatic evolution, metastasis, and therapeutic response. In this article, we review the progression of current understandings on the molecular interaction between cancer cell metabolism and the tumor microenvironment. In addition, we discuss the implications of these interactions in cancer therapy and chemoprevention.
Topics: Acidosis; Glycolysis; Humans; Hypoxia; Neoplasms; Protein Kinase Inhibitors; Tumor Microenvironment
PubMed: 25988385
DOI: 10.3390/ijms160511055 -
BMC Nephrology Feb 2022Globally, the prevalence of chronic kidney disease (CKD) is higher in women than in men; however, women have been historically under-represented in nephrology clinical... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of veverimer on serum bicarbonate and physical function in women with chronic kidney disease and metabolic acidosis: a subgroup analysis from a randomised, controlled trial.
BACKGROUND
Globally, the prevalence of chronic kidney disease (CKD) is higher in women than in men; however, women have been historically under-represented in nephrology clinical trials. Metabolic acidosis increases risk of progressive loss of kidney function, causes bone demineralization and muscle protein catabolism, and may be more consequential in women given their lower bone and muscle mass. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis.
METHODS
This was a Phase 3, multicenter, randomised, blinded, placebo-controlled trial in 196 patients with CKD (eGFR: 20-40 mL/min/1.73 m) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo. We present the findings from a pre-specified subgroup analysis evaluating the effects of veverimer on metabolic acidosis and physical function among women (N = 77) enrolled in this trial.
RESULTS
At week 52, women treated with veverimer had a greater increase in mean (± standard error) serum bicarbonate than the placebo group (5.4 [0.5] vs. 2.2 [0.6] mmol/L; P < 0.0001). Physical Function reported by patients on the Kidney Disease and Quality of Life - Physical Function Domain, a measure that includes items related to walking, stair climbing, carrying groceries and other activities improved significantly in women randomized to veverimer vs placebo (+ 13.2 vs. -5.2, respectively, P < 0.0031). Objectively measured performance time on the repeated chair stand test also improved significantly in the veverimer group vs. placebo (P = 0.0002).
CONCLUSIONS
Veverimer was effective in treating metabolic acidosis in women with CKD, and significantly improved how they felt and functioned.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03390842 . Registered on January 4, 2018.
Topics: Acidosis; Aged; Bicarbonates; Double-Blind Method; Female; Humans; Middle Aged; Polymers; Renal Insufficiency, Chronic
PubMed: 35216581
DOI: 10.1186/s12882-022-02690-1 -
Anaesthesia Mar 2008Metabolic acidaemia (pH < 7.35 not primarily related to hypoventilation) is common amongst the critically ill and it is essential that clinicians caring for such... (Review)
Review
Metabolic acidaemia (pH < 7.35 not primarily related to hypoventilation) is common amongst the critically ill and it is essential that clinicians caring for such patients have an understanding of the common causes. The exclusive elimination routes of volatile (carbon dioxide), organic (lactic and ketone) and inorganic (phosphate and sulphate) acids mean compensation for a defect in any one is limited and requires separate provision during critical illness. We discuss the models available to diagnose metabolic acidosis including CO2/HCO3(-) and physical chemistry-derived (Stewart or Fencl-Stewart) approaches, but we propose that the base excess and anion gap, corrected for hypoalbuminaemia and iatrogenic hyperchloraemia, remain most appropriate for clinical usage. Finally we provide some tips for interpreting respiratory responses to metabolic acidosis and how to reach a working diagnosis, the consequences of which are considered in Part 2 of this review.
Topics: Acid-Base Equilibrium; Acidosis; Chemical Phenomena; Chemistry, Physical; Critical Illness; Humans; Hydrogen-Ion Concentration
PubMed: 18289237
DOI: 10.1111/j.1365-2044.2007.05370.x -
Journal of Renal Nutrition : the... May 2023Studies have shown that low or high serum bicarbonate levels (reflecting metabolic acidosis or alkalosis) are associated with increased all-cause mortality rates in...
OBJECTIVE
Studies have shown that low or high serum bicarbonate levels (reflecting metabolic acidosis or alkalosis) are associated with increased all-cause mortality rates in moderate and advanced chronic kidney disease (CKD) cases. Correction of presumed acidosis using sodium bicarbonate, targeting serum levels around 22 mmol/L, has proven to be beneficial in delaying the progression of the disease and provided mortality benefit. A similar prognostic association may exist between uncorrected metabolic acidosis in chronic liver disease. Correcting it with sodium-containing salts may require more interventions due to increased sodium/fluid load. In patients with liver failure, a naturally alkalotic state, where sodium load is a concern, the impact of this intervention is unclear.
DESIGN
This study aims to generate proof of concept through a retrospective chart review in individuals with CKD-related metabolic acidosis and liver cirrhosis.
RESULT
Our analysis revealed a statistically significant association between the need for paracentesis and bicarbonate therapy. Our study has multiple drawbacks, including a retrospective chart review and limitation of data due to single-center patients.
CONCLUSION
We extrapolate that lowering bicarbonate targets in other clinical scenarios like liver failure, pregnancy, and cardiac failure may be prudent and will lead to a lower sodium load.
Topics: Humans; Bicarbonates; Retrospective Studies; Acidosis; Chronic Disease; Renal Insufficiency, Chronic; Sodium; Liver Diseases; Kidney; Liver Failure
PubMed: 36736470
DOI: 10.1053/j.jrn.2022.12.008 -
Iranian Journal of Kidney Diseases Nov 2016The information on burden of alcohol abuse in Iran is scarce. However, the available data show that mortality rates and frequency of its use have increased in the... (Review)
Review
The information on burden of alcohol abuse in Iran is scarce. However, the available data show that mortality rates and frequency of its use have increased in the Iranian community. In particular, Iran occupies the 1st rank in the number of outbreak incidents and victims of toxic alcohols such as methanol in the Middle East. Mortality and morbidity of toxic alcohols are high if prompt diagnosis and treatment are not initiated rapidly. On-time diagnosis, proper case finding, and standard treatment have an essential role to reduce mortality and morbidity of toxic alcohols particularly blindness and other physical and psychological disabilities. This review focuses on intoxication with methanol, ethylene glycol, and isopropanol, and their treatment.
Topics: 2-Propanol; Acidosis; Alcoholism; Antidotes; Ethanol; Ethylene Glycol; Fomepizole; Humans; Iran; Methanol; Poisoning; Pyrazoles; Renal Dialysis; Sodium Bicarbonate; Solvents
PubMed: 27903992
DOI: No ID Found -
Journal of Veterinary Internal Medicine 2012Metabolic acidosis is an important abnormality in ill and injured dogs and cats.
BACKGROUND
Metabolic acidosis is an important abnormality in ill and injured dogs and cats.
OBJECTIVES
To describe the incidence, nature, and etiology of metabolic acidosis in dogs and cats that had arterial or venous blood gases measured for any reason at a university teaching hospital.
ANIMALS
Dogs and cats at the Veterinary Medical Teaching Hospital.
METHODS
Acid base parameters and electrolyte and lactate concentrations in dogs and cats measured during a 13-month period were retrospectively retrieved from a computer database. Metabolic acidosis was defined as a standardized base excess (SBE) in dogs of <-4 mmol/L and in cats <-5 mmol/L.
RESULTS
A total of 1,805 dogs and cats were included; of these, 887 (49%) were classified as having a metabolic acidosis (753 dogs and 134 cats). Primary metabolic acidosis was the most common disorder in dogs, whereas mixed acid base disorder of metabolic acidosis and respiratory acidosis was most common in cats. Hyperchloremic metabolic acidosis was more common than a high anion gap (AG) metabolic acidosis; 25% of dogs and 34% of cats could not be classified as having either a hyperchloremic metabolic acidosis or a high AG metabolic acidosis.
CONCLUSIONS AND CLINICAL IMPORTANCE
Metabolic acidosis was found commonly in this patient population and was associated with a wide variety of disease processes. Mixed acid base disorders occur frequently and routine categorization of metabolic acidosis based on the presence of high AG or hyperchloremia may be misleading in a large proportion of cases.
Topics: Acidosis; Animals; California; Cat Diseases; Cats; Dog Diseases; Dogs; Electrolytes; Hydrogen-Ion Concentration; Incidence; Lactates; Retrospective Studies
PubMed: 22860759
DOI: 10.1111/j.1939-1676.2012.00983.x -
International Journal of Molecular... May 2024Metabolic acidosis is a frequent complication of chronic kidney disease and is associated with a number of adverse outcomes, including worsening kidney function, poor... (Review)
Review
Metabolic acidosis is a frequent complication of chronic kidney disease and is associated with a number of adverse outcomes, including worsening kidney function, poor musculoskeletal health, cardiovascular events, and death. Mechanisms that prevent metabolic acidosis detrimentally promote further kidney damage, creating a cycle between acid accumulation and acid-mediated kidney injury. Disrupting this cycle through the provision of alkali, most commonly using sodium bicarbonate, is hypothesized to preserve kidney function while also mitigating adverse effects of excess acid on bone and muscle. However, results from clinical trials have been conflicting. There is also significant interest to determine whether sodium bicarbonate might improve patient outcomes for those who do not have overt metabolic acidosis. Such individuals are hypothesized to be experiencing acid-mediated organ damage despite having a normal serum bicarbonate concentration, a state often referred to as subclinical metabolic acidosis. Results from small- to medium-sized trials in individuals with subclinical metabolic acidosis have also been inconclusive. Well-powered clinical trials to determine the efficacy and safety of sodium bicarbonate are necessary to determine if this intervention improves patient outcomes.
Topics: Humans; Acidosis; Renal Insufficiency, Chronic; Sodium Bicarbonate; Animals; Treatment Outcome
PubMed: 38791238
DOI: 10.3390/ijms25105187