Premix versus On-Demand Workflow Models in a Veterans Affairs Hematology/Oncology Pharmacy: Impact on Estimated Waste Costs and Patient Wait Time.

Background: The balance between reducing patient wait time and mitigating waste of parenteral products has not been well described in literature. Objective: Evaluate the patient wait times and cost-effectiveness of employing a premix versus an on-demand workflow model for compounding parenteral admixtures in a hematology/oncology infusion setting. Methods: This single center, retrospective cost analysis compiled manually documented monthly waste reports and estimated drug pricing for the institution to calculate the cost of waste during both premix and on-demand compounding workflows. Time to administration was audited for one week with both models. Results: Over a period of 28.5 months following the premix model, 564 products were documented as wasted ($1,196,014.01 in estimated drug purchasing cost). Over a period of 3 months following the on-demand model, 12 products were wasted ($34,823.98 in estimated drug purchasing cost). Switching models reduced the monthly average number of wasted products from 20 to 4 per month; the average cost of waste was reduced from $41,965.40 to $11,607.99 per month (P < .0001). Overall patient wait time from clearance until administration, excluding any recommended wait times after premedication administration (if applicable), was similar in both models: an average of 38.26 minutes in the premix model and 40.97 minutes in the on-demand model. Conclusion: Premixing parenteral admixtures was not cost effective at our institution. After resuming an on-demand compounding model, the monthly cost of waste (based on drug pricing alone) was reduced by over 70%. The wait time from clearance to treatment administration was similar in both models.

Biomarkers of bleeding and venous thromboembolism in patients with acute leukemia.

BACKGROUND: Coagulopathy and associated bleeding and deep vein thrombosis (DVT) are major causes of morbidity and mortality in patients with acute leukemia. The underlying mechanisms of these complications have not been fully elucidated. OBJECTIVES: To evaluate the associations between biomarker levels and bleeding and DVT in acute leukemia patients. PATIENTS/METHOD: We examined plasma levels of activators, inhibitors and biomarkers of the coagulation and fibrinolytic pathways in patients ≥18 years with newly diagnosed acute leukemia compared to normal controls. Multivariable regression models were used to examine the association of biomarkers with bleeding and DVT in acute leukemia patients. The study included 358 patients with acute leukemia (29 acute promyelocytic leukemia [APL], 253 non-APL acute myeloid leukemia [AML] and 76 acute lymphoblastic leukemia [ALL]), and 30 normal controls. RESULTS: Patients with acute leukemia had higher levels of extracellular vesicle (EV) tissue factor (TF) activity, phosphatidylserine-positive EVs, plasminogen activator inhibitor-1 (PAI-1), plasmin-antiplasmin complexes, cell-free DNA and lower levels of citrullinated histone H3-DNA complexes compared to normal controls. APL patients had the highest levels of EVTF activity and the lowest levels of tissue plasminogen activator among acute leukemia patients. There were 41 bleeding and 24 DVT events in acute leukemia patients. High EVTF activity was associated with increased risk of bleeding (sHR 2.30, 95%CI 0.99-5.31) whereas high PAI-1 was associated with increased risk of DVT (sHR 3.00, 95%CI 0.95-9.47) in these patients. CONCLUSIONS: Our study shows alterations in several biomarkers in acute leukemia and identifies biomarkers associated with risk of bleeding and DVT.

Panaxynol improves crypt and mucosal architecture, suppresses colitis-enriched microbes, and alters the immune response to mitigate colitis.

Ulcerative colitis (UC) is an idiopathic inflammatory disease of the large intestine, which impacts millions worldwide. Current interventions aimed at treating UC symptoms can have off-target effects, invoking the need for alternatives that may provide similar benefits with less unintended consequences. This study builds on our initial data, which showed that panaxynol - a novel, potent, bioavailable compound found in American ginseng - can suppress disease severity in murine colitis. Here we explore the underlying mechanisms by which panaxynol improves both chronic and acute murine colitis. 14-week-old C57BL/6 female mice were either given 3 rounds of dextran sulfate sodium (DSS) in drinking water to induce chronic colitis or 1 round to induce acute colitis. Vehicle or panaxynol (2.5 mg/kg) was administered via oral gavage 3x/week for the study duration. Consistent with our previous findings, panaxynol significantly (p<0.05) improved the disease activity index and endoscopic scores in both models. Using the acute model to examine potential mechanisms, we show that panaxynol significantly (p<0.05) reduced DSS-induced crypt distortion, goblet cell loss, and mucus loss in the colon. 16s sequencing revealed panaxynol altered microbial composition to suppress colitis-enriched genera (i.e., Enterococcus, Eubacterium, and Ruminococcus). Additionally, panaxynol significantly (p<0.05) suppressed macrophages and induced regulatory T-cells in the colonic lamina propria. The beneficial effects of panaxynol on mucosal and crypt architecture, combined with its microbial and immune-mediated effects, provide insight into mechanisms by which panaxynol suppresses murine colitis. Overall, this data is promising for the use of panaxynol to improve colitis in the clinic.

Response to MHC-based olfactory cues in a mate choice context in two species of darter (Percidae: Etheostoma).

Mate choice is hypothesized to play an important role in maintaining high diversity at major histocompatibility complex (MHC) genes in vertebrates. Many studies have revealed that females across taxa prefer the scent of males with MHC genotypes different to their own. In this study we tested the "opposites-attract" hypothesis in two species of darter with known differences in female criteria used in mate choice: in the fantail darters (a paternal-care species), females prefer males with visual traits related to nest guarding and egg tending, while in rainbow darters (not a paternal-care species) female mate choice criteria are unknown. In dichotomous mate-choice trials, we presented females of both species with the scents of conspecific males with MHC class IIb genotypes that were either similar or dissimilar to that of the focal female. We evaluated the proportion of time each female spent with each male and calculated the average strength of female preference for both species. Female fantail darters demonstrated a preference for the scent of males with similar (rather than dissimilar) MHC genotypes, but this result was not statistically significant. Rainbow darter females showed no preference for the scent of males with similar or dissimilar MHC genotypes. Our results do not support the "opposites-attract" hypothesis in darters.

The complex heterogeneity of immune cell signatures across wasting tissues with C26 and 5-fluorouracil-induced cachexia.

Immune cell-driven pathways are linked to cancer cachexia. Tumor presence is associated with immune cell infiltration whereas cytotoxic chemotherapies reduce immune cell counts. Despite these paradoxical effects, both cancer and chemotherapy can cause cachexia; however, our understanding of immune responses in the cachexia condition with cancer and chemotherapy is largely unknown. We sought to advance our understanding of the immunology underlying cancer and cancer with chemotherapy-induced cachexia. CD2F1 mice were given 106 C26 cells, followed by five doses of 5-fluorouracil (5FU; 30 mg/kg LM, ip) or PBS. Indices of cachexia and tumor (TUM), skeletal muscle (SKM), and adipose tissue (AT) immune cell populations were examined using high-parameter flow cytometry. Although 5FU was able to stunt tumor growth, % body weight loss and muscle mass were not different between C26 and C26 + 5FU. C26 increased CD11b+Ly6g+ and CD11b+Ly6cInt inflammatory myeloid cells in SKM and AT; however, both populations were reduced with C26 + 5FU. tSNE analysis revealed 24 SKM macrophage subsets wherein 8 were changed with C26 or C26 + 5FU. C26 + 5FU increased SKM CD11b-CD11c+ dendritic cells, CD11b-NK1.1+ NK-cells, and CD11b-B220+ B-cells, and reduced Ly6cHiCX3CR1+CD206+CD163IntCD11c-MHCII- infiltrated macrophages and other CD11b+Ly6cHi myeloid cells compared with C26. Both C26 and C26 + 5FU had elevated CD11b+F480+CD206+MHCII- or more specifically Ly6cLoCX3CR1+CD206+CD163IntCD11c-MHCII- profibrotic macrophages. 5FU suppressed tumor growth and decreased SKM and AT inflammatory immune cells without protecting against cachexia suggesting that these cells are not required for wasting. However, profibrotic cells and muscle inflammatory/atrophic signaling appear consistent with cancer- and cancer with chemotherapy-induced wasting and remain potential therapeutic targets.NEW & NOTEWORTHY Despite being an immune-driven condition, our understanding of skeletal muscle and adipose tissue immune cells with cachexia is limited. Here, we identified immune cell populations in tumors, skeletal muscle, and adipose tissue in C26 tumor-bearing mice with/without 5-fluorouracil (5FU). C26 and C26 + 5FU had increased skeletal muscle profibrotic macrophages, but 5FU reduced inflammatory myeloid cells without sparing mass. Tumor presence and chemotherapy have contrasting effects on certain immune cells, which appeared not necessary for wasting.

Obesity worsens mitochondrial quality control and does not protect against skeletal muscle wasting in murine cancer cachexia.

BACKGROUND: More than 650 million people are obese (BMI > 30) worldwide, which increases their risk for several metabolic diseases and cancer. While cachexia and obesity are at opposite ends of the weight spectrum, leading many to suggest a protective effect of obesity against cachexia, mechanistic support for obesity's benefit is lacking. Given that obesity and cachexia are both accompanied by metabolic dysregulation, we sought to investigate the impact of obesity on skeletal muscle mass loss and mitochondrial dysfunction in murine cancer cachexia. METHODS: Male C57BL/6 mice were given a purified high fat or standard diet for 16 weeks before being implanted with 106 Lewis lung carcinoma (LLC) cells. Mice were monitored for 25 days, and hindlimb muscles were collected for cachexia indices and mitochondrial assessment via western blotting, high-resolution respirometry and transmission electron microscopy (TEM). RESULTS: Obese LLC mice experienced significant tumour-free body weight loss similar to lean (-12.8% vs. -11.8%, P = 0.0001) but had reduced survival (33.3% vs. 6.67%, χ2  = 10.04, P = 0.0182). Obese LLC mice had reduced muscle weights (-24%, P < 0.0354) and mCSA (-16%, P = 0.0004) with similar activation of muscle p65 (P = 0.0337), and p38 (P = 0.0008). ADP-dependent coupled respiration was reduced in both Obese and Obese LLC muscle (-30%, P = 0.0072) consistent with reductions in volitional cage activity (-39%, P < 0.0001) and grip strength (-41%, P < 0.0001). TEM revealed stepwise reductions in intermyofibrillar and subsarcolemmal mitochondrial size with Obese (IMF: -37%, P = 0.0009; SS: -21%, P = 0.0101) and LLC (IMF: -40%, P = 0.0019; SS: -27%, P = 0.0383) mice. Obese LLC mice had increased pAMPK (T172; P = 0.0103) and reduced FIS1 (P = 0.0029) and DRP1 (P < 0.0001) mitochondrial fission proteins, which were each unchanged in Lean LLC. Further, mitochondrial TEM analysis revealed that Obese LLC mice had an accumulation of damaged and dysfunctional mitochondria (IMF: 357%, P = 0.0395; SS: 138%, P = 0.0174) in concert with an accumulation of p62 (P = 0.0328) suggesting impaired autophagy and clearance of damaged mitochondria. Moreover, we observed increases in electron lucent vacuoles only in Obese LLC muscle (IMF: 421%, P = 0.0260; SS: 392%, P = 0.0192), further supporting an accumulation of damaged materials that cannot be properly cleared in the obese cachectic muscle. CONCLUSIONS: Taken together, these results demonstrate that obesity is not protective against cachexia and suggest exacerbated impairments to mitochondrial function and quality control with a particular disruption in the removal of damaged mitochondria. Our findings highlight the need for consideration of the severity of obesity and pre-existing metabolic conditions when determining the impact of weight status on cancer-induced cachexia and functional mitochondrial deficits.

Biomolecular condensates in fungi are tuned to function at specific temperatures.

Temperature can impact every reaction and molecular interaction essential to a cell. For organisms that cannot regulate their own temperature, a major challenge is how to adapt to temperatures that fluctuate unpredictability and on variable timescales. Biomolecular condensation offers a possible mechanism for encoding temperature-responsiveness and robustness into cell biochemistry and organization. To explore this idea, we examined temperature adaptation in a filamentous-growing fungus called Ashbya gossypii that engages biomolecular condensates containing the RNA-binding protein Whi3 to regulate mitosis and morphogenesis. We collected wild isolates of Ashbya that originate in different climates and found that mitotic asynchrony and polarized growth, which are known to be controlled by the condensation of Whi3, are temperature sensitive. Sequence analysis in the wild strains revealed changes to specific domains within Whi3 known to be important in condensate formation. Using an in vitro condensate reconstitution assay we found that temperature impacts the relative abundance of protein to RNA within condensates and that this directly impacts the material properties of the droplets. Finally, we found that exchanging Whi3 genes between warm and cold isolates was sufficient to rescue some, but not all, condensate-related phenotypes. Together these data demonstrate that material properties of Whi3 condensates are temperature sensitive, that these properties are important for function, and that sequence optimizes properties for a given climate.

Biomarkers of bleeding and venous thromboembolism in patients with acute leukemia.

Background: Coagulopathy and associated bleeding and venous thromboembolism (VTE) are major causes of morbidity and mortality in patients with acute leukemia. The underlying mechanisms of these complications have not been fully elucidated. Objectives: To evaluate the associations between biomarker levels and bleeding and VTE in acute leukemia patients. Patients/Method: We examined plasma levels of activators, inhibitors and biomarkers of the coagulation and fibrinolytic pathways in patients ≥18 years with newly diagnosed acute leukemia compared to healthy controls. Multivariable regression models were used to examine the association of biomarkers with bleeding and VTE in acute leukemia patients. The study included 358 patients with acute leukemia (29 acute promyelocytic leukemia [APL], 253 non-APL acute myeloid leukemia [AML] and 76 acute lymphoblastic leukemia [ALL]), and 30 healthy controls. Results: Patients with acute leukemia had higher levels of extracellular vesicle (EV) tissue factor (TF) activity, phosphatidylserine-positive EVs, plasminogen activator inhibitor-1 (PAI-1), plasmin-antiplasmin complexes, cell-free DNA and lower levels of citrullinated histone H3-DNA complexes compared to healthy controls. APL patients had the highest levels of EVTF activity and the lowest levels of tissue plasminogen activator among the acute leukemia patients. There were 41 bleeding and 37 VTE events in acute leukemia patients. High EVTF activity was associated with increased risk of bleeding (sHR 2.30, 95%CI 0.99-5.31) whereas high PAI-1 was associated with increased risk of VTE (sHR 3.79, 95%CI 1.40-10.28) in these patients. Conclusions: Our study shows alterations in several biomarkers in acute leukemia and identifies biomarkers associated with risk of bleeding and VTE.

An optimized electro-fenton pretreatment for the degradation and mineralization of a mixture of ofloxacin, norfloxacin, and ciprofloxacin.

The electro-Fenton process (EFP) is a powerful advanced oxidation process beneficial to treating recalcitrant contaminants, and there has been a continuing interest in combining this technology to enhance the efficiency of conventional wastewater treatment processes. In this work, an optimized EFP process is performed as pretreatment for the degradation and mineralization of three blank fluoroquinolones (FQs) drugs: ofloxacin (OFL), norfloxacin (NOR), and ciprofloxacin (CIP). The optimization of the experiment was carried out using a Box-Behnken experimental design. Faster and complete degradation of the drugs mixture was achieved in 90 min with 61.12 ± 2.0% of mineralization in 180 min, under the optimized conditions: j = 244.0 mA cm-2, [Fe2+] = 0.31 mM, and [FQs] = 87.0 mg L-1. Furthermore, a low toxicity effluent was obtained in 90 min of the experiment, according to bioassay toxicity with Vibrio fischeri. Five short-chain carboxylic acids, including oxalic, maleic, oxamic, formic, and fumaric acids, were detected and quantified, in addition to F- and NO3- inorganic ions. The inhibition of the reactive oxygen species with scavenger proof was also evaluated in this paper.

Emodin reduces surgical wounding-accelerated tumor growth and metastasis via macrophage suppression in a murine triple-negative breast cancer model.

It has been suspected that tumor resection surgery itself may accelerate breast cancer (BC) lung metastasis in some patients. Emodin, a natural anthraquinone found in the roots and rhizomes of various plants, exhibits anticancer activity. We examined the perioperative use of emodin in our established surgery wounding murine BC model. Emodin reduced primary BC tumor growth and metastasis in the lungs in both sham and surgical wounded mice, consistent with a reduction in proliferation and enhanced apoptosis (primary tumor and lungs). Further, emodin reduced systemic inflammation, most notably the number of monocytes in the peripheral blood and reduced pro-tumoral M2 macrophages in the primary tumor and the lungs. Consistently, we show that emodin reduces gene expression of select macrophage markers and associated cytokines in the primary tumor and lungs of wounded mice. Overall, we demonstrate that emodin is beneficial in mitigating surgical wounding accelerated lung metastasis in a model of triple-negative BC, which appears to be mediated, at least in part, by its actions on macrophages. These data support the development of emodin as a safe, low-cost, and effective agent to be used perioperatively to alleviate the surgery triggered inflammatory response and consequential metastasis of BC to the lungs.

Solar heterogeneous photo-Fenton for complete inactivation of Escherichia coli and Salmonella typhimurium in secondary-treated wastewater effluent.

In this work, complete elimination of Escherichia coli and Salmonella typhimurium was achieved in 120 min using a heterogeneous photo-Fenton process under sunlight at pH 6.5 in distilled water. A face-centered composite central design 22 with one categoric factor and three replicates at the central point was used to evaluate the effect of iron (III) oxide concentration (0.8-3.4 mg L-1), H2O2 (2-10 mg L-1), and the type of iron oxide phase (maghemite and hematite) on the inactivation of both bacteria. The results showed that the amount of catalyst, H2O2 concentration and their interaction were significant factors (p < 0.05) in the elimination of the microorganisms. Thus, under the best conditions (3.4 mg L-1 of iron (III) oxide and 10 mg L-1 of H2O2) in the experimental ranges, complete inactivation of E. coli and S. typhimurium was achieved (6-log reduction) in 120 min using the photo-Fenton treatment with both iron-oxide phases. Furthermore, the photocatalytic elimination of both bacteria by the photo-Fenton process using hematite and maghemite in secondary-treated wastewater effluent was performed obtaining slower inactivation rates (1.2-5.9 times) than in distilled water due to the matrix effect of the effluent from a wastewater treatment plant. Nevertheless, the process continued to be effective in the effluent, achieving complete bacterial elimination in 150 min using the hematite phase. Additionally, the SEM images of the bacterial cells showed that the heterogeneous photo-Fenton treatment generated permanent and irreversible cell damage, resulting in complete cell death.

Androgen deprivation therapy in localized prostate cancer. Current status and future trends.

INTRODUCTION: Prostate cancer (PCa) has been recognized as an androgen-sensitive disease since the investigations from Huggins and Hodges in 1941. Thanks to these findings, they received the Nobel Prize in 1966. This was the beginning of the development of androgen deprivation therapy (ADT) as treatment for patients with PCa. OBJECTIVE: To summarize the current indications of ADT in localized PCa. EVIDENCE ACQUISITION: We conducted a comprehensive English and Spanish language literature research, focused on the main indications for ADT in localized PCa. EVIDENCE SYNTHESIS: Nowadays, the indications for ADT as monotherapy in localized PCa have been limited to specific situations, to patients unwilling or unable to receive any form of local treatment if they have a PSA-DT < 12 months, and either a PSA > 50 ng/mL, a poorly differentiated tumor, or troublesome local disease-related symptoms. ADT can be used in combination with local treatment in different scenarios. Although neoadjuvant treatment with ADT prior to surgery with curative intent has no clear oncological impact, as a future sight, PCa is a heterogeneous disease, and there could be a group of patients with high-risk localized disease that could benefit. CONCLUSIONS: We need to optimize the treatment with ADT in localized PCa, selecting the patients accordingly to their disease characteristics. Given that the therapeutic armamentarium evolves day by day, there is a need for the development of new clinical trials, as well as a molecular studies of patients to identify those who might benefit from an early multimodal treatment.

Native amphibian toxin reduces invasive crayfish feeding with potential benefits to stream biodiversity.

BACKGROUND: Biodiversity is generally reduced when non-native species invade an ecosystem. Invasive crayfish, Procambarus clarkii, populate California freshwater streams, and in the Santa Monica Mountains (Los Angeles, USA), their introduction has led to trophic cascades due to omnivorous feeding behavior and a rapid rate of population growth. The native California newt, Taricha torosa, possesses a neurotoxin, tetrodotoxin (TTX), that affects freshwater animal behavior. Given P. clarkii has a limited evolutionary history with TTX, we hypothesized that TTX may affect crayfish feeding behaviors. To determine if TTX affects P. clarkii behavior, we measured cumulative movement and various feeding behaviors of P. clarkii exposed to (i) waterborne, ecologically realistic concentrations of TTX (~ 3.0 × 10- 8 moles/L), (ii) an anuran chemical cue to account for intraguild cues, or (iii) a T. torosa chemical cue with quantitated TTX in it (~ 6.2 × 10- 8 moles/L). RESULTS: We found that the presence of TTX in any form significantly reduced crayfish movement and decreased the amount of food consumed over time. Crayfish responses to the anuran treatment did not significantly differ from controls. CONCLUSION: Our laboratory results show that naturally occurring neurotoxin from native California newts limits invasive crayfish foraging and feeding rates, which may play a role in preserving local stream ecosystems by limiting invasive crayfish behaviors that are detrimental to biodiversity.

Terapia de privación de andrógenos en el cáncer de próstata localizado. Situación actual y tendencias futuras / Androgen deprivation therapy in localized prostate cancer. Current status and future trends

Introducción El cáncer de próstata (CaP) se ha reconocido como una enfermedad sensible a los andrógenos desde las investigaciones de Huggins y Hodges en 1941, quienes, gracias a estos hallazgos, recibieron el Premio Nobel en 1966. Aquí se originó el desarrollo de la terapia de privación de andrógenos (TPA) como tratamiento para los pacientes con CaP. Objetivo Resumir las indicaciones actuales de la TPA en el CaP localizado. Adquisición de la evidencia Hemos realizado una investigación bibliográfica exhaustiva en inglés y español, centrada en las principales indicaciones de la TPA en el CaP localizado. Síntesis de la evidencia En la actualidad, las indicaciones de la TPA como monoterapia en el CaP localizado se han limitado a situaciones específicas, a pacientes que no desean o no pueden recibir ninguna forma de tratamiento local y que tienen un PSA-DT<12 meses y un PSA>50 ng/mL, un tumor poco diferenciado o síntomas locales molestos relacionados con la enfermedad. La TPA puede utilizarse en combinación con tratamiento local en diferentes escenarios. Aunque el tratamiento neoadyuvante con TPA antes de la cirugía con intención curativa no tiene un impacto oncológico claro, el CaP es una enfermedad heterogénea y en el futuro podría haber un grupo de pacientes con enfermedad localizada de alto riesgo que se beneficiaran de este tratamiento. Conclusiones Necesitamos optimizar el tratamiento con TPA en el CaP localizado, seleccionando a los pacientes en función de las características de su enfermedad. Dado que el arsenal terapéutico evoluciona día a día, es necesario el desarrollo de nuevos ensayos clínicos, así como el estudio molecular en los pacientes, para identificar a aquellos que podrían beneficiarse de un tratamiento multimodal temprano (AU)

Introduction Prostate cancer (PCa) has been recognized as an androgen-sensitive disease since the investigations from Huggins and Hodges in 1941. Thanks to these findings, they received the Nobel Prize in 1966. This was the beginning of the development of androgen deprivation therapy (ADT) as treatment for patients with PCa. Objective To summarize the current indications of ADT in localized PCa. Evidence acquisition We conducted a comprehensive English and Spanish language literature research, focused on the main indications for ADT in localized PCa. Evidence synthesis Nowadays, the indications for ADT as monotherapy in localized PCa have been limited to specific situations, to patients unwilling or unable to receive any form of local treatment if they have a PSA-DT<12 months, and either a PSA>50 ng/mL, a poorly differentiated tumor, or troublesome local disease-related symptoms. ADT can be used in combination with local treatment in different scenarios. Although neoadjuvant treatment with ADT prior to surgery with curative intent has no clear oncological impact, as a future sight, PCa is a heterogeneous disease, and there could be a group of patients with high-risk localized disease that could benefit. Conclusions We need to optimize the treatment with ADT in localized PCa, selecting the patients accordingly to their disease characteristics. Given that the therapeutic armamentarium evolves day by day, there is a need for the development of new clinical trials, as well as a molecular studies of patients to identify those who might benefit from an early multimodal treatment (AU)

Changes in dorsomedial striatum activity mediate expression of goal-directed vs. habit-like cue-induced cocaine seeking.

A preclinical model of cue exposure therapy, cue extinction, reduces cue-induced cocaine seeking when drug seeking is goal-directed but not habitual. Goal-directed and habitual behaviors differentially rely on the dorsomedial striatum (DMS) and dorsolateral striatum (DLS), but the effects of cue extinction on dorsal striatal responses to cue-induced drug seeking are unknown. We used fiber photometry to examine how dorsal striatal intracellular calcium and extracellular dopamine activity differs between goal-directed and habitual cue-induced cocaine seeking and how it is impacted by cue extinction. Rats trained to self-administer cocaine paired with an audiovisual cue on schedules of reinforcement that promote goal-directed or habitual cocaine seeking had different patterns of dorsal striatal calcium and dopamine responses to cue-reinforced lever presses. Cue extinction reduced calcium and dopamine responses during subsequent drug seeking in the DMS, but not in the DLS. Therefore, cue extinction may reduce goal-directed behavior through its effects on the DMS, whereas habitual behavior and the DLS are unaffected.

Occupational exposure to cosmetic talc and mesothelioma in barbers, hairdressers, and cosmetologists: A systematic review of the epidemiology.

Inhalation exposure to cosmetic talc has generated much scientific debate regarding its potential as a risk factor for mesothelioma, a rare, but fatal cancer. Barbers, hairdressers, and cosmetologists have regularly used cosmetic talc-containing products, but the collective epidemiological evidence for mesothelioma in these occupations has yet to be described. As such, we conducted a systematic review of PubMed and the National Institute for Occupational Safety and Health's (NIOSH) Numbered Publications list to identify original epidemiological literature reporting measures of association between these occupations and incidence of or death from mesothelioma. Literature screening was performed independently twice, the results of which were summarized and tabulated and underwent a review for their accuracy. A total of 12 studies met our inclusion criteria, including three cohort, six case-control, and three proportionate mortality/registration studies. The data from these studies were collected in 13 European and North American countries, spanning more than 50 years. We supplemented this review with queries of occupational mortality databases that are managed by the Washington State Department of Health and NIOSH for 26 U.S. states. Most findings were null and if statistically significant, nearly all showed an inverse relationship, indicative of a protective effect of these occupations on mesothelioma risk. Overall, the epidemiological evidence does not support an increased risk of mesothelioma for these occupations. This research fills an important data gap on the etiology of mesothelioma in barbers, hairdressers, and cosmetologists, and provides a benchmark for those with comparatively less exposure, such as non-occupational users of similar cosmetic talc-containing products.

Tissue factor activates the coagulation cascade in mouse models of acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is associated with a high risk of bleeding and thrombosis. APL patients have an activated coagulation system, hyperfibrinolysis, and thrombocytopenia. APL cells express tissue factor (TF), a receptor and cofactor for factor VII/VIIa. This study had 2 goals. Firstly, we measured biomarkers of coagulation and fibrinolysis activation as well as platelet counts and bleeding in both mouse xenograft and allograft models of APL. Secondly, we determined the effect of inhibiting TF on the activation of coagulation in these models. We observed increased levels of plasma thrombin-antithrombin complexes (TAT), D-dimer, and plasmin-antiplasmin complexes, reduced platelet counts, and increased tail bleeding in both mouse models of APL. Fibrinogen levels decreased in the xenograft model but not in the allograft model. In contrast, the red blood cell count decreased in the allograft model but not in the xenograft model. Inhibition of APL-derived human TF with an anti-human TF monoclonal antibody reduced the level of TAT, increased platelet count, and normalized tail bleeding in a xenograft model. Inhibition of all sources of TF (APL cells and host cells) in the allograft model with a rat anti-mouse TF monoclonal antibody decreased the levels of TAT but did not affect the platelet count. Our study demonstrates that TF plays a central role in the activation of coagulation in both the xenograft and allograft mouse models of APL. These APL mouse models can be used to investigate the mechanisms of coagulopathy and thrombocytopenia in APL.

Panaxynol alleviates colorectal cancer in a murine model via suppressing macrophages and inflammation.

Currently available colorectal cancer (CRC) therapies have limited efficacy and severe adverse effects that may be overcome with the alternative use of natural compounds. We previously reported that panaxynol (PA), a bioactive component in American ginseng, possesses anticancer properties in vitro and suppresses murine colitis through its proapoptotic and anti-inflammatory properties. Because colitis is a predisposing factor of CRC and inflammation is a major driver of CRC, we sought to evaluate the therapeutic potential of PA in CRC. Azoxymethane-dextran sodium sulfate (AOM/DSS) mice (C57BL/6) were administered 2.5 mg/kg PA or vehicle 3 times/wk via oral gavage over 12 wk. PA improved clinical symptoms (P ≤ 0.05) and reduced tumorigenesis (P ≤ 0.05). This improvement may be reflective of PA's restorative effect on intestinal barrier function; PA upregulated the expression of essential tight junction and mucin genes (P ≤ 0.05) and increased the abundance of mucin-producing goblet cells (P ≤ 0.05). Given that macrophages play a substantial role in the pathogenesis of CRC and that we previously demonstrated that PA targets macrophages in colitis, we next assessed macrophages. We show that PA reduces the relative abundance of colonic macrophages within the lamina propria (P ≤ 0.05), and this was consistent with a reduction in the expression of important markers of macrophages and inflammation (P ≤ 0.05). We further confirmed PA's inhibitory effects on macrophages in vitro under CRC conditions (P ≤ 0.05). These results suggest that PA is a promising therapeutic compound to treat CRC and improve clinical symptoms given its ability to inhibit macrophages and modulate the inflammatory environment in the colon.NEW & NOTEWORTHY We report that panaxynol (PA) reduces colorectal cancer (CRC) by improving the colonic and tumor environment. Specifically, we demonstrate that PA improves crypt morphology, upregulates crucial tight junction and mucin genes, and promotes the abundance of mucin-producing goblet cells. Furthermore, PA reduces macrophages and associated inflammation, important drivers of CRC, in the colonic environment. This present study provides novel insights into the potential of PA as a therapeutic agent to ameliorate CRC tumorigenesis.

Evaluation of four commercial ELISAs to measure tissue factor in human plasma.

Background: Under pathological conditions, tissue factor (TF)-positive extracellular vesicles (EVs) are released into the circulation and activate coagulation. Therefore, it is important to identify methods that accurately quantitate levels of TF in plasma. Enzyme-linked immunosorbent assays (ELISAs) are a fast and simple method to quantitate levels of proteins. However, there are several specific challenges with measuring TF antigen in plasma including its low concentration and the complexity of plasma. Objectives: We aimed to evaluate the ability of 4 commercial ELISAs to measure TF in human plasma. Methods: We determined the ability of 4 commercial ELISAs (Imubind, Quantikine, Human SimpleStep, and CD142 Human) to detect recombinant human TF (Innovin) (12.5-100 pg/mL), TF-positive EVs isolated from the culture supernatant from a human pancreatic cancer cell line (57 pg/mL), TF in plasma containing low levels of EV TF activity (1.2-2.6 pg/mL) from lipopolysaccharide-stimulated whole blood, and plasma containing high levels of EV TF activity (151-696 pg/mL) from patients with acute leukemia. Results: The CD142 Human ELISA could not detect recombinant TF. Imubind and Quantikine but not Human SimpleStep detected recombinant TF spiked into plasma and TF-positive EVs isolated from the culture supernatant of a human pancreatic cancer cell line. Quantikine and Imubind could not detect low levels of TF in plasma from lipopolysaccharide-stimulated whole blood. However, Quantikine but not Imubind detected TF in plasma from acute leukemia patients with high levels of EV TF activity. Conclusion: Our results indicate that commercial ELISAs have different abilities to detect TF. Quantikine and Imubind could not detect low levels of TF in plasma, but Quantikine detected TF in plasma with high levels of TF.