Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma.

Pancreatic Ductal Adenocarcinoma (PDAC) has a five-year survival under 10%. Treatment is compromised due to a fibrotic-like stromal remodeling process, known as desmoplasia, which limits therapeutic perfusion, supports tumor progression, and establishes an immunosuppressive microenvironment. These processes are driven by cancer-associated fibroblasts (CAFs), functionally activated through transforming growth factor beta1 (TGFß1). CAFs produce a topographically aligned extracellular matrix (ECM) that correlates with reduced overall survival. Paradoxically, ablation of CAF populations results in a more aggressive disease, suggesting CAFs can also restrain PDAC progression. Thus, unraveling the mechanism(s) underlying CAF functions could lead to therapies that reinstate the tumor-suppressive features of the pancreatic stroma. CAF activation involves the f-actin organizing protein palladin. CAFs express two palladin isoforms (iso3 and iso4) which are up-regulated in response to TGFß1. However, the roles of iso3 and iso4 in CAF functions remain elusive. Using a CAF-derived ECM model, we uncovered that iso3/iso4 are required to sustain TGFß1-dependent CAF activation, secrete immunosuppressive cytokines, and produce a pro-tumoral ECM. Findings demonstrate a novel role for CAF palladin and suggest that iso3/iso4 regulate both redundant and specific tumor-supportive desmoplastic functions. This study highlights the therapeutic potential of targeting CAFs to restore fibroblastic anti-tumor activity in the pancreatic microenvironment.

Rate effects on transformation kinetics in a metastable austenitic stainless steel.

In this study, the effects of strain rate on the mechanical properties and the strain-induced austenite-to-martensite transformation in type 201 austenitic stainless steel (SS201) were investigated. This grade was selected as a low-cost stainless steel with good lightweighting potential for automotive applications. The material was tested in tension at a quasi-static rate (5×10-2 s-1), two low-intermediate rates (100 s-1 and 101 s-1), and a high rate (5×102 s-1). 3D digital image correlation was used to enable accurate strain measurements during mechanical testing. Magnetic induction and X-ray diffraction were used ex-situ of deformation to measure the volume fraction of martensite formed at each strain rate, for different plastic strain levels. The effects of strain rate on deformation-induced martensite formation and on the stress/strain behavior was determined in this study, and was compared to results reported in the literature for 300 series austenitic stainless steels. The results show a favourable response for the SS201, which exhibits a substantial increase in strength and energy absorption at high rates without compromising tensile ductility.

Radioimmunoassay of oxytocin.

The evaluation of a radioimmunoassay of oxytocin is described. The method involved careful collection and transportation of blood at 4 degrees C, acidification of the plasma, extraction with Fuller's earth and radioimmunoassay using antisera raised in rabbits immunized against oxytocin conjugated to bovine serum albumin and 125I-labelled oxytocin. The antisera showed insignificant cross-reaction with a variety of small peptides including vasopressin and vasotocin. The limit of detection of the assay was 2.5 pg with intra-assay and interassay coefficients of variation of 7-15% and 12-18% respectively. Seventy-seven per cent (88 out of 116) of the pregnant women tested had detectable maternal plasma oxytocin. Serial samples of maternal plasma showed a significant increase in oxytocin from the first to the second stage of labour and a significant decrease in the third stage. Oxytocin concentrations in the umbilical arterial plasma were significantly higher in patients in labour. The significance of these findings is discussed.

A study on gelatin capsule brittleness: moisture tranfer between the capsule shell and its content.

Variation in moisture content of the capsule shells either due to the change of storage conditions or the moisture transfer between the capsule shell and its contents may lead to undesired physical properties, such as capsule brittleness and stickiness. DMP 504, a developmental bile-acid sequestrant, is a strongly basic anion-exchange polymer which contains randomly distributed primary, secondary, tertiary, and quaternary amine groups in their hydrochoride salt form. The alkylammonium groups which comprise this polymer form a random network containing a high level of branching and a low level of cross-linking. DMP 504 is very hygroscopic and has a tendency to gain or lose moisture with ease. The transfer of moisture from the capsule shell to DMP 504 powder contained in a hard gelatin capsule can be expected, and if a low water content of the capsule shell is achieved, the capsules become brittle and fracture easily. The sorption isotherm for DMP 504 was generated by storing the drug substance under various relative humidity conditions. After equilibrium, the moisture contents for the samples of individual isotherm points were measured by thermogravimetric analyses. This report applies the sorption-desorption moisture transfer (SDMT) model to predict the equilibrium relative humidity in a system containing DMP 504 in hard gelatin capsules and to establish target loss on drying values for DMP 504 and the capsule shell. Application of this SDMT model resulted in finding a solution to the brittleness problem. The moisture levels of capsule shells and contents for two formulations in a 12-month stability program are also reported here. Results of this study further demonstrate that the SDMT model can be used as a tool to guide the formulator to select optimal initial moisture contents for the empty capsule shell and the formulation to avoid the incidence of brittle capsule problems.

MANAGEMENT OF INTRACTABLE POSTPARTUM HEMORRHAGE SECONDARY TO UTERINE ATONY WITH INTRAMUSCULAR 15(S)15 METHYL PGF2α.

In a multicentre trial the efficacy of 250 µg of intramuscular 15(S)15 methyl PGF2α (Prostin 15M, Upjohn) was tested in controlling the postpartum hemorrhage following delivery at term. All patients included in this study did not respond to the conventional therapy of intravenous oxytocin infusion and methergin. Forty-eight patients were included in this analysis. Forty patients responded to therapy. The blood loss following Prostin 15M injection was significantly (p<0.01) reduced from 666 ml to 341 ml. The mean blood replacement was 833 ml.

RANDOMIZED COMPARISON BETWEEN TWO-HOURLY AND THREE-HOURLY INTRAMUSCULAR TREATMENT WITH 15(S)15 METHYL PGF2α FOR TERMINATION OF SECOND TRIMESTER PREGNANCY.

In a multicentre trial, intramuscular 15(S)15 methyl PGF2α (Prostin 15M, Up-john) was tried at 2-hourly and 3-hourly intervals for induction of second trimester abortion. The time schedule was assigned randomly. Eighty-eight patients for 2-hourly schedule and 89 patients for 3-hourly schedule were recruited. Of 2-hourly 83% and of 3-hourly schedule 88.8% of the patients aborted with the treatment. The induction abortion interval was 15.9 hours in 2-hourly and 17.2 hours in 3-hourly schedule. The dose of Prostin 15M was 2.2 mg and 1.7 mg respectively. The incidence of incomplete abortion was 21.9% in 2-hourly and 27.8% in the 3-hourly. The incidence of vomiting was less in the 3-hourly schedule, however, there was no difference in the incidence of diarrhoea.

STUDIES ON 15(S)15 METHYL PGF2α BY INTRAMUSCULAR ROUTE FOR SECOND TRIMESTER ABORTION (TWO HOURLY SCHEDULE).

A multicentre study was undertaken to study intramuscular 15(S)15 methyl PGF2α (Prostin 15M, Upjohn) for induction of second trimester abortion. The patients were premedicated with Imodium and Perinorm to control the gastrointestinal side effects. The dose of Prostin 15M was 250 µg every two hours and the progress of the abortion was assessed before each injection. If there was no progress at the end of 10 injections the case was classified as a failure. Ninety-seven patients were recruited for the study, 39 were primigravidae and 58 multigravidae. Twenty-four out of 39 primigravidae and 52 out of 58 multigravidae aborted with the treatment. The mean induction abortion interval was 17.8 hours in the primigravidae and 14.5 hours in the multigravidae patients. The mean number of episodes of vomiting was 2.9 and diarrhoea 4.2 per patient per trial. The primigravidae had slightly higher incidence of gastrointestinal side effects. The overall incidence of incomplete abortion was 17.1%.

INTRAMUSCULAR 15(S)15 METHYL PGF2α IN THE TREATMENT OF MISSED ABORTION.

Intramuscular 15(S)15 methyl PGF2α (Prostin 15M, Upjohn) was used for induction of labour in cases of missed abortion and intra-uterine fetal death. The patients received premedication to control the gastrointestinal side effects. Prostin 15M was given at a dose of 250 µg every three hours and escalated whenever required. The trial was interrupted in two out of 83 patients. Altogether 75 patients (92.6%) expelled the fetus with the treatment. The mean induction abortion interval was 14.7 hours. The primigravidae had a longer (18.2 hrs) interval than the multigravidae (13.8 hrs). The mean number of episodes of vomiting was 2.9 and of diarrhoea 3.5 per patient and treatment.

Midtrimester abortion with intravenous administration of 15 methyl prostaglandin F2 alpha.

In a trial of 71 women, 15(S) 15 methyl PGF2 alpha was administered intravenously at the dose level of 1 microgram/min for termination of pregnancy of between 11 weeks and 20 weeks of gestation. Sixty-one subjects (85.9%) aborted within 30 h of administration of the drug. The mean induction abortion interval was 15.65 h. The mean number of episodes of vomiting and diarrhea was 0.9 and 0.6, respectively. The effectiveness of the method is comparable to that of intramuscular method of administration, but the side effects are much less in comparison.

PIP: A group of 71 women between 11-20 weeks of gestation who desired termination of pregnancy and had no contraindications for prostaglandin (PG) administration were given complete physical and gynecological examinations; hemoglobin was estimated and urinalysis was done. They were then given orally 2 tablets of Lomotil (diphenoxylate HCl 2.5 mg + atropine sulphate 0.025 mg) and 1 tablet of Stemetil (Prochlorperazine 5 mg). They were then given 15 (S) 15 methyl PGF2alpha intravenously at the dose level of 1 mcg/min. 61 subjects (85.9%) aborted within 30 hours. At regular intervals pulse rate, blood pressure, uterine pain, nausea, vomiting, diarrhea, temperature, and respiratory rate were measured and any other side effects were recorded. The mean induction abortion interval was 15.65 hours, the mean number of episodes of vomiting and diarrhea was 0.9 and 0.6 respectively. This study compared well with the intramuscular route of administration with a higher rate of complete abortions and lower rate of side effects. The latter is explained on the basis of smaller amounts of the drug being infused at a slower rate. Disadvantages include confinement to bed, discomfort, and need of constant supervision. Compared with intraamniotic and extraamniotic case studies, the latter are invasive procedures while the intravenous method is not. Also, the intravenous route allows for adjusted drug dosage and stopping the procedure in the event of an undesirable reaction.