BACKGROUND.Cytokines have been implicated in diverse processes that are relevant to pancreatic carcinoma, including cachexia, asthenia, and tumor growth. The objective of this study was to examine the association between serum levels of proinflammatory and antiinflammatory or angiogenic cytokines and the outcomes of patients with pancreatic carcinoma. METHODS.Serum cytokine levels were measured by enzyme-linked immunosorbent assay from 51 patients with pancreatic carcinoma and from 48 -62 healthy volunteers. Cytokine levels were compared with disease manifestations and overall survival. RESULTS.Circulating levels of vascular endothelial growth factor, tumor necrosis factor alpha, interleukin-1␣ (IL-1␣), and IL-1 were not elevated significantly in patients with pancreatic carcinoma, but levels of IL-6, IL-8, IL-10, and IL-1 receptor antagonist (IL-1RA) were elevated significantly (P Ͻ 0.05). Cytokine levels were dichotomized based on an analysis of null Martingale residuals. Patients who had IL-6 levels Ͼ 5.2 pg/mL or IL-10 levels Ͼ 9.8 pg/mL had significantly worse survival compared with patients who had lower IL-6 or IL-10 levels (P Ͻ 0.05). IL-8 levels were not associated with survival differences. Patients who had IL-1RA levels Ͻ 159 pg/mL had significantly worse survival compared with patients who had higher IL-1RA levels (P Ͻ 0.05). Higher IL-6, IL-10, and IL-8 levels were associated with poor performance status and/or weight loss. In multivariate analysis, only T 4 tumors and high IL-6 levels were selected as independent prognostic factors for poor survival. CONCLUSIONS.Circulating levels of several cytokines were high in patients with pancreatic carcinoma, and their association with weight loss and poor performance status suggested that they may be involved in these disease manifestations.
Induced pluripotent stem cells are powerful tools for disease modeling, drug screening, and cell transplantation therapies. These cells can be generated directly from somatic cells by ectopic expression of defined factors through a reprogramming process. However, pluripotent reprogramming is an inefficient process because of various defined and unidentified barriers. Recent studies dissecting the molecular mechanisms of reprogramming have methodically improved the quality, ease, and efficiency of reprogramming. Different strategies have been applied for enhancing reprogramming efficiency, including depletion/inhibition of barriers (p53, p21, p57, p16Ink4a/p19Arf, Mbd3, etc.), overexpression of enhancing genes (e.g., FOXH1, C/EBP alpha, UTF1, and GLIS1), and administration of certain cytokines and small molecules. The current review provides an in-depth overview of the cutting-edge findings regarding distinct barriers of reprogramming to pluripotency and strategies to enhance reprogramming efficiency. By incorporating the mechanistic insights from these recent findings, a combined method of inhibition of roadblocks and application of enhancing factors may yield the most reliable and effective approach in pluripotent reprogramming.
BackgroundApicomplexan parasites of the genus Cryptosporidium infect a wide range of animal species as well as humans. Cryptosporidium spp. can cause life threatening diarrhea especially in young animals, children, immunocompromised patients and malnourished individuals. Asymptomatic cryptosporidial infections in animals can also occur, making these animals potential reservoirs of infection.MethodsIn the present study, a molecular survey of Cryptosporidium spp. in ruminants that were slaughtered for human consumption in Yazd Province, located in central Iran was conducted. Faeces were collected per-rectum from 484 animals including 192 cattle, 192 sheep and 100 goats. DNA was extracted from all samples and screened for Cryptosporidium by PCR amplification of the 18S rRNA gene. Positives were Sanger sequenced and further subtyped by sequence analysis of the 60 kDa glycoprotein (gp60) locus.ResultsIn total, Cryptosporidium spp. were detected in 22 animals: C. andersoni and C. bovis in seven and two cattle faecal samples, respectively, C. ubiquitum in five sheep, and C. xiaoi in six sheep and two goat samples, respectively. To our knowledge, this study provides for the first time, molecular information concerning Cryptosporidium species infecting goats in Iran, and is also the first report of C. ubiquitum and C. xiaoi from ruminants in Iran.ConclusionThe presence of potentially zoonotic species of Cryptosporidium in ruminants in this region may suggest that livestock could potentially contribute to human cryptosporidiosis, in particular among farmers and slaughterhouse workers, in the area. Further molecular studies on local human populations are required to more accurately understand the epidemiology and transmission dynamics of Cryptosporidium spp. in this region.
BackgroundThe incidence of menopausal symptoms, including hot flashes and sleep disturbance, caused by drug treatment is a common problem in breast cancer survivors. Considering the limitations of hormone therapy in such patients, several studies have been conducted to find alternative methods. The aim of this study was to investigate and compare the effectiveness of stellate ganglion block (SGB) with that of paroxetine, which was approved by the US Food and Drug Administration (FDA) as a medicine for the treatment of hot flashes and ensuing sleep disturbance.Patients and methodsA total of 40 patients survived from breast cancer and complaining of these symptoms were equally assigned to two groups of 20 each. In the study group, SGB was performed successfully under sonography guidance using 10 mL of 0.5% bupivacaine, and in the control group (paroxetine), the daily administration of 7.5 mg of paroxetine was conducted for 6 weeks. The frequency and severity of hot flash attacks and sleep quality of patients were evaluated prior to the intervention and after 2, 4 and 6 weeks. The incidence of adverse events during treatment or follow-up was recorded.ResultsA significant decrease in hot flash score and sleep disturbance index (SDI) was observed in both groups. Comparison of the results showed no noticeable difference between the two groups. Two participants in the control group had discontinued medication due to gastrointestinal symptoms, and only one case of mild headache was reported in the study group.ConclusionSGB is as much effective as paroxetine in controlling hot flashes and sleep disturbances in breast cancer survivors and is associated with few complications.
Background: CDK4/6 inhibitors modulate immune response in breast cancer. This phase I/II trial was designed to test the safety and efficacy of palbociclib, pembrolizumab and letrozole in women with hormone receptor positive (HR þ ) human epidermal growth factor receptor 2 negative (HER2 À ) metastatic breast cancer (MBC). Patients and methods: Women with stage IV HR þ HER2 À MBC were enrolled and treated with palbociclib, pembrolizumab and letrozole. Primary end-points were safety, tolerability and efficacy. Results: Between November 2016 and July 2020, 23 patients were enrolled with 20 evaluable for response, including 4 patients in cohort 1 and 16 patients in cohort 2. Cohort 1 median age was 48 years (33e70) and cohort 2 median age was 55 (37e75). Cohort 1 closed early due to limited accrual. Grade IIIeIV adverse events were neutropenia (83%), leucopaenia (65%), thrombocytopenia (17%) and elevated liver enzymes (17%). In cohort 1, 50% achieved a partial response (PR) and 50% had stable disease (SD). In cohort 2, 31% achieved complete
Endometrial cancer (EC) is the fourth most common cancer in women. Advanced-stage EC has limited treatment options with a poor prognosis. There is an unmet need for the identification of actionable drivers for the development of targeted therapies in EC. Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a major role in cancer progression, metastasis, stemness, and therapy resistance. However, little is known about the functional significance of the LIF/LIFR axis in EC progression. In this study using endometrial tumor tissue arrays, we identified that expression of LIF, LIFR is upregulated in EC. Knockout of LIFR using CRISPR/Cas9 in two different EC cells resulted in a significant reduction of their cell viability and cell survival. In vivo studies demonstrated that LIFR-KO significantly reduced EC xenograft tumor growth. Treatment of established and primary patient-derived EC cells with a novel LIFR inhibitor, EC359 resulted in the reduction of cell viability with an IC50 in the range of 20–100 nM and induction of apoptosis. Further, treatment with EC359 reduced the spheroid formation of EC cancer stem cells and reduced the levels of cancer stem cell markers SOX2, OCT4, NANOG, and Axin2. Mechanistic studies demonstrated that EC359 treatment attenuated the activation of LIF-LIFR driven pathways, including STAT3 and AKT/mTOR signaling in EC cells. Importantly, EC359 treatment resulted in a significant reduction of the growth of EC patient-derived explants ex vivo, EC cell line-derived xenografts, and patient-derived xenografts in vivo. Collectively, our work revealed the oncogenic potential of the LIF/LIFR axis in EC and support the utility of LIFR inhibitor, EC359, as a novel targeted therapy for EC via the inhibition of LIF/LIFR oncogenic signaling.
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