Cisplatin in cancer treatment.

Cisplatin is a widely used chemotherapy agent in the treatment of various forms of carcinomas and sarcomas. Its effectiveness in delaying negative outcome in cancer patients has been amply documented, and attributed primarily to its ability to crosslink DNA purine bases, thus interfering with DNA repair mechanisms in cancer cells. Ultimately, this interference causes DNA damage and leads to cell apoptosis. However, the chemotherapy use of cisplatin and cisplatin-derivatives is hampered by the occurrence of major side effects in a significant percentage of cancer patients, thus limiting considerably its prolonged utilization. Acute kidney injury, gastrointestinal disorders, hemorrhage, and decreased immune response to infections are among the most common side-effects observed. On the other hand, synergistic utilization of cisplatin with other anti-cancer agents and especially its ability to induce immunomodulation in otherwise immune-depressed patients has gained significant therapeutic traction in recent times, validating the continuing clinical utilization of this agent and its derivatives. In this review, we will examine the basic physico-chemical properties of cisplatin and related derivatives, and discuss the main molecular mechanisms of actions that results in the therapeutic benefit of this class of anti-cancer agents but also in the development of major organ complications. Lastly, we will address the more recent conceptual utilization of cisplatin-induced anti-cancer immunomodulation in synergistic therapies that can also benefit of the traditional chemotherapy advantages of this class of anti-cancer agents.

Rediscovering a valuable manual Deep Anterior Lamellar Keratoplasty (DALK) technique: Outcomes of 42 "Peeling-off" DALK.

PURPOSE: Residual bed thickness in DALK should be less than 80µm to provide optimal visual outcomes. "Peeling-off" is a manual DALK technique, which separates the anterior stroma by pulling the deep stromal lamellae following the plane of their lowest adhesion, which is usually very deep. The purpose of this study is to measure the residual bed thickness achievable with this technique. METHODS: Retrospective case series of "Peeling-off" DALK cases performed between January 2014 and January 2021 with at least 1 year of follow-up. Indications for DALK, intraoperative and postoperative complications, residual recipient bed thickness at 1 day and at 1 month after surgery, and postoperative best corrected visual acuity (BCVA) at 1 year of follow up were evaluated. RESULTS: 42 eyes (42 patients) underwent DALK performed with "Peeling-off" technique. Indications for surgery were keratoconus in 33 eyes and stromal scar in 9 eyes. "Peeling-off" technique was used as a rescue approach to perform a DALK after a failed Big-Bubble in all cases, and also failed Air-Visco-Bubble in some cases. No intraoperative and postoperative complications were recorded. Residual recipient bed thickness was deep and regular, measuring 42 microns at 1 day postoperative (range 21-65 microns) and 23 microns (range 17-26 microns) at 1 month postoperative. Mean postoperative BCVA at 1 year of follow up was 0.18 logMAR ± 0.09. CONCLUSION: "Peeling-off" DALK is a valuable manual technique that achieves a deep stromal plane with optimal visual outcomes.

Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.

Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.

The Relationship between Obesity and Pre-Eclampsia: Incidental Risks and Identification of Potential Biomarkers for Pre-Eclampsia.

Obesity has been steadily increasing over the past decade in the US and worldwide. Since 1975, the prevalence of obesity has increased by 2% per decade, unabated despite new and more stringent guidelines set by WHO, CDC, and other public health organizations. Likewise, maternal obesity has also increased worldwide over the past several years. In the United States, pre-pregnancy rates have increased proportionally across all racial groups. Obesity during pregnancy has been directly linked to obstetric complications including gestational diabetes, HTN, hematomas, pre-eclampsia, and congenital defects. In the particular case of pre-eclampsia, the incidence rate across the globe is 2.16%, but the condition accounts for 30% of maternal deaths, and a robust body of evidence underscored the relationship between obesity and pre-eclampsia. More recently, attention has focused on the identification of reliable biomarkers predictive of an elevated risk for pre-eclampsia. The aim of this literature review is to elucidate the relationship between obesity and these predictive biomarkers for future prediction and prevention of pre-eclampsia condition in women at risk.

The controversy on the beneficial effect of phytoestrogens in diabetic treatment in postmenopausal women.

Phytoestrogens have been identified as a natural, plant-based alternative to synthetically derived estrogens, to supplement the absence of endogenous estrogens in post-menopausal women, and attenuate the progression of pathologies and side-effects associated with menopause. The increased availability of these plant's derived compounds as diet or nutritional supplements makes their ingestion and consumption easier and more accessible as compared to pharmacological alternatives. Further, phytoestrogen intake has shown beneficial effects as estrogens alternatives in attenuating severe complications in diseases such as type 2 diabetes, metabolic syndrome, NAFLD, and obesity. However, in many cases phytoestrogen effectiveness remains largely circumstantial or just anecdotal as significant uncertainties on the relative abundance of different phytoestrogens in a given diet, the need for conversion to an active principle through the gut microbiome, the possibility of an effect threshold, the synergistic effect of different phytoestrogens possible due to different modality of actions still persist. The present article aims at highlighting the main issues and concerns plaguing the field as well as some of the possible causes of inconsistencies observed in the various nutritional and clinical studies attempted so far.

Why should you stay one night? Prospective observational study of enhanced recovery in elderly patients.

BACKGROUND: Delirium is a severe condition that can arise in many contexts during hospitalization. The aim of this research was to measure the incidence of postoperative delirium in patients aged 75 years or older, with the exclusion of those with preexisting neurocognitive disorders (NCD), who underwent fast-track, moderate surgery. METHODS: We conducted a prospective cohort study with patients ≥ 75 years of age who were eligible for fast-track, moderate surgery, without severe dementia, with a planned hospitalization of 24 h and with a physical status varying from very fit to vulnerable. The 4-item confusion assessment method (CAM4) was used to measure delirium. RESULTS: Of the 209 eligible patients, 195 subjects were enrolled in the study. The percentage of the population with a CAM4 score above 0 before surgery was 2.56%; after surgery, the percentage was 10.25%; and on the following day, the percentage was 4.61%. There was a statistically significant difference in the CAM4 scores between immediately after surgery and at 24 h after surgery (p = 0.0172). CONCLUSION: The data from this study support an enhanced recovery approach for elderly patients, in which after a minor surgical procedure with anaesthesia, a recovery period of one night in the hospital can contribute to normalizing the CAM4 score and reducing the incidence of delirium.

Iontophoresis Corneal Cross-linking With Enhanced Fluence and Pulsed UV-A Light: 3-Year Clinical Results.

PURPOSE: To assess 3-year safety and efficacy of enhanced-fluence pulsed-light iontophoresis cross-linking (EF I-CXL) in patients with progressive keratoconus. METHODS: This prospective interventional pilot study included 24 eyes of 20 patients, with a mean age of 23.9 years (range: 15 to 36 years). Iontophoresis with riboflavin solution was used for stromal imbibition. The treatment energy was optimized at 30% (7 J/cm2) and ultraviolet-A power set at 18 mW/cm2 × 6.28 minutes of pulsed-light on-off exposure, with a total irradiation time of 12.56 minutes. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), corneal tomography, and corneal optical coherence tomography (OCT) at baseline and 1, 3, 6, 12, 24, and 3 years postoperatively were evaluated. RESULTS: At 3 years, average UDVA decreased from 0.50 ± 0.10 to 0.36 ± 0.08 logMAR (P < .05), average maximum keratometry decreased from 52.94 ± 1.34 to 51.4 ± 1.49 diopters (D) (Delta: -1.40 ± 0.80 D; P < .05), average coma improved from 0.24 ± 0.05 to 0.12 ± 0.02 µm (P = .001), and symmetry index decreased from 4.22 ± 1.01 to 3.53 ± 0.90 D. Corneal OCT showed demarcation line detection at 285.8 ± 20.2 µm average depth in more than 80% at 1 month postoperatively. CONCLUSIONS: The 3-year results of EF I-CXL showed satisfactory I-CXL functional outcomes, increasing the visibility and the depth of demarcation line closer to epithelium-off standard CXL. [J Refract Surg. 2020;36(5):286-292.].

Erratum to "Nonpharmacologic Interventions in Prevention and Treatment of Hypertension".

[This corrects the article DOI: 10.1155/2019/6709817.].

Progesterone and cAMP synergize to inhibit responsiveness of myometrial cells to pro-inflammatory/pro-labor stimuli.

Progesterone (P4) acting through the P4 receptor (PR) isoforms, PR-A and PR-B, promotes uterine quiescence for most of pregnancy, in part, by inhibiting the response of myometrial cells to pro-labor inflammatory stimuli. This anti-inflammatory effect is inhibited by phosphorylation of PR-A at serine-344 and -345 (pSer344/345-PRA). Activation of the cyclic adenosine monophosphate (cAMP) signaling pathway also promotes uterine quiescence and myometrial relaxation. This study examined the cross-talk between P4/PR and cAMP signaling to exert anti-inflammatory actions and control pSer344/345-PRA generation in myometrial cells. In the hTERT-HMA/B immortalized human myometrial cell line P4 inhibited responsiveness to interleukin (IL)-1ß and forskolin (increases cAMP) and 8-Br-cAMP increased this effect in a concentration-dependent and synergistic manner that was mediated by activation of protein kinase A (PKA). Forskolin also inhibited the generation of pSer344/345-PRA and expression of key contraction-associated genes. Generation of pSer344/345-PRA was catalyzed by stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK). Forskolin inhibited pSer344/345-PRA generation, in part, by increasing the expression of dual specificity protein phosphatase 1 (DUSP1), a phosphatase that inactivates mitogen-activated protein kinases (MAPKs) including SAPK/JNK. P4/PR and forskolin increased DUSP1 expression. The data suggest that P4/PR promotes uterine quiescence via cross-talk and synergy with cAMP/PKA signaling in myometrial cells that involves DUSP1-mediated inhibition of SAPK/JNK activation.

Beneficial Role of Mg2+ in Prevention and Treatment of Hypertension.

Hypertension constitutes one of the most widespread pathological conditions in developed and developing countries. Currently, more than 1 billion people worldwide are affected by the condition, either as frank hypertension or as prehypertension, raising the risk for major long-term complications and life-threatening pathologies. The costs in terms of health care services, medications for the treatment of hypertension and its complications, and associated loss in productivity represent a major economic burden for the various countries. The necessity of developing treatments that are economically more sustainable and with better compliance has been increasing alongside the incidence of the pathology. Along these lines, attention has been paid to the implementation of affordable but nutritious diets that deliver appropriate levels of macro- and micronutrients as integral part of the diets themselves or as supplements. In particular, experimental and clinical evidence suggests that an appropriate intake of dietary magnesium can be beneficial in controlling blood pressure. Additional advantages of a more diffuse therapeutic and/or preventive utilization of magnesium supplements are the virtual absence of side-effects and their affordable costs. The present review will attempt to frame our knowledge of how magnesium exerts its beneficial effects on blood pressure maintenance, which may lead to the development of more effective treatments of hypertension and its main complications.

Chronic Latent Magnesium Deficiency in Obesity Decreases Positive Effects of Vitamin D on Cardiometabolic Risk Indicators.

BACKGROUND: Obesity and micronutrient deficiencies contribute to the risk of cardiometabolic diseases such are type 2 diabetes mellitus and Cardiovascular Disease (CVD). OBJECTIVE: We examined the frequency of concomitant deficit of Magnesium (Mg) and vitamin D in obese patients and evaluated the connection of these combined deficiencies with indicators of cardiometabolic risk in non-diabetic subjects. METHODS: Non-diabetic middle aged adults (n = 80; mean age 36 ± 4 years, 52% women) were recruited based on weight/adiposity parameters [i.e. Body Mass Index (BMI) and body fat percentage (FAT%)]. Cardiometabolic risk indicators [insulin resistance (Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)) and CVD risk (Framingham risk score for predicting 10-year CVD)], Mg status (i.e. total serum Mg concentration (TMg), Chronic Latent Mg Deficiency (CLMD) - 0.75-0.85 mmol/L), vitamin D status (i.e. serum concentration of 25-hydroxyvitamin D (25(OH)D), vitamin D deficiency <50 nmol/l) were assessed. RESULTS: Among obese subjects 36% presented a combination of vitamin D deficiency and CLMD. In all studied patients, 25(OH)D and TMg levels both, individually and combined, showed a negative linear correlation with HOMA-IR and CVD risk. In subjects with CLMD (TMg <0.85 mmol/L), a negative linear coefficient was found between 25(OH)D and, HOMA-IR and CVD risk, compared with subjects with normal TMg status (TMg ≥0.85 mmol/L). CONCLUSION: CLMD and vitamin D deficiency may commonly be present in obese non-diabetic subjects. Individually and combined, both deficiencies predispose non-diabetic patients to increased risk of cardiometabolic diseases. Maintaining normal Mg status may improve the beneficial effects of vitamin D on cardiometabolic risk indicators.

A garça e as boas práticas: do conhecimento individual ao aprendizado coletivo

O artigo apresenta o papel das boas práticas nas agendas públicas, mostrando que o seu potencial vai além da premiação em si. Através da identificação, reconhecimento e divulgação de experiências bem-sucedidas é possível contribuir para a formulação e aperfeiçoamento de políticas públicas. A partir de experiência específica com o Prêmio Gestão Ambiental no Bioma Amazônia, o texto revela alguns elementos que podem ser úteis na formulação de premiações, em especial aquelas voltadas para práticas desenvolvidas por governos municipais.

The Metabolic Syndrome and the Relevance of Nutrients for its Onset.

BACKGROUND: Metabolic Syndrome is a pathological condition characterized by the copresence of various dysmetabolic and pathological processes including hypertension, dyslipidemia, type 2 diabetes mellitus, obesity, and cardiovascular complications. Because these conditions manifest themselves differently in a given patient, the ensuing pathophysiological state varies from patient to patient. Consequently, the order in which signs and symptoms manifest themselves can vary, making difficult to establish cause-effect relationship, and efficacious treatment and prevention options. Furthermore, the available therapeutic options do not necessarily apply in an effective manner to all patients due to the modality of the syndrome's onset and progression, and the fact that each patient presents different clinical manifestations. RESULTS: Where do the metabolic disturbances originate? Genetic predisposition, maternal health, age, and ethnicity are possible influential factors, which put individuals at higher risk for developing metabolic defects. More recently, dietary factors and deficiency in key macro- and micro-nutrients have been indicated as key players in the onset and progression of the disease. We revised all possible patents applying to this topic. Aside from pharmacological agents used to treat specific medical conditions, no patents were observed to be registered for specific dietary macro- and micro-nutrients. CONCLUSION: The present review attempts to provide a framework to help the reader understand the causes behind the development of the metabolic syndrome and its complication.

Effect of acute and prolonged alcohol administration on Mg(2+) homeostasis in cardiac cells.

Alcoholic cardiomyopathy represents a major clinical complication in chronic alcoholics. Previous studies from our laboratory indicate that acute and chronic exposure of liver cells to ethanol results in a major loss of cellular Mg(2+) as a result of alcohol oxidation. We investigated whether exposure to ethanol induces a similar Mg(2+) loss in cardiac cells. The results indicate that chronic exposure to a 6% ethanol-containing diet depleted cardiac myocytes of >25% of their cellular Mg(2+) content. Acute ethanol exposure, instead, induced a time- and dose-dependent manner of Mg(2+) extrusion from perfused hearts and collagenase-dispersed cardiac ventricular myocytes. Pretreatment with chlormethiazole prevented ethanol-induced Mg(2+) loss to a large extent, suggesting a role of ethanol oxidation via cyP4502E1 in the process. Magnesium extrusion across the sarcolemma occurred via the amiloride-inhibited Na(+)/Mg(2+) exchanger. Taken together, our data indicate that Mg(2+) extrusion also occurs in cardiac cells exposed to ethanol as a result of alcohol metabolism by cyP4502E1. The extrusion, which is mediated by the Na(+)/Mg(2+) exchanger, only occurs at doses of ethanol ≥0.1%, and depends on ethanol-induced decline in cellular ATP. The significance of Mg(2+) extrusion for the onset of alcoholic cardiomyopathy remains to be elucidated.

Reduced cellular Mg²âº content enhances hexose 6-phosphate dehydrogenase activity and expression in HepG2 and HL-60 cells.

We have reported that Mg(2+) dynamically regulates glucose 6-phosphate entry into the endoplasmic reticulum and its hydrolysis by the glucose 6-phosphatase in liver cells. In the present study, we report that by modulating glucose 6-phosphate entry into the endoplasmic reticulum of HepG2 cells, Mg(2+) also regulates the oxidation of this substrate via hexose 6-phosphate dehydrogenase (H6PD). This regulatory effect is dynamic as glucose 6-phosphate entry and oxidation can be rapidly down-regulated by the addition of exogenous Mg(2+). In addition, HepG2 cells growing in low Mg(2+) show a marked increase in hexose 6-phosphate dehydrogenase mRNA and protein expression. Metabolically, these effects on hexose 6-phosphate dehydrogenase are important as this enzyme increases intra-reticular NADPH production, which favors fatty acid and cholesterol synthesis. Similar effects of Mg(2+) were observed in HL-60 cells. These and previously published results suggest that in an hepatocyte culture model changes in cytoplasmic Mg(2+) content regulates glucose 6-phosphate utilization via glucose 6 phosphatase and hexose-6 phosphate dehydrogenase in alternative to glycolysis and glycogen synthesis. This alternative regulation might be of relevance in the transition from fed to fasted state.

Effect of Alcohol Administration on Mg2+ Homeostasis in H9C2 Cells.

Alcoholic cardiomyopathy represents one of the main clinical complications in chronic alcoholics. This pathology contrasts the seemingly beneficial effect of small doses of alcohol on the cardiovascular system. Studies carried out in liver cells exposed acutely or chronically to varying doses of EtOH indicate that intrahepatic alcohol metabolism results in a major loss of cellular Mg2+. To investigate whether EtOH administration also induced Mg2+ extrusion in cardiac cells, H9C2 cells were exposed to varying doses of EtOH for short- or ling-term periods of time. The results indicate that H9C2 cells exposed to EtOH doses higher than 0.1% (v/v, or 15 mM) extruded Mg2+ into the extracellular medium on a time- and dose-dependent manner. Consistent with the involvement of cyP4502E1 in metabolizing EtOH, administration of chloro-methiazole (CMZ) as an inhibitor of the cytochrome prevented EtOH-induced Mg2+ loss to a large extent. EtOH-induced Mg2+ extrusion was also prevented by the administration of di-thio-treitol (DTT) and n-acetyl-cysteine (NAC), two agents that prevent the negative effects of ROS formation and free radicals generation associated with EtOH metabolism by cyP4502E1. Taken together, our data indicate that Mg2+ extrusion also occur in cardiac cells exposed to EtOH as a result of alcohol metabolism by cyP4502E1 and associated free radical formation. Interestingly, Mg2+ extrusion only occurs at doses of EtOH higher than 0.1% administered for an extended period of time. The significance of Mg2+ extrusion for the onset of alcoholic cardiomyopathy remains to be elucidated.

Role of Cellular Magnesium in Human Diseases.

Magnesium is required for many of the major organs to function and plays a crucial role in human and mammalian physiology. Magnesium is essential for the structure of bones and teeth, acts as a cofactor for more than 300 enzymes in the body, including binding to ATP for kinase reactions, and affects permeability of excitable membranes and neuromuscular transmission. Despite these essential roles, much is still unknown about magnesium physiology and homeostasis. Currently, nutritionists believe that the general population intakes insufficient magnesium daily through the diet. The effects of magnesium deficiency are, for the most part undetected, and simple, widespread assessments of magnesium intake remain unavailable for humans. Many of the patients admitted to hospitals or medical care facilities are unaware of their low magnesium levels. Moreover, because magnesium is predominantly an intracellular cation (>99%), serum magnesium levels remain a poor predictor of tissue magnesium content and availability. This review will discuss the effects of magnesium deficiency in various pathologies affecting the human population. The underlying causes for magnesium depletion in major physiological systems will be examined along with the involved signaling pathways and the main roles of magnesium homeostasis. Where possible (e.g. alcoholism), the implications of administering supplemental magnesium will be discussed. Ultimately, this review will advocate for the necessity of identifying easy and reproducible methods to assess serum and cellular magnesium levels and to identify magnesium deficiency in order to alleviate related pathological conditions.