Factores pronósticos de eficacia y seguridad que afectan a la supervivencia global de los pacientes con cáncer de próstata metastásico sometidos a tratamiento con [177Lu]Lu-PSMA-617: estudio en un único centro / Efficacy, safety and prognostic factors affecting overall survival among metastatic prostate cancer patients undergoing treatment with 177Lu-PSMA-617: A single center study

Objetivo: Determinación de los factores pronósticos de eficacia y seguridad que afectan a la supervivencia global (SG) entre los pacientes con cáncer de próstata metastásico que han sido sometidos a terapia con radioligandos (RLT) con PSMA. Método: Estudio retrospectivo, desde noviembre del año 2016 a diciembre del año 2019, se incluyeron 43 pacientes con cáncer de próstata metastásico, con una media de edad de 71 años (entre 51 y 88 años), los cuales habían recibido varias líneas de tratamiento previas (el 90,7%, primera línea de la terapia de privación de andrógenos [ADT], el 53,5% en la segunda línea ADT y el 58,1% en docetaxel). Los ciclos del tratamiento con RLT se repetían cada 8 semanas (entre 6 y 12 semanas). Con el fin de evaluar la respuesta bioquímica tras cada ciclo, los niveles del antígeno específico prostático (PSA) se medían y se analizaban de acuerdo con los criterios del Equipo de Trabajo del Cáncer de Próstata 3 (PCWG3). Los eventos adversos posibles tras la terapia fueron retrospectivamente clasificados de acuerdo con los Criterios de Toxicidad Común para Eventos Adversos (CTCAE) v.5. Para identificar los factores asociados con SG se utilizaron las curvas de Kaplan-Meier, y los análisis de regresión de riesgos proporcionales de Cox. Resultados: Fueron administrados un total de 112 ciclos de RLT con una mediana de 3 ciclos (entre 1 y 6) y una actividad administrada mediana por ciclo de 6,29GBq (entre 4,45 y 7,7). Se observó una disminución en la PSA en el 65,1% de los pacientes, la mayor disminución en la PSA, de ≥50 y ≥90%, se obtuvo en los 39,5 y 23,3% de los pacientes, respectivamente. El mayor grado de anemia (grado III) y trombocitopenia ocurrió en el 11,6 y 7% de los pacientes, respectivamente. La mediana de SG y mediana de supervivencia libre de progresión fueron 52 y 20 semanas, respectivamente. En los análisis univariantes, la hemoglobina basal (AU)

Background: Determining the efficacy, safety, and prognostic factors affecting overall survival (OS) among metastatic prostate cancer patients undergoing PSMA-targeted radioligand therapy (PRLT). Method: In this retrospective study, from November 2016 and December 2019, 43 heavily pretreated (90.7% on 1st line androgen deprivation therapy (ADT), 53.5% on 2nd line ADT, 58.1% on docetaxel) metastatic prostate cancer patients with median age of 71 years (range: 51-88 years) were enrolled. Treatment cycles were repeated every 8 weeks (range: 6-12 weeks). To evaluate the biochemical response after each cycle, prostate specific antigen (PSA) levels were measured and analyzed according to the Prostate Cancer Working Group 3 (PCWG3) criteria cutoffs. Possible adverse events after therapy were retrospectively classified according to the Common Toxicity Criteria for Adverse Events (CTCAE) v.5.0. Kaplan-Meier and multivariable Cox proportional hazard regression analyses were used to identify factors associated with OS. Results: A total of 112 cycles of PRLT with a median of 3 cycles (range: 1-6) and median administered activity per cycle of 6.29 GBq (range: 4.45-7.7 GBq) were used. PSA decline was observed in 65.1% of patients, and best PSA decline of ≥50% and ≥90% were achieved in 39.5% and 23.3% of patients, respectively. Major (grade III) anemia and thrombocytopenia occurred in 11.6% and 7% of patients, respectively. Median OS and median PSA progression-free survival were 52 and 20 weeks, respectively. In univariate analysis, baseline hemoglobin <11.2 g/dL, baseline platelets count ≥327,000/μL, PSA decline <20.94% after first cycle of therapy, Eastern Cooperative Oncology Group (ECOG) >2, baseline PSA ≥115 ng/ml, cumulative dose of 177Lu-PSMA <12.95 GBq, initial alkaline phosphatase ≥196.5 U/L, initial lactate dehydrogenase ≥380 U/L and superscan pattern in bone scintigraphy were associated with worse OS (AU)

Short communication: Influence of an aqueous myrrh suspension on yogurt culture bacteria over yogurt shelf life.

Myrrh is an essential oil and natural flavoring approved by the US Food and Drug Administration, and it has antibacterial and antifungal activity against pathogens. Our objective was to determine the effect of an aqueous myrrh suspension on Streptococcus thermophilus and Lactobacillus delbrueckii ssp. bulgaricus counts in peptone solution and yogurt, as well as pH and titratable acidity of yogurt during 5 wk of storage at 1 to 4°C. The myrrh suspension (10% wt/vol) was prepared and incorporated into a pure culture dilution in peptone and into yogurt mix at a 1% (vol/vol) level. A control with no myrrh was also prepared, and 3 replications were conducted. Streptococcus thermophilus were enumerated using Streptococcus thermophilus agar with aerobic incubation at 37°C for 24 h, and Lactobacillus delbrueckii ssp. bulgaricus were enumerated using de Man, Rogosa, and Sharpe agar adjusted to pH 5.2, with anaerobic incubation at 43°C for 72 h. During the 8-h period after inoculation, S. thermophilus and L. delbrueckii ssp. bulgaricus counts in peptone solution at 37°C and 43°C, respectively, were not significantly different in the presence or absence of the aqueous myrrh suspension. Counts of S. thermophilus in yogurt containing myrrh (mean ± SD; 4.96 ± 0.58 log cfu/mL) were not significantly different from those in the control yogurt (4.87 ± 0.39 log cfu/mL). The log counts for L. delbrueckii ssp. bulgaricus in yogurt containing myrrh (5.04 ± 1.44 log cfu/mL) and those of the control (5.52 ± 1.81 log cfu/mL) did not differ, and the counts remained within 1 log of each other throughout 5 wk of storage. The pH of the yogurts containing the aqueous myrrh suspension was not significantly different from that of the control yogurts, and their pH values were within 0.1 pH unit of each other in any given week. Titratable acidity values remained steady around 1.1 to 1.2% lactic acid for both yogurt types throughout the storage period, with no significant differences between them. Yogurt culture bacteria can survive in the presence of a myrrh suspension in yogurt with no significant change in pH or titratable acidity. Therefore, it may be beneficial to add an aqueous myrrh suspension to yogurt.

Myo-inositol oxygenase accentuates renal tubular injury initiated by endoplasmic reticulum stress.

Besides oxidant stress, endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of various metabolic disorders affecting the kidney. These two forms of stresses are not mutually exclusive to each other and may operate by a feedback loop in worsening the cellular injury. To attest to this contention, studies were performed to assess whether in such a setting, there is worsening of tubulointerstitial injury. We employed tunicamycin as a model of ER stress and used tubular cells and mice overexpressing myo-inositol oxygenase (MIOX), an enzyme involved in glycolytic events with excessive generation of ROS. Concomitant treatment of tunicamycin and transfection of cells with MIOX-pcDNA led to a marked generation of ROS, which was reduced by MIOX-siRNA. Likewise, an accentuated expression of ER stress sensors, GRP78, XBP1, and CHOP, was observed, which was reduced with MIOX-siRNA. These sensors were markedly elevated in MIOX-TG mice compared with WT treated with tunicamycin. This was accompanied with marked deterioration of tubular morphology, along with impairment of renal functions. Interestingly, minimal damage and elevation of ER stressors was observed in MIOX-KO mice. Downstream events that were more adversely affected in MIOX-TG mice included accentuated expression of proapoptogenic proteins, proinflammatory cytokines, and extracellular matrix constituents, although expression of these molecules was unaffected in MIOX-KO mice. Also, their tunicamycin-induced accentuated expression in tubular cells was notably reduced with MIOX-siRNA. These studies suggest that the biology of MIOX-induced oxidant stress and tunicamycin-induced ER stress are interlinked, and both of the events may feed into each other to amplify the tubulointerstitial injury.

Contribution of myo-inositol oxygenase in AGE:RAGE-mediated renal tubulointerstitial injury in the context of diabetic nephropathy.

Advanced glycation end products (AGEs) play a role in pathogenesis of diabetic nephropathy (DN). Myo-inositol oxygenase (MIOX) has been implicated in tubulointerstitial injury in the context of DN. We investigated the effect of AGEs on MIOX expression and delineated mechanisms that lead to tubulointerstitial injury. The status of MIOX, RAGE, and relevant cellular signaling pathways activated following AGE:RAGE interaction was examined in tubular cells and kidneys of AGE-BSA-treated mice. A solid-phase assay revealed an enhanced binding of RAGE with AGE-BSA, AGE-laminin, and AGE-collagen IV. The cells treated with AGE-BSA had increased MIOX activity/expression and promoter activity. This was associated with activation of various signaling kinases of phosphatidylinositol 3-kinase (PI3K)-AKT pathway and increased expression of NF-κB, transforming growth factor (TGF)-ß, and fibronectin, which was negated with the treatment of MIOX/RAGE- small interfering (si) RNA. Concomitant with MIOX upregulation, there was an increased generation of reactive oxygen species (ROS), which could be abrogated with MIOX/RAGE- siRNA treatment. The kidneys of mice treated with AGE-BSA had significantly high urinary A/C ratio, upregulation of MIOX, RAGE and NF-κB, along with influx of monocytes into the tubulointerstitium, increased the expression of MCP-1, IL-6, and fibronectin and increased the generation of ROS. Such perturbations were abrogated with the concomitant treatment of inhibitors MIOX or RAGE (d-glucarate and FPS-ZM1). These studies support a role of AGE:RAGE interaction in the activation of PI3K-AKT pathway and upregulation of MIOX, with excessive generation of ROS, increased expression of NF-κB, inflammatory cytokines, TGF-ß, and fibronectin. Collectively, these observations highlight the relevance of the biology of MIOX in the contribution toward tubulointerstitial injury in DN.

Short communication: The effects of frozen storage on the survival of probiotic microorganisms found in traditionally and commercially manufactured kefir.

Kefir is a fermented milk traditionally made from a unique starter culture, which consists of numerous bacteria and yeast species bound together in an exopolysaccharide matrix produced by certain lactic acid bacteria. Many health benefits are associated with traditionally produced kefir; however, bulging and leaking packaging, caused by secondary yeast fermentation during storage, has limited large-scale manufacture. Commercial kefir products have been designed to reduce these effects by using a pure starter culture consisting of a mixture of bacteria and yeast species that give a flavor similar to traditional kefir, but some health benefits may be lost in commercial production due to reduced microbial diversity and lack of beneficial exopolysaccharides. In this study, traditional and commercial kefir was frozen to study the effects of frozen storage on the viability of probiotic bacteria over time. Traditional kefir was prepared by inoculating 1L of pasteurized whole goat milk with approximately 30g of kefir grains. Commercial kefir was prepared by inoculating 1L of full-fat, pasteurized goat milk with a commercial kefir starter. The milk was allowed to ferment at room temperature (24-28°C) until pH 4.6 was reached. Samples were frozen (-8 to -14°C) immediately following the completion of fermentation and were thawed and plated for lactobacilli, lactococci, and yeasts on d 0, 7, 14, and 30 of frozen storage. Lactobacilli, lactococci, and yeasts were significantly reduced in number during frozen storage; however, the traditionally produced kefir was shown to have significantly higher counts of bacteria and yeast at each sampling. We concluded that frozen storage and the development of frozen kefir products could eliminate most packaging concerns associated with the large-scale manufacture of traditionally produced kefir, resulting in increased production and marketability of this healthful product.

The effects of postexercise consumption of a kefir beverage on performance and recovery during intensive endurance training.

This study was designed to determine whether kefir accentuates the positive health benefits assessed by measures in fitness, body composition, or both, as a measure of cardiovascular disease risk as well as the biomarker C-reactive protein (CRP). Sixty-seven adult males and females aged 18 to 24 yr were assigned to 1 of 4 groups: (1) endurance training + control beverage, (2) endurance training +kefir beverage,(3) active control + control beverage, or (4) active control + kefir beverage. The exercise groups completed 15 wk of structured endurancetraining while the active control groups maintained their usual exercise routine. Additionally, each group was assigned to either a kefir or a calorie/macronutrient matched placebo beverage that was consumed twice per week. No significant interactions were found among groups with respect to outcome variables with the exception of serum CRP. The endurance training was effective in improving 1.5-mile (2.41 km) times and kefir supplementation may have been a factor in attenuating the increase in CRP that was observed over the course of the intervention period. This preliminary study suggests that kefir may be involved in improving the risk profile for cardiovascular disease as defined by CRP.

(99m)Tc-labeled ubiquicidin scintigraphy: a promising method in hip prosthesis infection diagnosis.

AIM: Hip prosthesis implantation has witnessed a significant increase in recent years. Despite the advantages of this surgical procedure, it has some complications, the most serious of which is prosthetic infection. This study was conducted to investigate the feasibility of 99mTc-UBI scintigraphy in detection of infectious foci in painful hip prosthesis. UBI (Ubiquicidin 29-41) is an antimicrobial peptide fragment with the ability to target the bacterial colony directly. PATIENTS, METHODS: 34 patients, aged 20-79 years, with painful hip prosthesis were included. 99mTc-UBI scan and three phase bone scan were performed and two nuclear medicine specialists interpreted the UBI scans with and without bone scan results at hand. Both qualitative and semi-quantitative methods were used to interpret the 30 minute post injection images. The patients were actively followed up. According to the surgical findings, microbiological culture and active follow up, final diagnosis was made. RESULTS: 24 negative and 10 positive UBI scans were recorded. The sensitivity, specificity, negative and positive predictive values and accuracy of the study were all 100%. Bone scan did not have any influence on UBI interpretation. We were able to achieve excellent differentiation between infected and non-infected prostheses with a cut off value of 1.8 for target to non target (T/NT) ratio. No adverse effects were noticed following UBI scan. CONCLUSION: Based on the findings, the authors believe that 99mTc-UBI scintigraphy, with its high sensitivity and specificity, provides the physician with an excellent tool for differentiating infection from aseptic loosening of hip prostheses. Using this radiopharmaceutical, it is possible to obtain highly accurate results only 30 minutes after the beginning of the study.

Some low homogenization pressures improve certain probiotic characteristics of yogurt culture bacteria and Lactobacillus acidophilus LA-K.

Lactobacillus delbrueckii ssp. bulgaricus, Streptococcus salivarius ssp. thermophilus, and Lactobacillus acidophilus are dairy cultures widely used in the manufacture of cultured dairy products. Commonly used homogenization pressures in the dairy industry are 13.80 MPa or less. It is not known whether low homogenization pressures can stimulate bacteria to improve their probiotic characteristics. Objectives were to determine the effect of homogenization at 0, 3.45, 6.90, 10.34, and 13.80 MPa on acid tolerance, bile tolerance, protease activity, and growth of L. delbrueckii ssp. bulgaricus LB-12, S. salivarius ssp. thermophilus ST-M5, and L. acidophilus LA-K. The cultures were individually inoculated in cool autoclaved skim milk (4°C) and homogenized for 5 continuous passes. Growth and bile tolerance of samples were determined hourly for 10h of incubation. Acid tolerance was determined every 20 min for 120 min of incubation. Protease activity was determined at 0, 12, and 24h of incubation. All homogenization pressures studied improved acid tolerance of L. delbrueckii ssp. bulgaricus LB-12 but had no beneficial effect on protease activity and had negative effects on growth and bile tolerance. A pressure of 6.90 MPa improved acid tolerance, bile tolerance, and protease activity of S. salivarius ssp. thermophilus ST-M5, but none of the homogenization pressures studied had an effect on its growth. Homogenization pressures of 13.80 and 6.90 MPa improved acid tolerance and bile tolerance, respectively, of L. acidophilus LA-K but had no effect on protease activity and its growth. Some low homogenization pressures positively influenced some characteristics of yogurt culture bacteria and L. acidophilus LA-K. Culture pretreatment with some low homogenization pressures can be recommended for improvement of certain probiotic characteristics.

Fat-free plain yogurt manufactured with inulins of various chain lengths and Lactobacillus acidophilus.

Inulin is a prebiotic food ingredient that increases the activity of Lactobacillus acidophilus, increases calcium absorption, and is a good source of dietary fiber. The objective was to determine the effect of short, medium, and long chain inulins on the physicochemical, sensory, and microbiological characteristics of fat-free plain yogurt containing L. acidophilus. Inulins of short (P95), medium (GR), and long (HP) chain lengths were incorporated at 1.5% w/w of the yogurt mix. Viscosity, pH, syneresis, sensory properties (flavor, body and texture, and appearance and color), L. acidophilus counts, and color (L*, a*, and b*) of yogurts were determined at 1, 11, and 22 d after yogurt manufacture. The P95 containing yogurt had a significantly lower pH than the remaining yogurts, higher flavor scores than the yogurt containing HP, and comparable flavor scores with the control. The yogurts containing HP had less syneresis than the control and a better body and texture than the remaining yogurts. Yogurts containing prebiotics of different chain lengths had comparable L. acidophilus counts with each other but higher counts than the control. However, inulins of various chain lengths did not affect viscosity, color, and product appearance. Chain length of prebiotics affected some quality attributes of probiotic yogurts.

Characteristics of reduced fat milks as influenced by the incorporation of folic acid.

Folic acid plays an important role in the prevention of neural tube defects (e.g., spina bifida and anencephaly), heart defects, facial clefts, urinary abnormalities, and limb deficiencies. Milk and milk products serve as a potential source for folic acid fortification because of the presence of folate-binding proteins that seem to be involved in folate bioavailability. Although milk is not a good source of folic acid, fortification could help in the prevention of the above-mentioned defects. The objective of this study was to examine the physicochemical characteristics of reduced fat milks fortified with folic acid. Reduced fat milks were prepared using 25, 50, 75, and 100% of the recommended dietary allowance of 400 microg of folic acid. Treatments included addition of folic acid at these levels before and after pasteurization. Color, pH, fat, protein, viscosity, folic acid concentration, folate-binding protein concentration, folate-binding protein profile, standard plate count, and coliform counts were determined on d 1, 7, 14, and 21. A consumer acceptability test was conducted on d 7. Data from the consumer panel were analyzed using ANOVA (PROC GLM) with means separation to determine the differences among treatments. Data obtained from the color, pH, fat, protein, viscosity, folic acid concentration, folate-binding protein concentration, standard plate count, and coliform counts were analyzed using the GLM with a repeated measure in time. Significant differences were determined at P < 0.05 using Tukey's Studentized Range Test. There were no differences in the electrophoretic mobility of folate-binding protein in the samples. The concentration of folic acid was significantly higher in reduced fat milks fortified with folic acid after pasteurization compared with the treatments in which folic acid was added before pasteurization. The consumer panelists did not find any significant differences in flavor, appearance, or texture of folic acid fortified reduced fat milks compared with that of the control. Fortification of reduced fat milks with folic acid can be accomplished without adversely affecting the product characteristics.

Storage stability of lutein during ripening of cheddar cheese.

Lutein (3,3'-dihydroxy-alpha-carotene) has been identified as a dietary factor that can delay the onset of age-related macular degeneration (AMD). However, available food sources of lutein contain only modest amounts of the carotenoid. Food fortification with lutein extract has been identified as a low-budget approach to prevent the onset or progression of AMD. The objectives of this study were to 1) incorporate various amounts of lutein into Cheddar cheese; 2) examine the color, pH, microbiological, and sensory characteristics of the Cheddar cheese during storage; and 3) analyze the stability of lutein during the cheese maturation process. Lutein extracted from corn was added to Cheddar cheese in quantities of 1, 3, and 6 mg per serving size. Measurements of the lutein stability were carried out by HPLC using a YMC C30 carotenoid column. Microbiological analyses of cheese samples included aerobic plate count, coliform, and yeast/mold counts. The color attributes a* and b* were significantly different between the treatment and control groups; however, no significant difference was observed in L* value and pH. Significant differences among 1, 3, and 6 mg lutein-enriched cheeses were observed in the aerobic plate count and yeast/mold compared with the control. Cheese samples contained no detectable levels of coliforms (< 10 cfu/g). The HPLC data showed quantitative recovery of lutein during the storage period, and no lutein degradation products were identified. These results indicate that lutein, a functional additive with purported ability to prevent or reduce the onset of AMD, can be incorporated into cheese adding value to this product.

Aging-Induced Changes in Populations of Lactococci, Lactobacilli, and Aerobic Microorganisms in Low-Fat and Full-Fat Cheddar Cheese †.

The objective of this study was to observe the impact of lowering fat content on the microflora of Cheddar cheese. Full-fat (32%) and low-fat (5%) Cheddar cheeses were produced and evaluated one day after manufacture and at monthly intervals for 5 months. The cheeses were aged at 4°C after being dipped in mold inhibitor and vacuum packed in high-density polythene bags. Standard plate counts and counts of lactococci and lactobacilli were performed. Transmission and scanning electron microscopy of the microflora were also conducted. The lactococci decreased gradually over the ripening period, while the lactobacilli, though not knowingly added during Cheddar cheese preparation, increased concomitantly. Transmission electron microscopic observations revealed affinity of lactococci for the fat phase in aged cheese.