Umbilical artery tone in maternal obesity

Background: The increasing prevalence of obesity constitutes a major health problem in obstetrics with implications for feto-maternal growth and wellbeing. This study investigated and compared the contractile properties of umbilical arteries excised from obese women, with those excised from women with a normal body mass index (BMI). Methods: Sections of umbilical artery were obtained from umbilical cord samples immediately after delivery and mounted for isometric recording in organ tissue baths under physiological conditions. Cumulative additions of 5-Hydroxytryptamine (5-HT) and Prostaglandin F-2alpha (PgF2alpha) were added in the concentration range of 1 nmol/L to 10 micromol/L. Control vessels were exposed to Krebs physiological salt solution (PSS) only. The resultant effects of each drug addition were measured using the Powerlab hardware unit. Results: 5-HT exerted a significant effect on human umbilical artery tone at concentrations of 100 nmol/L, 1 micromol/L, and 10 micromol/L in normal (n = 5; P < 0.05) and obese ( n = 5; P < 0.05) women. The contractile effect was significantly greater in vessels from obese women {Mean Maximum Tension (MMT) = 4.2532 g} than in those from women of normal BMI (MMT = 2.97 g; P < 0.05). PgF2alpha exerted a significant contractile effect on vessels at 1 micromol/L and 10 micromol/L concentrations when compared with controls (n = 5; P < 0.05). There was a nonsignificant trend towards an enhanced tone response in vessels from obese women (MMT = 3.02 g; n = 5), in comparison to vessels from women of a normal BMI (MMT = 2.358 g; n = 5; P > 0.05). Conclusion: These findings support the hypothesis that endogenous regulation of umbilical artery tone is altered in association with maternal obesity. This may be linked to the cardiovascular effects of secretory products of adipose tissue, with implications for the feto-maternal circulation

Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma

Published in final edited form as: Sci Transl Med. 2017 May 10; 9(389). https://doi.org/10.1126/scitranslmed.aal2668.Multiple myeloma (MM) is a frequently incurable hematological cancer in which overactivity of MYC plays a central role, notably through up-regulation of ribosome biogenesis and translation. To better understand the oncogenic program driven by MYC and investigate its potential as a therapeutic target, we screened a chemically diverse small-molecule library for anti-MM activity. The most potent hits identified were rocaglate scaffold inhibitors of translation initiation. Expression profiling of MM cells revealed reversion of the oncogenic MYC-driven transcriptional program by CMLD010509, the most promising rocaglate. Proteome-wide reversion correlated with selective depletion of short-lived proteins that are key to MM growth and survival, most notably MYC, MDM2, CCND1, MAF, and MCL-1. The efficacy of CMLD010509 in mouse models of MM confirmed the therapeutic relevance of these findings in vivo and supports the feasibility of targeting the oncogenic MYC-driven translation program in MM with rocaglates

The LIN28B/let-7 axis is a novel therapeutic pathway in Multiple Myeloma

MYC is a major oncogenic driver of Multiple Myeloma (MM) and yet almost no therapeutic agents exist that target MYC in MM. Here we report that the let-7 biogenesis inhibitor LIN28B correlates with MYC expression in MM and is associated with adverse outcome. We also demonstrate that the LIN28B/let-7 axis modulates the expression of MYC, itself a let-7 target. Further, perturbation of the axis regulates the proliferation of MM cells in vivo in a xenograft tumor model. RNA sequencing and gene set enrichment analyses of CRISPR-engineered cells further suggest that the LIN28/let-7 axis regulates MYC and cell cycle pathways in MM. We provide proof-of-principle for therapeutic regulation of MYC through let-7 with an LNA-GapmeR containing a let-7b mimic in vivo, demonstrating that high levels of let-7 expression repress tumor growth by regulating MYC expression. These findings reveal a novel mechanism of therapeutic targeting of MYC through the LIN28B/let-7 axis in MM that may impact other MYC dependent cancers as well

Umbilical artery tone in maternal obesity

Background: The increasing prevalence of obesity constitutes a major health problem in obstetrics with implications for feto-maternal growth and wellbeing. This study investigated and compared the contractile properties of umbilical arteries excised from obese women, with those excised from women with a normal body mass index (BMI). Methods: Sections of umbilical artery were obtained from umbilical cord samples immediately after delivery and mounted for isometric recording in organ tissue baths under physiological conditions. Cumulative additions of 5-Hydroxytryptamine (5-HT) and Prostaglandin F-2alpha (PgF2alpha) were added in the concentration range of 1 nmol/L to 10 micromol/L. Control vessels were exposed to Krebs physiological salt solution (PSS) only. The resultant effects of each drug addition were measured using the Powerlab hardware unit. Results: 5-HT exerted a significant effect on human umbilical artery tone at concentrations of 100 nmol/L, 1 micromol/L, and 10 micromol/L in normal (n = 5; P < 0.05) and obese ( n = 5; P < 0.05) women. The contractile effect was significantly greater in vessels from obese women {Mean Maximum Tension (MMT) = 4.2532 g} than in those from women of normal BMI (MMT = 2.97 g; P < 0.05). PgF2alpha exerted a significant contractile effect on vessels at 1 micromol/L and 10 micromol/L concentrations when compared with controls (n = 5; P < 0.05). There was a nonsignificant trend towards an enhanced tone response in vessels from obese women (MMT = 3.02 g; n = 5), in comparison to vessels from women of a normal BMI (MMT = 2.358 g; n = 5; P > 0.05). Conclusion: These findings support the hypothesis that endogenous regulation of umbilical artery tone is altered in association with maternal obesity. This may be linked to the cardiovascular effects of secretory products of adipose tissue, with implications for the feto-maternal circulation

Umbilical artery tone in maternal obesity

Abstract Background The increasing prevalence of obesity constitutes a major health problem in obstetrics with implications for feto-maternal growth and wellbeing. This study investigated and compared the contractile properties of umbilical arteries excised from obese women, with those excised from women with a normal body mass index (BMI). Methods Sections of umbilical artery were obtained from umbilical cord samples immediately after delivery and mounted for isometric recording in organ tissue baths under physiological conditions. Cumulative additions of 5-Hydroxytryptamine (5-HT) and Prostaglandin F-2alpha (PgF2alpha) were added in the concentration range of 1 nmol/L to 10 micromol/L. Control vessels were exposed to Krebs physiological salt solution (PSS) only. The resultant effects of each drug addition were measured using the Powerlab hardware unit. Results 5-HT exerted a significant effect on human umbilical artery tone at concentrations of 100 nmol/L, 1 micromol/L, and 10 micromol/L in normal (n = 5; P 0.05). Conclusion These findings support the hypothesis that endogenous regulation of umbilical artery tone is altered in association with maternal obesity. This may be linked to the cardiovascular effects of secretory products of adipose tissue, with implications for the feto-maternal circulation.</p

Training for Translation – The Physician Scientist’s Career Path

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Inhibitory effect of leptin on human uterine contractility in vitro

Leptin Myometrium Maternal obesity Parturition Objective: The purpose of this study was to investigate the effects of leptin on human uterine contractility in vitro. Study design: Biopsies of human myometrium were obtained at elective cesarean section (n = 18). Dissected myometrial strips suspended under isometric conditions, undergoing spontaneous and oxytocin-induced contractions, were exposed to cumulative additions of leptin in the concentration range of 1 nmol/L to 1 mmol/L. Control strips were run simultaneously. Integrals of contractile activity were measured using the PowerLab hardware unit and Chart v3.6 software. Results: Leptin exerted a potent and cumulative inhibitory effect on spontaneous and oxytocininduced contractions compared to control strips. The mean maximal inhibition values were as follows: 46.794 G 5.133% (n = 6; P ! .001) for spontaneous contractions and 42.323 G 3.692% (n = 6; P ! .001) for oxytocin-induced contractions. There was an apparent reduction in both frequency and amplitude of contractions. Conclusion: This physiologic inhibitory effect of leptin on uterine contractility may play a role in the dysfunctional labor process associated with maternal obesity, and the resultant high cesarean section rates

The impact of dialysis on the survival of patients with immunoglobulin light chain (al) amyloidosis undergoing autologous stem cell transplantation

Acute renal failure requiring dialysis is associated with high mortality during autologous stem cell transplantation (ASCT). This study examined the association between acute renal failure and mortality in immunoglobulin light chain (AL) amyloidosis during ASCT. Between 1996 and 2010, 408 ASCT patients were evaluated. Data were collected from electronic medical records. Dialysis was performed on 72 (17.6%) patients. Eight patients started dialysis &amp;gt; 30 days prior to ASCT (Group II), 36 started +/- 30 days after ASCT (Group III) and 28 initiated dialysis &amp;gt; 1 month after ASCT (Group IV). Patients who never dialyzed were assigned to Group I. There were no significant age or sex differences. Median overall survival (OS) had not been reached in Groups I and II but was 7.0 months in Group III and 48.5 months in Group IV (P &amp;lt; 0.001). Treatment-related mortality (TRM) was observed in 44.4% of the patients in Group III, 6-fold higher than the next highest group (P &amp;lt; 0.001). The most common causes of TRM were cardiac and sepsis. In the multivariate analysis, only hypoalbuminemia (&amp;lt; 2.5 g/dL, P &amp;lt; 0.001) and estimated glomerular filtration rate (eGFR) &amp;lt; 40 mL/min/1.73 m(2) (P &amp;lt; 0.001) were independently associated with starting dialysis within 30 days of ASCT. The study found significant differences in the OS depending on when the acute renal failure occurred. Patients who required dialysis within 30 days of ASCT had the highest rate of TRM. Screening with serum albumin and eGFR may reduce the risk

The impact of dialysis on the survival of patients with immunoglobulin light chain (al) amyloidosis undergoing autologous stem cell transplantation

Acute renal failure requiring dialysis is associated with high mortality during autologous stem cell transplantation (ASCT). This study examined the association between acute renal failure and mortality in immunoglobulin light chain (AL) amyloidosis during ASCT. Between 1996 and 2010, 408 ASCT patients were evaluated. Data were collected from electronic medical records. Dialysis was performed on 72 (17.6%) patients. Eight patients started dialysis &amp;gt; 30 days prior to ASCT (Group II), 36 started +/- 30 days after ASCT (Group III) and 28 initiated dialysis &amp;gt; 1 month after ASCT (Group IV). Patients who never dialyzed were assigned to Group I. There were no significant age or sex differences. Median overall survival (OS) had not been reached in Groups I and II but was 7.0 months in Group III and 48.5 months in Group IV (P &amp;lt; 0.001). Treatment-related mortality (TRM) was observed in 44.4% of the patients in Group III, 6-fold higher than the next highest group (P &amp;lt; 0.001). The most common causes of TRM were cardiac and sepsis. In the multivariate analysis, only hypoalbuminemia (&amp;lt; 2.5 g/dL, P &amp;lt; 0.001) and estimated glomerular filtration rate (eGFR) &amp;lt; 40 mL/min/1.73 m(2) (P &amp;lt; 0.001) were independently associated with starting dialysis within 30 days of ASCT. The study found significant differences in the OS depending on when the acute renal failure occurred. Patients who required dialysis within 30 days of ASCT had the highest rate of TRM. Screening with serum albumin and eGFR may reduce the risk