The impact of freezing and multiple freeze-thaw cycles on Brix refractometry estimates of immunoglobulin concentration in beef cattle colostrum.

Evaluation of immunoglobulin G (IgG) concentration in colostrum is important to guide on-farm management. Studies have shown that digital Brix refractometry accurately estimates colostrum IgG concentration in both dairy and beef cattle colostrum. Colostrum is often frozen in both clinical and research settings. The implications of this freezing on the accuracy of Brix refractometry measurements are largely unknown. The first objective of this study was to evaluate the agreement between digital Brix percentage measurements of IgG in beef cattle colostrum taken before and after different durations of freezing. The second objective was to evaluate the effects of multiple freeze-thaw (FT) cycles on Brix percentage measurements of IgG in beef cattle colostrum. There was good agreement between Brix percentages in fresh colostrum and after short (2 to 8 d), medium (4 to 7 mo), and long (3 y) periods of freezing (concordance correlation coefficient: 0.95, 0.96, and 0.96, respectively). Although there was no significant change in mean Brix percentages over 2 FT cycles (P > 0.05), mean Brix percentages decreased with 3 FT cycles (P = 0.017). Samples from the fourth and fifth FT cycles were observably coagulated, and these measurements were therefore deemed inaccurate. Data from this study indicate that freezing had minimal impact on digital Brix refractometer estimates of IgG concentration in beef cattle colostrum, but that samples stored for future testing should not undergo more than 2 FT cycles.

L'évaluation de la concentration d'immunoglobuline G (IgG) dans le colostrum est importante pour guider la gestion à la ferme. Des études ont montré que la réfractométrie Brix numérique estime avec précision la concentration d'IgG du colostrum dans le colostrum des bovins laitiers et de boucherie. Le colostrum est souvent congelé dans les milieux cliniques et de recherche. Les implications de cette congélation sur la précision des mesures de réfractométrie Brix sont largement inconnues. Le premier objectif de cette étude était d'évaluer la concordance entre les mesures numériques du pourcentage de Brix d'IgG dans le colostrum de bovins de boucherie prises avant et après différentes durées de congélation. Le deuxième objectif était d'évaluer les effets de plusieurs cycles de congélation-décongélation (FT) sur les mesures du pourcentage Brix d'IgG dans le colostrum de bovins de boucherie. Il y avait un bon accord entre les pourcentages de Brix dans le colostrum frais et après des périodes de congélation courtes (2 à 8 jours), moyennes (4 à 7 mois) et longues (3 ans) (coefficient de corrélation de concordance : 0,95, 0,96 et 0,96, respectivement). Bien qu'il n'y ait pas eu de changement significatif dans les pourcentages moyens de Brix sur deux cycles FT (P > 0,05), les pourcentages moyens de Brix ont diminué avec trois cycles FT (P = 0,017). Les échantillons des quatrième et cinquième cycles FT étaient coagulés de manière observable, et ces mesures ont donc été jugées inexactes. Les données de cette étude indiquent que la congélation a eu un impact minimal sur les estimations du réfractomètre numérique Brix de la concentration d'IgG dans le colostrum de les bovins de boucherie, mais que les échantillons stockés pour les tests futurs ne doivent pas subir plus de deux cycles FT.(Traduit par Docteur Serge Messier).

Evaluation of 3 refractometers to determine transfer of passive immunity in neonatal beef calves.

BACKGROUND: Refractometry is used to assess transfer of passive immunity (TPI), but studies evaluating different refractometers and appropriate thresholds for recommended target immunoglobulin G (IgG) concentrations for beef calves are limited. OBJECTIVES: To evaluate test performance of digital (DSTP) and optical (OSTP) serum total protein (STP) refractometers and a digital Brix (DBRIX) refractometer for assessment of passive immunity in beef calves. ANIMALS: A total of 398 beef calves from 6 herds, 1 to 7 days of age. METHODS: Serum IgG concentration was estimated by DSTP, OSTP, and DBRIX, and measured by radial immunodiffusion (RID). Correlation coefficients (r) among results were calculated. Optimal STP and Brix thresholds for identification of IgG <10, <16, and <24 g/L were determined using interval likelihood ratios. Refractometer performance and agreement were assessed using areas under the curve (AUC), diagnostic test characteristics, Cohen's kappa (κ), and Bland-Altman analysis. RESULTS: Refractometer results were highly correlated with RID (r = 0.82-0.91) and with each other (r = 0.91-0.95), and overall test performance was excellent (AUC = 0.93-0.99). The STP concentrations of ≤5.1, ≤5.1, and ≤5.7 g/dL and Brix percentages of ≤7.9%, ≤8.3%, and ≤8.7% indicated IgG concentrations <10, <16, and <24 g/L, respectively. Agreement of refractometers with RID was variable (κ = 0.46-0.80) and among refractometers was substantial (κ = 0.62-0.89). CONCLUSIONS AND CLINICAL IMPORTANCE: All refractometers showed good utility as monitoring tools for assessment of TPI in beef calves.

Quantifying the Forces Applied During Manually and Mechanically Assisted Calvings in Beef Cattle.

Dystocia is a leading cause of calf mortality, yet there is little available information quantifying the duration and forces applied to assisted deliveries. Objectives of this study were to: (1) develop a method to measure the magnitude and duration of various forces applied to a calf during calving assistance, and (2) quantify the forces applied to beef calves during manual or mechanical calving assistance. Twenty-five primiparous dams requiring calving assistance were enrolled. Calvings were assisted by manual (1 or 2 people pulling) or mechanical (calf extractor) delivery. A set of modified obstetric chains with integrated force measuring devices (Calving Assistance Force Logger; CAF-Log) were applied to the calf for delivery. The CAF-Log system was calibrated using known masses ranging from 25 to 200 kg in increasing increments of 25 kg. Duration of the assisted delivery and force parameters (peak force applied to one leg, peak force applied to both legs, cumulative force, and maximum jerk force) were described and assessed for their associations with method of delivery and ranch. Median duration was 112.6 s (IQR: 88.4-149.7) for manual and 312.6 s (IQR: 221.6-462.3) for mechanical deliveries. Mean peak force applied to one leg was 56.9 kg (SD: 22.9) for manual and 126.8 kg (SD: 48.2) for mechanical deliveries. Mean peak force applied to both legs was 95.4 kg (SD: 34.1) for manual and 188.6 kg (SD: 83.9) for mechanical deliveries. Median cumulative force was 178.3 kg min (IQR: 21.1-38.8) for manual and 380.6 kg min (IQR: 252.1-581.3) for mechanical deliveries. The maximum jerk force for manual deliveries was 36.6 kg/s (IQR: 21.1-38.8) and 77.2 kg/s (IQR: 60.9-97.1) for mechanical deliveries. An interaction occurred between ranch and method of delivery for peak force applied to one leg, peak force applied to both legs, and cumulative force. The CAF-Log system demonstrated that significantly greater forces were applied to mechanically delivered calves compared to manually delivered calves and could be used in future studies to investigate forces applied to a calf during calving assistance and their impacts on cow and calf well-being.

Assessment of Brix refractometry to estimate immunoglobulin G concentration in beef cow colostrum.

BACKGROUND: Brix refractometry can be used to assess colostral immunoglobulin G (IgG) concentration, but studies identifying Brix percentages to detect high- and low-IgG colostrum are lacking for beef cows and interlaboratory agreement is unknown. OBJECTIVES: Evaluate Brix refractometer performance and interlaboratory agreement for assessing beef cow colostrum IgG concentration, including determination of thresholds to identify colostrum containing IgG concentrations <100 g/L and ≥150 g/L. ANIMALS: Beef cows (n = 416) from 11 cow-calf operations in Alberta, Canada. METHODS: Colostral IgG concentrations were measured using radial immunodiffusion (RID) and estimated by Brix refractometry for this retrospective study. Spearman correlation coefficients were assessed between RID and Brix refractometry. Likelihood ratios and misclassification cost-term analysis were used to determine optimal Brix percentages for detecting colostrum containing IgG concentrations <100 g/L and ≥150 g/L. Concordance correlation coefficient (CCC) and Bland-Altman analyses were performed for Brix percentages obtained at 3 different laboratories. RESULTS: Brix percentages obtained at 3 laboratories were positively correlated with IgG results (r = 0.72, 0.68, and 0.76, respectively). Colostrum Brix percentages of <24% and ≥30% were optimal for indicating IgG concentrations of <100 g/L and ≥150 g/L, respectively. Interlaboratory agreement was substantial, with CCC ranging from 0.89 to 0.96 and Bland-Altman analysis showing small mean differences (-1.2% to 0.09% Brix) and narrow limits of agreements (-4.8% to 2.4% Brix) among laboratories. CONCLUSIONS AND CLINICAL IMPORTANCE: Brix refractometry shows good potential for reliably estimating IgG concentrations in beef cow colostrum across multiple laboratories and can be recommended to aid colostrum management decisions on farms.

Sphingosine kinase-2 is overexpressed in large granular lymphocyte leukaemia and promotes survival through Mcl-1.

Sphingolipid metabolism is increasingly recognised as a therapeutic target in cancer due to its regulation of cell proliferation and apoptosis. The sphingolipid rheostat is proposed to control cell fate through maintaining balance between pro-apoptotic and pro-survival sphingolipids. This balance is regulated by metabolising enzymes involved in sphingolipid production. One such enzyme, sphingosine kinase-2 (SPHK2), produces pro-survival sphingosine 1-phosphate (S1P) by phosphorylation of pro-apoptotic sphingosine. Elevated SPHK2 has been found in multiple cancer types and contributes to cell survival, chemotherapeutic resistance and apoptosis resistance. We have previously shown elevation of S1P in large granular lymphocyte (LGL) leukaemia serum and cells isolated from patients. Here, we examined SPHK2 expression in LGL leukaemia and found SPHK2 mRNA and protein upregulation in a majority of LGL leukaemia patient samples. Knockdown of SPHK2 with siRNA in LGL leukaemia cell lines decreased proliferation. Additionally, the use of ABC294640 or K145, both SPHK2-specific inhibitors, decreased viability of LGL leukaemia cell lines. ABC294640 selectively induced apoptosis in LGL cell lines and freshly isolated LGL leukaemia patient cells compared to normal controls. Mechanistically, SPHK2 inhibition downregulated pro-survival myeloid cell leukaemia-1 (Mcl-1) protein through proteasomal degradation. Targeting of SPHK2 therefore provides a novel therapeutic approach for the treatment of LGL leukaemia.

Ceramide Analogue SACLAC Modulates Sphingolipid Levels and MCL-1 Splicing to Induce Apoptosis in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a disease characterized by uncontrolled proliferation of immature myeloid cells in the blood and bone marrow. The 5-year survival rate is approximately 25%, and recent therapeutic developments have yielded little survival benefit. Therefore, there is an urgent need to identify novel therapeutic targets. We previously demonstrated that acid ceramidase (ASAH1, referred to as AC) is upregulated in AML and high AC activity correlates with poor patient survival. Here, we characterized a novel AC inhibitor, SACLAC, that significantly reduced the viability of AML cells with an EC50 of approximately 3 µmol/L across 30 human AML cell lines. Treatment of AML cell lines with SACLAC effectively blocked AC activity and induced a decrease in sphingosine 1-phosphate and a 2.5-fold increase in total ceramide levels. Mechanistically, we showed that SACLAC treatment led to reduced levels of splicing factor SF3B1 and alternative MCL-1 mRNA splicing in multiple human AML cell lines. This increased proapoptotic MCL-1S levels and contributed to SACLAC-induced apoptosis in AML cells. The apoptotic effects of SACLAC were attenuated by SF3B1 or MCL-1 overexpression and by selective knockdown of MCL-1S. Furthermore, AC knockdown and exogenous C16-ceramide supplementation induced similar changes in SF3B1 level and MCL-1S/L ratio. Finally, we demonstrated that SACLAC treatment leads to a 37% to 75% reduction in leukemic burden in two human AML xenograft mouse models. IMPLICATIONS: These data further emphasize AC as a therapeutic target in AML and define SACLAC as a potent inhibitor to be further optimized for future clinical development.

A randomised controlled trial investigating the effects of administering a non-steroidal anti-inflammatory drug to beef calves assisted at birth and risk factors associated with passive immunity, health, and growth.

BACKGROUND: The objectives of this study were to investigate the impact of pain mitigation at birth to assisted beef calves and determine the risk factors associated with transfer of passive immunity (TPI), health, and growth. METHODS: Two hundred and thirty cow-calf pairs requiring calving assistance were enrolled. Calves were randomised to receive meloxicam (0.5 mg/kg) or an equivalent volume of placebo subcutaneously at birth. Calf blood samples were collected between one and seven days of age to determine serum immunoglobulin (IgG) concentration. Colostrum intake, treatment for disease, mortality, and weaning weights were recorded. Multilevel linear or logistic regression models were used to determine the effects of meloxicam and to identify risk factors. RESULTS: There was no effect of meloxicam on serum IgG concentrations, average daily gain (ADG), or risk of inadequate TPI (serum IgG concentration <24 g/l), treatment for disease, or mortality (P>0.05). Bottle or tube feeding calves were associated with decreased serum IgG concentrations (P=0.01) compared with nursing. Calves with an incomplete tongue withdrawal reflex had higher odds of being treated for disease compared with those with complete withdrawal (P=0.009). Being born meconium-stained and having decreased serum IgG concentrations were associated with an increased risk of mortality (P=0.03). Being born of a mature cow, having a higher birth weight, and increased serum IgG concentrations were associated with greater ADG to weaning (P<0.05). CONCLUSION: Vigour assessment at birth along with good colostrum management may be important to improve TPI and health in high-risk calves such as those assisted at birth.

Clinical impacts of administering a nonsteroidal anti-inflammatory drug to beef calves after assisted calving on pain and inflammation, passive immunity, health, and growth.

Assisted calves are often born weak, injured, or oxygen deprived and have a higher risk of morbidity and mortality. The objective was to investigate the impact of using pain mitigation at birth in assisted beef calves on physiological indicators of pain and inflammation, passive immunity, health, and growth. Thirty-three primiparous cows and their calves requiring assistance at birth on two ranches located in southern Alberta were enrolled. Data collected at birth include date and time of calving, calf sex, meconium staining, presentation of calf, and calving difficulty (easy assist: one person manually delivered the calf; difficult assist: delivery by two or more people, or mechanical assistance). Within 10 min of birth, calves were stratified by calving difficulty, randomized to a medication group, and received a subcutaneous dose of meloxicam (0.5 mg/kg BW) or an equivalent volume of placebo. Cow-calf pairs were then placed in individual box stalls for observation and sampling. At birth, 1, 4, and 24 h after birth, heart rate, respiratory rate, and rectal temperature were assessed and blood samples collected to measure indicators of pain and inflammation (cortisol, corticosterone, substance P, and haptoglobin). Serum IgG concentration and failed transfer of passive immunity (serum IgG concentration <24 g/L) were assessed in the 24-h blood samples. Preweaning treatment for disease and mortality information was collected and calves were weighed at 7 to 10 d of age and at weaning. Of the 33 calves enrolled, 17 calves received meloxicam and 16 calves received a placebo. Meloxicam-medicated calves had significantly greater ADG to 7 to 10 d of age (P = 0.05) (mean = 0.9 kg/d; SE = 0.10) compared with placebo-medicated calves (mean = 0.6 kg/d; SE = 0.12). There was no significant effect of meloxicam on physiological indicators of pain and inflammation, standing or nursing by 1 h, passive immunity, health outcomes, or ADG to weaning (P > 0.1). Although this was a small sample population, meloxicam given to assisted calves at birth improved ADG in the first week of life, which may indicate an important production management tool for improving well-being in assisted calves.

Quantifying subclinical trauma associated with calving difficulty, vigour, and passive immunity in newborn beef calves.

This cross-sectional study quantifies subclinical trauma associated with calving difficulty, calf vigour, and passive immunity (PI) in newborn beef calves. The degree of calving difficulty was categorised as: unassisted, easy assist (one or two people manually pulling to deliver the calf) and difficult assist (more than two people pulling, a fetal extractor (ie, calf jack), or caesarean section). Vigour assessment occurred at 10 minutes and blood sampling at 24 hours after birth in 77 beef calves. The measured blood parameters associated with trauma were creatine kinase (CK), aspartate aminotransferase (AST), and haptoglobin. Serum IgG concentration was measured, and an IgG concentration at least 24 g/l was considered as adequate PI. Calving difficulty was associated with elevated levels of CK (P=0.002) and AST (P=0.01), weak suckle reflex (P=0.001), abnormal mucous membrane colour (P<0.0001), and decreased odds of adequate PI (P=0.004). Elevated levels of CK and AST were associated with abnormal mucous membrane colour, incomplete tongue withdrawal and weak suckle reflex at birth (P<0.001). An incomplete tongue withdrawal (P=0.005) and weak suckle reflex (P=0.02) were associated with decreased IgG concentrations. Abnormal mucous membrane colour, incomplete tongue withdrawal, and a weak suckle reflex were associated with decreased odds of having adequate PI (P<0.05). Haptoglobin was not associated with any of the parameters measured. Subclinical trauma was associated with calving difficulty, decreased vigour and decreased odds of having adequate PI. Understanding the impacts of a traumatic birth may aid the development of management strategies for compromised newborn beef calves.

Benchmarking calving management practices on western Canada cow-calf operations.

Benchmarking current calving management practices and herd demographics in the western Canadian cow-calf production system helps to fill the gap in knowledge and understanding of how this production system works. Further investigation into the relationships between management decisions and calf health may guide the development of management practices and protocols to improve calf health, especially in compromised calves after a difficult birth. Therefore, the objectives of this cross-sectional study were to describe current calving management practices on western Canadian cow-calf ranches and to investigate the association of herd demographics with herd-level incidence of calving assistance, morbidity, mortality, and use of calving and colostrum management practices. Cow-calf producers were surveyed in January 2017 regarding herd inventory and management practices during the 2016 calving season. Ninety-seven of 110 producers enrolled in the western Canadian Cow-Calf Surveillance Network responded. Average herd-level incidence of assisted calvings was 4.9% (13.5% heifers, 3.2% cows), stillbirths was 2.1% (3.3% heifers, 1.9% cows), preweaning mortality was 4.5%, and preweaning treatment for disease was 9.4% (3.0% neonatal calf diarrhea, 3.8% bovine respiratory disease, 2.6% other diseases). Greater than 90% of producers assisted calvings and would intervene with colostrum consumption if the calf did not appear to have nursed from its dam. Late calving herds (i.e., started calving in March or later) had significantly lower average herd-level incidence of assistance, treatment for disease, and mortality (P < 0.05). In earlier calving herds (i.e., started calving in January or February) producers had shorter intervals between checking on dams for signs of calving or intervening to assist with a calving (P < 0.05). In early calving herds, producers were more likely to perform hands-on colostrum management techniques such as placing the cow and calf together or feeding stored, frozen colostrum (P < 0.05). There were no associations between herd size and herd-level incidences or management techniques (P > 0.05). This study suggests that in western Canada earlier calving herds are more intensively managed, whereas later calving herds are more extensively managed. Herd demographics may be important to consider when investigating factors associated with management strategies, health, and productivity in cow-calf herds.

Assessing the Efficacy of Ventilation of Anesthetized Neonatal Calves Using a Laryngeal Mask Airway or Mask Resuscitator.

Calves that have undergone a dystocia are often hypoxic and acidemic, which can result in reduced vigor and subsequent mortality. Methods of field resuscitation of apneic newborn calves are often ineffective and therefore underutilized. This proof-of-concept study aimed to determine the efficacy of the laryngeal mask airway (LMA) as well as the current industry standard method of ventilation, the McCulloch Calf Aspirator/ Resuscitator (MMR) for positive pressure ventilation of neonatal calves. Five LMA models of various sizes were first tested in cadaver heads to assess anatomical fit. Three LMA models in two sizes each were then tested in two anesthetized calves to determine the model best suited to ventilate calves. Next, the selected LMA and the MMR were both assessed for efficacy of ventilation. Six anesthetized calves had hypoventilation induced by administering alfaxalone intravenously. Calves were ventilated for 3 min with the LMA, allowed a brief washout period, then given a second administration of alfaxalone prior to ventilation with the MMR. Serial arterial blood gas analyses were performed prior to ventilation (baseline), at 1, 2, and 3 min during ventilation, and 1 min after ventilation had ceased. Success of ventilation was assessed by monitoring partial pressure of oxygen (PaO2), partial pressure of carbon dioxide (PaCO2), bicarbonate ( HCO 3 - ), pH, L-lactate, and hemoglobin saturation (SaO2) in arterial blood. A one-way ANOVA for repeated measures with Bonferroni correction was used to assess the efficacy of ventilation of each device compared to baseline. For the LMA, PaO2, SaO2, and pH were significantly higher than baseline throughout ventilation and PaCO2 was significantly lower than baseline at 1 min of ventilation. For the MMR, PaO2 and SaO2 were significantly higher and PaCO2 and HCO 3 - were significantly lower than baseline for 1 to 2 min of ventilation. This proof-of-concept study showed the LMA is an effective means of ventilating neonatal calves, as was the MMR.

Application of transmission infrared spectroscopy and partial least squares regression to predict immunoglobulin G concentration in dairy and beef cow colostrum.

The objective of this study was to explore the potential of transmission infrared (TIR) spectroscopy in combination with partial least squares regression (PLSR) for quantification of dairy and beef cow colostral immunoglobulin G (IgG) concentration and assessment of colostrum quality. A total of 430 colostrum samples were collected from dairy (n = 235) and beef (n = 195) cows and tested by a radial immunodiffusion (RID) assay and TIR spectroscopy. Colostral IgG concentrations obtained by the RID assay were linked to the preprocessed spectra and divided into combined and prediction data sets. Three PLSR calibration models were built: one for the dairy cow colostrum only, the second for beef cow colostrum only, and the third for the merged dairy and beef cow colostrum. The predictive performance of each model was evaluated separately using the independent prediction data set. The Pearson correlation coefficients between IgG concentrations as determined by the TIR-based assay and the RID assay were 0.84 for dairy cow colostrum, 0.88 for beef cow colostrum, and 0.92 for the merged set of dairy and beef cow colostrum. The average of the differences between colostral IgG concentrations obtained by the RID- and TIR-based assays were -3.5, 2.7, and 1.4 g/L for dairy, beef, and merged colostrum samples, respectively. Further, the average relative error of the colostral IgG predicted by the TIR spectroscopy from the RID assay was 5% for dairy cow, 1.2% for beef cow, and 0.8% for the merged data set. The average intra-assay CV% of the IgG concentration predicted by the TIR-based method were 3.2%, 2.5%, and 6.9% for dairy cow, beef cow, and merged data set, respectively.The utility of TIR method for assessment of colostrum quality was evaluated using the entire data set and showed that TIR spectroscopy accurately identified the quality status of 91% of dairy cow colostrum, 95% of beef cow colostrum, and 89% and 93% of the merged dairy and beef cow colostrum samples, respectively. The results showed that TIR spectroscopy demonstrates potential as a simple, rapid, and cost-efficient method for use as an estimate of IgG concentration in dairy and beef cow colostrum samples and assessment of colostrum quality. The results also showed that merging the dairy and beef cow colostrum sample data sets improved the predictive ability of the TIR spectroscopy.

The phosphatidic acid-binding, polybasic domain is responsible for the differences in the phosphoregulation of lipins 1 and 3.

Lipins 1, 2, and 3 are Mg2+-dependent phosphatidic acid phosphatases and catalyze the penultimate step of triacylglycerol synthesis. We have previously investigated the biochemistry of lipins 1 and 2 and shown that di-anionic phosphatidic acid (PA) augments their activity and lipid binding and that lipin 1 activity is negatively regulated by phosphorylation. In the present study, we show that phosphorylation does not affect the catalytic activity of lipin 3 or its ability to associate with PA in vitro The lipin proteins each contain a conserved polybasic domain (PBD) composed of nine lysine and arginine residues located between the conserved N- and C-terminal domains. In lipin 1, the PBD is the site of PA binding and sensing of the PA electrostatic charge. The specific arrangement and number of the lysines and arginines of the PBD vary among the lipins. We show that the different PBDs of lipins 1 and 3 are responsible for the presence of phosphoregulation on the former but not the latter enzyme. To do so, we generated lipin 1 that contained the PBD of lipin 3 and vice versa. The lipin 1 enzyme with the lipin 3 PBD lost its ability to be regulated by phosphorylation but remained downstream of phosphorylation by mammalian target of rapamycin. Conversely, the presence of the lipin 1 PBD in lipin 3 subjected the enzyme to negative intramolecular control by phosphorylation. These results indicate a mechanism for the observed differences in lipin phosphoregulation in vitro.

The emergence of acid ceramidase as a therapeutic target for acute myeloid leukemia.

INTRODUCTION: Acute myeloid leukemia (AML) is the most common adult leukemia. Only a fraction of AML patients will survive with existing chemotherapy regimens. Hence, there is an urgent and unmet need to identify novel targets and develop better therapeutics in AML. In the past decade, the field of sphingolipid metabolism has emerged into the forefront of cancer biology due to its importance in cancer cell proliferation and survival. In particular, acid ceramidase (AC) has emerged as a promising therapeutic target due to its role in neutralizing the pro-death effects of ceramide. Areas covered: This review highlights key information about AML biology as well as current knowledge on dysregulated sphingolipid metabolism in cancer and AML. We describe AC function and dysregulation in cancer, followed by a review of studies that report elevated AC in AML and compounds known to inhibit the enzyme. Expert opinion: AML has a great need for new drug targets and better therapeutic agents. The finding of elevated AC in AML supports the concept that this enzyme represents a novel and realistic therapeutic target for this common leukemia. More effort is needed towards developing better AC inhibitors for clinical use and combination treatment with existing AML therapies.

Gross and histological description of the epidermal membrane found on normal neonatal piglets.

The structure and composition of fetal and placental tissues vary among different species of placental mammals. Some mammals, including camelids and pigs, possess an epidermal membrane during the fetal stage, called the epithelion, that is absent from other domestic mammals. Because neonatal piglets are a common animal model for many research techniques, it is important that researchers correctly identify this tissue and recognize its lack of pathological consequence when working with fetal and neonatal piglets. Here, the authors describe gross and histological examinations of the epithelion, comparing this tissue with other extra-fetal tissues and coatings.

Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy.

Mutation and aberrant expression of apoptotic proteins are hallmarks of cancer. These changes prevent proapoptotic signals from being transmitted to executioner caspases, thereby averting apoptotic death and allowing cellular proliferation. Caspase-3 is the key executioner caspase, and it exists as an inactive zymogen that is activated by upstream signals. Notably, concentrations of procaspase-3 in certain cancerous cells are significantly higher than those in noncancerous controls. Here we report the identification of a small molecule (PAC-1) that directly activates procaspase-3 to caspase-3 in vitro and induces apoptosis in cancerous cells isolated from primary colon tumors in a manner directly proportional to the concentration of procaspase-3 inside these cells. We found that PAC-1 retarded the growth of tumors in three different mouse models of cancer, including two models in which PAC-1 was administered orally. PAC-1 is the first small molecule known to directly activate procaspase-3 to caspase-3, a transformation that allows induction of apoptosis even in cells that have defective apoptotic machinery. The direct activation of executioner caspases is an anticancer strategy that may prove beneficial in treating the many cancers in which procaspase-3 concentrations are elevated.