Patterns of variation and relationships among fat, protein, and milk yield of individual dairy cattle in a Thai multibreed population.

This study systematically examines the patterns of milk yield (MY, kg), fat (FAT, %), and protein (PROT, %) in a diverse population of Thai multibreed dairy cattle, considering the tropical environment's impact on lactating cows. Using a dataset of 47,205 monthly test-day records from 4,440 first-lactation cows across 446 farms, we analyze variations and interrelationships through mathematical averaging and introduce the fat-to-protein ratio (FPR) to assess acidosis (FPR < 1.1) and ketosis (FPR > 1.5) risks during lactation. Pearson correlation analysis elucidated trait associations. The findings, aligned with established lactation norms, indicate peak production at 297 days in milk (DIM) for FAT (4.08%; SD = 0.96%), PROT (3.43%; SD = 0.47%), and 52 DIM for MY (18.09 kg; SD = 4.91 kg). Nadirs are observed at 72 DIM for FAT (3.27%; SD = 0.74%), 47 DIM for PROT (2.86%; SD = 0.36%), and 299 DIM for MY (9.05 kg; SD = 2.95 kg). FPR variations highlight acidosis (46.48%), normal (43.66%), and ketosis (9.86%), especially during early lactation (100 DIM). Significant negative correlations emerge between MY, FAT, and PROT (P < 0.05), while a positive correlation is identified between FAT and PROT (P < 0.01), with robust correlations during early lactation. This study contributes to understanding tailored nutritional strategies for dairy cows' holistic health and sustainability in tropical environments, guiding efficient production practices and mitigating health-related productivity impediments.

Effects of older age on contraction-induced intramyocellular acidosis and inorganic phosphate accumulation in vivo: A systematic review and meta-analysis.

Although it is clear that the bioenergetic basis of skeletal muscle fatigue (transient decrease in peak torque or power in response to contraction) involves intramyocellular acidosis (decreased pH) and accumulation of inorganic phosphate (Pi) in response to the increased energy demand of contractions, the effects of old age on the build-up of these metabolites has not been evaluated systematically. The purpose of this study was to compare pH and [Pi] in young (18-45 yr) and older (55+ yr) human skeletal muscle in vivo at the end of standardized contraction protocols. Full study details were prospectively registered on PROSPERO (CRD42022348972). PubMed, Web of Science, and SPORTDiscus databases were systematically searched and returned 12 articles that fit the inclusion criteria for the meta-analysis. Participant characteristics, contraction mode (isometric, dynamic), and final pH and [Pi] were extracted. A random-effects model was used to calculate the mean difference (MD) and 95% confidence interval (CI) for pH and [Pi] across age groups. A subgroup analysis for contraction mode was also performed. Young muscle acidified more than older muscle (MD = -0.12 pH; 95%CI = -0.18,-0.06; p<0.01). There was no overall difference by age in final [Pi] (MD = 2.14 mM; 95%CI = -0.29,4.57; p = 0.08), although sensitivity analysis revealed that removing one study resulted in greater [Pi] in young than older muscle (MD = 3.24 mM; 95%CI = 1.72,4.76; p<0.01). Contraction mode moderated these effects (p = 0.02) such that young muscle acidified (MD = -0.19 pH; 95%CI = -0.27,-0.11; p<0.01) and accumulated Pi (MD = 4.69 mM; 95%CI = 2.79,6.59; p<0.01) more than older muscle during isometric, but not dynamic, contractions. The smaller energetic perturbation in older muscle indicated by these analyses is consistent with its relatively greater use of oxidative energy production. During dynamic contractions, elimination of this greater reliance on oxidative energy production and consequently lower metabolite accumulations in older muscle may be important for understanding task-specific, age-related differences in fatigue.

Association between early metabolic acidosis and bronchopulmonary dysplasia/death in preterm infants born at less than 28 weeks' gestation: an observational cohort study.

BACKGROUND: Metabolic acidosis occurs frequently during the first postnatal days in extremely preterm infants and is mainly attributed to renal immaturity. Recent studies suggested a link between metabolic acidosis and the development of BPD. The aim of this study was to systematically investigate the association between severe metabolic acidosis during the first two weeks of life and bronchopulmonary dysplasia (BPD) / mortality among preterm infants born before 28 weeks' gestation. METHODS: Monocentric observational cohort study including 1748 blood gas samples of 138 extremely preterm infants born 2020-2022. Metabolic acidosis was defined as pH < 7.2 with base excess (BE) < -10 mmol/L or standard bicarbonate (SBC) < 12 mmol/L. Primary outcome was BPD and/or death at 36 weeks postmenstrual age. RESULTS: Fifty-six (40.6%) infants had BPD/death. Metabolic acidosis occurred in 50.0% of infants with BPD/death, compared to 22.0% of BPD-free survivors (p = 0.001) during the first 14 postnatal days. Minimum pH (median 7.12 vs. 7.19, p < 0.001), BE (median -10.9 vs. -9.5 mmol/L, p = 0.005), SBC (median 14.7 vs. 16.1 mmol/L, p < 0.001) were different between the two groups. After adjusting for confounders, pH (postnatal days 2-6), BE (postnatal day 3) and SBC (postnatal days 2-4) were significantly lower in infants with BPD/death. Metabolic acidosis on postnatal days 1-7 was associated with higher odds of BPD (adjusted Odds Ratio (aOR) 3.461, 95% CI 1.325-9.042) and BPD/death (aOR 3.087, 95% CI 1.225-7.778). CONCLUSIONS: Metabolic acidosis during the first week of life was associated with higher odds of BPD/death in extremely preterm infants.

Potassium Intake and Bone Health: A Narrative Review.

Potassium is a cation involved in the resting phase of membrane potential. Diets rich in fresh fruit and vegetables, whole grains, dairy products, and coffee have high potassium content. The shift from a pre-agriculture diet to today's consumption has led to reduced potassium intake. Indeed, the Western diet pattern is characterized by a high daily intake of saturated fats, sugars, sodium, proteins from red meat, and refined carbohydrates with a low potassium intake. These reductions are also mirrored by high sodium intakes and a high consumption of acid-generating food, which promote a chronic state of low-grade metabolic acidosis. The low-grade metabolic acidosis is a cause of the bone-wasting effect. Therefore, a long-standing acidotic state brings into play the bone that contributes to the buffering process through an increase in osteoclastic resorption. In consideration of this background, we carried out a review that focused on the pathophysiological mechanisms of the relationship between dietary potassium intake and bone health, underlining the detrimental effects of the Western dietary patterns characterized by low potassium consumption.

Electrolyte and Acid-Base Abnormalities After Kidney Transplantation.

Kidney transplantation is the optimal therapeutic approach for individuals with end-stage kidney disease. The Scientific Registry of Transplant Recipients has reported a continuous rise in the total number of kidney transplants performed in the United States, with 25,500 new kidney recipients in 2022 alone. Despite an improved glomerular filtration rate, the post-transplant period introduces a unique set of electrolyte abnormalities that differ from those encountered in chronic kidney disease. A variety of factors contribute to the high prevalence of hypomagnesemia, hyperkalemia, metabolic acidosis, hypercalcemia, and hypophosphatemia seen after kidney transplantation. These include the degree of allograft function, immunosuppressive medications and their diverse mechanisms of action, and metabolic changes after transplant. This article aims to provide a comprehensive review of the key aspects surrounding the most commonly encountered electrolyte and acid-base abnormalities in the post-transplant setting.

Enhanced glycolysis causes extracellular acidification and activates acid-sensing ion channel 1a in hypoxic pulmonary hypertension.

In pulmonary hypertension (PHTN), a metabolic shift to aerobic glycolysis promotes a hyperproliferative, apoptosis-resistant phenotype in pulmonary arterial smooth muscle cells (PASMCs). Enhanced glycolysis induces extracellular acidosis, which can activate proton-sensing membrane receptors and ion channels. We previously reported that activation of the proton-gated cation channel acid-sensing ion channel 1a (ASIC1a) contributes to the development of hypoxic PHTN. Therefore, we hypothesize that enhanced glycolysis and subsequent acidification of the PASMC extracellular microenvironment activate ASIC1a in hypoxic PHTN. We observed decreased oxygen consumption rate and increased extracellular acidification rate in PASMCs from chronic hypoxia (CH)-induced PHTN rats, indicating a shift to aerobic glycolysis. In addition, we found that intracellular alkalization and extracellular acidification occur in PASMCs following CH and in vitro hypoxia, which were prevented by the inhibition of glycolysis with 2-deoxy-d-glucose (2-DG). Inhibiting H+ transport/secretion through carbonic anhydrases, Na+/H+ exchanger 1, or vacuolar-type H+-ATPase did not prevent this pH shift following hypoxia. Although the putative monocarboxylate transporter 1 (MCT1) and -4 (MCT4) inhibitor syrosingopine prevented the pH shift, the specific MCT1 inhibitor AZD3965 and/or the MCT4 inhibitor VB124 were without effect, suggesting that syrosingopine targets the glycolytic pathway independent of H+ export. Furthermore, 2-DG and syrosingopine prevented enhanced ASIC1a-mediated store-operated Ca2+ entry in PASMCs from CH rats. These data suggest that multiple H+ transport mechanisms contribute to extracellular acidosis and that inhibiting glycolysis-rather than specific H+ transporters-more effectively prevents extracellular acidification and ASIC1a activation. Together, these data reveal a novel pathological relationship between glycolysis and ASIC1a activation in hypoxic PHTN.NEW & NOTEWORTHY In pulmonary hypertension, a metabolic shift to aerobic glycolysis drives a hyperproliferative, apoptosis-resistant phenotype in pulmonary arterial smooth muscle cells. We demonstrate that this enhanced glycolysis induces extracellular acidosis and activates the proton-gated ion channel, acid-sensing ion channel 1a (ASIC1a). Although multiple H+ transport/secretion mechanisms are upregulated in PHTN and likely contribute to extracellular acidosis, inhibiting glycolysis with 2-deoxy-d-glucose or syrosingopine effectively prevents extracellular acidification and ASIC1a activation, revealing a promising therapeutic avenue.

Electrolyte disorders related emergencies in children.

This article provides a comprehensive overview of electrolyte and water homeostasis in pediatric patients, focusing on some of the common serum electrolyte abnormalities encountered in clinical practice. Understanding pathophysiology, taking a detailed history, performing comprehensive physical examinations, and ordering basic laboratory investigations are essential for the timely proper management of these conditions. We will discuss the pathophysiology, clinical manifestations, diagnostic approaches, and treatment strategies for each electrolyte disorder. This article aims to enhance the clinical approach to pediatric patients with electrolyte imbalance-related emergencies, ultimately improving patient outcomes.Trial registration This manuscript does not include a clinical trial; instead, it provides an updated review of literature.

Medium acidosis drives cardiac differentiation during mesendoderm cell fate specification from human pluripotent stem cells.

Effective lineage-specific differentiation is essential to fulfilling the great potentials of human pluripotent stem cells (hPSCs). In this report, we investigate how modulation of medium pH and associated metabolic changes influence mesendoderm differentiation from hPSCs. We show that daily medium pH fluctuations are critical for the heterogeneity of cell fates in the absence of exogenous inducers. Acidic environment alone leads to cardiomyocyte generation without other signaling modulators. In contrast, medium alkalinization is inhibitory to cardiac fate even in the presence of classic cardiac inducers. We then demonstrate that acidic environment suppresses glycolysis to facilitate cardiac differentiation, while alkaline condition promotes glycolysis and diverts the differentiation toward other cell types. We further show that glycolysis inhibition or AMPK activation can rescue cardiac differentiation under alkalinization, and glycolysis inhibition alone can drive cardiac cell fate. This study highlights that pH changes remodel metabolic patterns and modulate signaling pathways to control cell fate.

A case report of Paracetamol related pyroglutamic acidosis: mind the gap in a malnourished patient.

BACKGROUND: Pyroglutamic acidosis is a rare cause of high anion gap metabolic acidosis. Most cases of paracetamol related pyroglutamic acidosis are described in malnourished women and patients with kidney/liver failure, alcohol use or severe sepsis. In this report, we describe how pyroglutamic acidosis could be related to the use of chronic therapeutic paracetamol with only malnutrition as an associated risk factor. CASE PRESENTATION: We report a case of a 67-year-old male patient developing a pyroglutamic acidosis. The patient was initially admitted to hospital for infectious osteoarthritis and developed a metabolic acidosis during his hospital stay. Analgesics included daily therapeutic doses of paracetamol. What makes our case unusual is that our malnourished male patient did not have renal or hepatic failure. The diagnosis of paracetamol related pyroglutamic acidosis was made after ruling out the main causes of metabolic acidosis. It was further confirmed by urine organic acids measurement showing a markedly elevated level of pyroglutamic aciduria. Paracetamol was discontinued allowing a prompt correction of the anion gap. CONCLUSION: This case is a representative of pyroglutamic acidosis related to chronic therapeutic paracetamol with only malnutrition as an associated risk factor. Physicians should be aware of such unusual cause of metabolic acidosis, which may be more common than expected in hospitalized patients. A high clinical suspicion is needed when urine organic acids analysis is not available.

Analysis of CTG patterns in cases with metabolic acidosis at birth with and without neonatal neurological alterations.

OBJECTIVE: To determine cardiotocographic patterns in newborns with metabolic acidosis, based on clinical signs of neurological alteration (NA) and the need for hypothermic treatment. METHODS: All term newborns with metabolic acidosis in a single center from 2016 to 2020 were included in the study. Three segments of intrapartum CTG (cardiotocography) were considered (first 30 min of active labor, 90 to 30 min before birth, and last 30 min before delivery) and a longitudinal analysis of CTG pattern was performed according to the 2015 FIGO classification. RESULTS: Three hundred and twenty-four neonates with metabolic acidosis diagnosed at birth were divided into three groups: the first group included all neonates with any clinical sign of neurological alteration, requiring hypothermia according to the recommendation of the Italian Society of Neonatology (group TNA-Treated neurological Alteration, n = 17), the second encompassed neonates with any clinical sign of neurological alteration not requiring hypothermia (group NTNA-Not Treated neurological Alteration, n = 83), and the third enclosed all neonates without any sign of clinical neurological involvement (group NoNA-No neurological Alteration, n = 224). The most frequent alterations of CTG in TNA group were late decelerations, reduced variability, bradycardia, and tachysystole. Unexpectedly, from the longitudinal analysis of the CTG, 49% of all cases with metabolic acidosis never showed a pathological CTG with normal trace at the beginning of labor followed by normal or suspicious trace in the final part of labor, the same as in TNA and NTNA groups (10 and 39%, respectively). CONCLUSIONS: CTG has limited specificity in identifying cases of acidosis at birth, even in babies who will develop NA.

Performance of five cardiotocography classification templates in labor: a cohort study.

OBJECTIVE: New guidelines for the interpretation of cardiotocography (CTG) have been presented by FIGO in 2015 (FIGO-15) and by NICE in 2017 (NICE-17) and 2022 (NICE-22) In Sweden, a previous template from 2009 (SWE-09) was replaced in 2017 (SWE-17).The objective of the study was to compare these five different templates for CTG classification regarding sensitivity, specificity, positive and negative predictive values in identifying neonates with acidemia at birth (cord artery pH <7.10). METHODS: This is a historical cohort study including singleton births in Lund November 2015-February 2016, after spontaneous or induced labor at ≥34 completed gestational weeks with validated umbilical cord acid-base samples.Characteristics of cardiotocographic traces during the last hour before birth were reviewed by two independent assessors blinded to outcome. Each template was then used to classify the CTG as normal, suspicious, or pathological. Traces for which classification differed between the two assessors for any of the templates were assessed by a third assessor. The classification by majority (at least 2 of 3) was used for analyses.Main outcome measures were the sensitivity, specificity, and positive and negative predictive values for each template to identify neonates with cord artery pH <7.10 by the classification pathological. In a secondary analysis, these outcome measures were calculated for the classifications suspicious + pathological together. RESULTS: SWE-09 and NICE-22 had significantly higher sensitivity (both 92%; 95% CI 79-98%) than NICE-17 (68%; 51-82%), FIGO-15 (42%; 26-59%) and SWE-17 (39%; 24-57%) to identify neonates with acidemia by the classification pathological. Specificity was significantly higher for SWE-17 (91%; 88-93%), FIGO-15 (90%; 88-93%) and NICE-17 (78%; 74-81%) than for NICE-22 (63%; 59-67%) and SWE-09 (62%; 58-66%). The positive predictive value of a pathological pattern ranged between 15% (SWE-09 and NICE-22) and 24% (FIGO-15), and negative predictive values between 95% (SWE-17) and 99% (SWE-09 and NICE-22). Combining suspicious and pathological patterns increased the sensitivity and decreased the specificity for all templates. CONCLUSIONS: Current CTG interpretation templates either have low sensitivity to identify fetal acidemia or low specificity. Among current guidelines, NICE 2022 had the highest sensitivity to identify neonates with acidemia and is considered the safest current classification system. Efforts to further improve diagnostic precision are warranted.

The relationship between anti-seizures medications and metabolic acidosis in craniotomy operations: is topiramate or zonisamide the cause of metabolic acidosis?

BACKGROUND/AIM: The most commonly prescribed anti-seizures medications (ASMs) for the treatment of epilepsy are currently topiramate, zonisamide, lacosamide, carbamazepine and levetiracetam. The objective of this study was to examine the correlation between preoperative, intraoperative, and postoperative metabolic acidosis and the use of ASMs prior to craniotomy operations. MATERIALS AND METHODS: This retrospective cross-sectional study evaluated patients who underwent intracranial surgery with craniotomy under general anaesthesia between May 2020 and April 2023 and used ASMs. The patients were classified into four groups based on the pharmacological mechanisms of action of the ASMs administered before intracranial surgery (Group-I, zonisamide or topiramate; Group-II, lacosamide; Group-III, carbamazepine; Group-IV, levetiracetam). Metabolic acidosis severity was defined based on base excess (BE) levels: mild (-3 to -5), moderate (-5 to -10), and severe (below - 10). The study investigated the correlation between ASMs and the severity of metabolic acidosis in preoperative, intraoperative, and postoperative blood gas measurements. RESULTS: Out of 35 patients, 24 patients underwent intracranial surgery and 11 patients underwent epilepsy surgery. There were statistically significant differences in the severity of metabolic acidosis between preoperative (p < 0.001), intraoperative (p < 0.001) and postoperative (p = 0.01) groups. The preoperative mean BE of group-I was - 4.7, which was statistically lower than that of group-III (p = 0.01) and group-IV (p < 0.001). Intraoperatively and postoperatively, group-I had a mean BE of -7.5 and - 3.2, respectively, which was statistically lower than that of groups II (p = 0.007; p = 0.04), III (p = 0.002; p = 0.03), and IV (p < 0.001; p = 0.009). There was no statistically significant difference in BE between groups II, III and IV at all three time points. Group I had the lowest BE at all three time points. Intraoperative bicarbonate was administered to all patients in group I, whereas no intraoperative bicarbonate was required in the other groups. In group I, 50% of patients required postoperative intensive care. CONCLUSION: The use of ASMs in patients undergoing surgery is important in terms of mortality and morbidity. Topirimat and zonisamide are ASMs that can cause preoperative, intraoperative and postoperative metabolic acidosis. Patients receiving topirimat or zonisamide are particularly susceptible to metabolic acidosis. Special care should be taken in the management of anaesthesia in patients receiving these drugs, and monitoring of the perioperative metabolic status is essential.

Failure to Thrive, Metabolic Acidosis, and Diarrhea in a 7-Week-Old Infant.

A 7-week-old infant presented to the emergency department with fussiness, decreased oral intake, loose stool, and respiratory distress for 2 days. The patient was born full-term with an uncomplicated birth history but had a history of slow weight gain. He was alert, but toxic-appearing at presentation, hypothermic with signs of dehydration, and with respiratory failure. He was found to have severe anion gap metabolic acidosis, hypokalemia, elevated lactate, and hyperammonemia. He responded well to initial resuscitation and was admitted to the ICU for intravenous electrolyte replacement, bowel rest, and respiratory support. A workup was pursued for failure to thrive with severe malnutrition, hyperammonemia, hyperlactatemia, anemia, vitamin D deficiency, and electrolyte abnormalities. After stabilization, he was restarted on enteral feeds and had a recurrence of loose stool and severe electrolyte abnormalities, which were refractory to enteral supplementations and required readmission to the ICU. His hospital course extended several weeks, included several subspecialty consultations, and ended with a surprising diagnosis of exclusion based on his clinical response to therapy.

Dual-enzyme inhibiting nanomedicines for enhanced cancer chemodynamic therapy by inducing intratumoral acidosis.

Deficiency of endogenous hydrogen peroxide and insufficient intracellular acidity are usually two important factors limiting chemodynamic therapy (CDT). Here we report a glutathione-responsive nanomedicine that can provide a suitable environment for CDT by inhibiting dual-enzymes simultaneously. The nanomedicine is constructed by encapsulation of a novel hydrogen sulfide donor in nanomicelle assembled by glutathione-responsive amphiphilic polymer. In response to intracellular glutathione, the nanomedicine can efficiently release the active ingredients hydrogen sulfide, carbonic anhydrase inhibitor and ferrocene. The hydrogen sulfide can increase the concentrations of hydrogen peroxide and lactic acid by inhibiting catalase and enhancing glycolysis. The carbonic anhydrase inhibitor can further induce intratumoral acidosis by inhibiting the function of carbonic anhydrase IX. Therefore, the nanomedicine can provide more efficient reaction conditions for the ferrocene-mediated Fenton reaction to generate abundant toxic hydroxyl radicals. In vivo results show that the combination of enhanced CDT and acidosis can effectively inhibit tumor growth. This design of nanomedicine provides a promising dual-enzyme inhibiting strategy to enhance antitumor efficacy of CDT.

Multimodal Model for Predicting Fetal Acidosis in Delivery Room.

In the delivery room, fetal well-being is evaluated through laboratory tests, biosignals like cardiotocography, and imaging techniques such as fetal echocardiography. We have developed a multimodal machine learning model that integrates medical records, biosignals, and imaging data to predict fetal acidosis, using a dataset from a tertiary hospital's delivery room (n=2,266). To achieve this, features were extracted from unstructured data sources, including biosignals and imaging, and then merged with structured data from medical records. The concatenated vectors formed the basis for training a classifier to predict post-delivery fetal acidosis. Our model achieved an Area Under the Receiver Operating Characteristic curve (AUROC) of 0.752 on the test dataset, demonstrating the potential of multimodal models in predicting various fetal outcomes.

Determining lactate concentrations in Korean indigenous calves and evaluating its role as a predictor for acidemia in calf diarrhea.

BACKGROUND: Calf diarrhea leads to high mortality rates and decreases in growth and productivity, causing negative effects on the livestock industry. Lactate is closely associated with metabolic acidosis in diarrheic calves. However, there have been no reports on lactate concentrations in Korean indigenous (Hanwoo) calves, especially those with diarrhea. This study aimed to determine the reference range of L-lactate and D-lactate concentrations in Hanwoo calves and to better understand the utility of lactate as predictive factors for acidemia in diarrheic calves. RESULTS: L-lactate and D-lactate concentrations were measured in healthy (n = 44) and diarrheic (n = 93) calves, and blood gas analysis was performed on diarrheic calves. The reference range in healthy calves was 0.2-2.25 mmol/L for L-lactate and 0.42-1.38 mmol/L for D-lactate. Diarrheic calves had higher concentrations of L-lactate and D-lactate than healthy calves. In diarrheic calves, L-lactate and D-lactate each had weak negative correlation with pH (r = - 0.31 and r = - 0.35). In diarrheic calves with hyper-L-lactatemia, the combined concentrations of L-lactate and D-lactate had moderate correlation with pH (r = - 0.51) and anion gap (r = 0.55). Receiver operating characteristic analysis showed D-lactate had fair predictive performance (AUC = 0.74) for severe acidemia, with an optimal cut-off value of > 1.43 mmol/L. The combined concentrations of L-lactate and D-lactate showed fair predictive performance for predicting acidemia (AUC = 0.74) and severe acidemia (AUC = 0.72), with cut-off values of > 6.05 mmol/L and > 5.95 mmol/L. CONCLUSIONS: The determined reference ranges for L-lactate and D-lactate in Hanwoo calves enable the identification of hyper-L-lactatemia and hyper-D-lactatemia. Diarrheic calves exhibited increased lactate concentrations correlated with acid-base parameters. While the concentrations of L-lactate and D-lactate have limitations as single diagnostic biomarkers for predicting acidemia or severe acidemia, their measurement remains important, and L-lactate has the advantage of being measurable at the point-of-care. Assessing lactate concentrations should be considered by clinicians, especially when used alongside other clinical indicators and diagnostic tests. This approach can improve calf diarrhea management, contributing positively to animal welfare and providing economic benefits to farms.

Regulation of cancer cell lipid metabolism and oxidative phosphorylation by microenvironmental acidosis.

The expansion of cancer cell mass in solid tumors generates a harsh environment characterized by dynamically varying levels of acidosis, hypoxia, and nutrient deprivation. Because acidosis inhibits glycolytic metabolism and hypoxia inhibits oxidative phosphorylation, cancer cells that survive and grow in these environments must rewire their metabolism and develop a high degree of metabolic plasticity to meet their energetic and biosynthetic demands. Cancer cells frequently upregulate pathways enabling the uptake and utilization of lipids and other nutrients derived from dead or recruited stromal cells, and in particular lipid uptake is strongly enhanced in acidic microenvironments. The resulting lipid accumulation and increased reliance on ß-oxidation and mitochondrial metabolism increase susceptibility to oxidative stress, lipotoxicity, and ferroptosis, in turn driving changes that may mitigate such risks. The spatially and temporally heterogeneous tumor microenvironment thus selects for invasive, metabolically flexible, and resilient cancer cells capable of exploiting their local conditions and of seeking out more favorable surroundings. This phenotype relies on the interplay between metabolism, acidosis, and oncogenic mutations, driving metabolic signaling pathways such as peroxisome proliferator-activated receptors (PPARs). Understanding the particular vulnerabilities of such cells may uncover novel therapeutic liabilities of the most aggressive cancer cells.

In Situ Live Monitoring of Extracellular Acidosis near Cancer Cells Using Digital Microfluidics with an Integrated Optical pH Sensor Film.

We demonstrate the live monitoring of extracellular acidification on digital microfluidics using a chip-integrated fluorescent pH sensor film. The metabolism of various types of live cells including cancer and healthy cells were investigated through recording the extracellular pH (pHe) change. An optical pH sensor array was integrated onto a digital microfluidic (DMF) interface with a diameter of 2 mm per pH-sensing spot. Miniaturized, label-free, and noninvasive monitoring of extracellular acidosis on DMF was realized within a pH range of 5.0-8.0 with good sensitivity and rapid response. The pH sensitive probe fluorescein-5-isothiocyanate was covalently bound to poly-2-hydroxyethyl methacrylate and immobilized on a circularly exposed indium tin oxide interface on the DMF top plate. The surface of the fabricated pH sensor spots was modified with polydopamine via self-polymerization. Direct cell attachment on the sensor surfaces enabled rapid pH detection near the cell membranes. Automatic medium exchange on cell-attached pH sensing sites was achieved though solution passive dispensing on DMF. The developed DMF platform was used to monitor the pHe decrease during MCF-7 and A549 cancer cell proliferation due to abnormal glycolysis metabolism. A rapid pH decrease at the pH sensing area in the presence of cancer cells could be detected within 2 min after fresh medium exchange, while no obvious pHe change was observed with HUVEC healthy cells. Real-time detection of cell acidification and cellular response to different metabolic conditions such as higher glucose levels or administered anticancer drugs was possible.