Role of taxanes in pancreatic cancer

Pancreatic cancer is one of the most deadly cancers and is characterized by a poor prognosis. Single agent gemcitabine, despite its limited activity and modest impact on disease outcome, is considered as the standard therapy in pancreatic cancer. Most of the combination regimens used in the treatment of this disease, also including the targeted agents, did not improve the outcome of patients. Also, taxanes have been tested as single agent and in combination chemotherapy, both in first line and as salvage chemotherapy, as another possible option for treating pancreatic cancer. The inclusion of taxanes in combination with gemcitabine as upfront therapy obtained promising results. Accordingly, taxanes, and above all, new generation taxanes, appear to be suitable candidates for further testing to assess their role against pancreatic cancer in various clinical settings.     

Aptamer BC 007’s Affinity to Specific and Less-Specific Anti-SARS-CoV-2 Neutralizing Antibodies

COVID-19 is a pandemic respiratory disease that is caused by the highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Anti-SARS-CoV-2 antibodies are essential weapons that a patient with COVID-19 has to combat the disease. When now repurposing a drug, namely an aptamer that interacts with SARS-CoV-2 proteins for COVID-19 treatment (BC 007), which is, however, a neutralizer of pathogenic autoantibodies in its original indication, the possibility of also binding and neutralizing anti-SARS-CoV-2 antibodies must be considered. Here, the highly specific virus-neutralizing antibodies have to be distinguished from the ones that also show cross-reactivity to tissues. The last-mentioned could be the origin of the widely reported SARS-CoV-2-induced autoimmunity, which should also become a target of therapy. We, therefore, used enzyme-linked immunosorbent assay (ELISA) technology to assess the binding of well-characterized publicly accessible anti-SARS-CoV-2 antibodies (CV07-209 and CV07-270) with BC 007. Nuclear magnetic resonance spectroscopy, isothermal calorimetric titration, and circular dichroism spectroscopy were additionally used to test the binding of BC 007 to DNA-binding sequence segments of these antibodies. BC 007 did not bind to the highly specific neutralizing anti-SARS-CoV-2 antibody but did bind to the less specific one. This, however, was a lot less compared to an autoantibody of its original indication (14.2%, range 11.0–21.5%). It was also interesting to see that the less-specific anti-SARS-CoV-2 antibody also showed a high background signal in the ELISA (binding on NeutrAvidin-coated or activated but noncoated plastic plate). These initial experiments suggest that the risk of binding and neutralizing highly specific anti-SARS CoV-2 antibodies by BC 007 should be low.     

Pilot study of the uricosuric effect of DuP-753, a new angiotensin II receptor antagonist,in healthy subjects

Summary The uricosuric effect of DuP-753, a novel, specific angiotensin II receptor antagonist, has been explored in a healthy male Japanese volunteers, given single oral doses of 25, 50, 100 or 200 mg (n=6), or 100 mg (n=6) or placebo (n=3) once daily for 7 consecutive days.In the single-dose study, serum uric acid measured at 4 h after dosing showed a dose dependent decrease; the reductions from the corresponding pre-dose values were: 0.32 (25 mg), 0.77 (50 mg), 1.25 (100 mg) and 1.33 mg dl^–1 (200 mg). The urinary excretion of uric acid within the first 4 h after treatment was also increased in a dose-dependent manner, whereas the urinary excretion of creatinine remained unchanged.In the multiple-dose study, DuP-753 significantly decreased the serum uric acid concentration measured 4 h both after the first (pre-dose value: 5.68 vs 4 h after: 4.48 mg·dl^–1) and last administrations (4.42 mg·dl^–1). Simultaneously, the ratio of urinary uric acid to creatinine excretion was significantly increased within the first 4 h both after the first (DuP-753: 1.190 vs placebo: 0.576) and last administrations (1.02 vs 0.576).The findings suggest that DuP-753 posesses a uricosuric effect both after single and multiple doses in healthy subjects. The effect should be further examined in hypertensive patients.     

Malnutrition Risk in Kidney Recipients Treated With Mycophenolate Mofetil Is Associated With IMPDH1 rs2278294 Polymorphism

Background

Malnutrition is known to increase morbidity and mortality in renal transplant recipients, whereas little is known about genetic predisposition to low body mass index (BMI) in the transplant setting. Inosine monophosphate dehydrogenase (IMPDH) regulates intracellular fat accumulation, pre-adipicytes maturation, and is a target of mycophenolic acid (MPA) used as a standard immunosuppressant. We hypothesized that MPA may interfere with fat tissue formation and weight gain in kidney transplant recipients and this process may be modified by IMPDH1 or IMPDH2 (genes encoding constitutive and inducible IMPDH) small nucleotide polymorphism variants.

Immune responses elicited by a fourth dose of the HPV-16/18 AS04-adjuvanted vaccine in previously vaccinated adult women

Background

Vaccines are now available for the prevention of HPV-16/18-related cervical infections and pre-cancers, primarily targeting adolescent girls. Since the risk of HPV exposure potentially persists throughout a woman's sexual life, vaccine-derived immunity should be long-term. The current study, HPV-024 (NCT00546078, http://clinicaltrials.gov), assessed the immune memory in North American women who received three doses of HPV-16/18 AS04-adjuvanted vaccine 7 years earlier in HPV-001 (NCT00689741).

Methods

Women vaccinated in HPV-001 received a 4th-dose of the HPV-16/18 vaccine (024-4DV group, N = 65). Post 4th-dose immune responses were compared with post 1st-dose immune responses in cross-vaccination controls (024-3DV group, N = 50). Reactogenicity was compared between the 4th-dose and the 1st-dose administration.

Results

Pre 4th-dose, 100% of subjects in the 024-4DV group remained seropositive for anti-HPV-16/18 antibodies (ELISA). Compared to pre 4th-dose, GMTs for anti-HPV-16 and anti-HPV-18 antibodies were respectively 9.3-fold and 8.7-fold higher at day 7, and 22.7-fold and 17.2-fold higher at month 1. Compared to post 1st-dose, GMTs for anti-HPV-16 and anti-HPV-18 were respectively 80.5-fold and 205.4-fold higher at day 7, and 11.8-fold and 20.5-fold higher at month 1. Furthermore, 68.2% and 77.3% of women had HPV-16/18 specific memory B-cells, respectively, pre 4th-dose, rising to 100% one month post 4th-dose vaccination. The 4th-dose was generally well tolerated.

Conclusion

A 4th-dose of HPV-16/18 AS04-adjuvanted vaccine triggered a rapid and strong anamnestic response in previously vaccinated women, demonstrating vaccine-induced immune memory.     

Low dose injectable contraceptive norethisterone enanthate 20mg monthly — I. Clinical trials

Clinical trials were undertaken with an injectable low dose progestational contraceptive, norethisterone enanthate 20 mg monthly (Net-en — 20). Data from the study indicate that Net-en — 20 is an effective contraceptivs with lower incidence of menstrual cycle disturbances than the currently used injectable progestogens. There was a prompt return of fertility after the withdrawal of the drug. Net-en — 20 did not have any adverse effect on maternal nutritional status as assessed by anthropometric indices of nutritional scatus, and clinical sign of nutritional deficiencies or on lactational performance as assessed by mothers' impression on milk output and mean duration of lactation.     

Effect of heparin in anticoagulant doses on the electrocardiogram and cardiac enzymes in patients with acute myocardial infarction. A clinical pilot study.

The effect of heparin in clinical anticoagulant doses on S-T segment and cardiac enzymes was studied in 18 patients with acute myocardial infarction by electrocardiogram and enzyme evaluation 1 hour and 24 hours after initial heparin infusion. Intestinal mucosa heparin was given by infusion, 10,000 units after the admission electrocardiogram, and 5,000 units every 6 hours. Data in the nine control and nine treated patients were statistically similar on admission. The electrocardiograph findings were improved, but not significantly, 1 hour after administration of heparin. At 24 hours of heparin therapy, the S-T deviations were reduced 64% (from 139 +/- 2.1 [standard error of the mean] to 50.5 +/- 1.2 mm); in control patients S-T deviations were reduced 21% (from 109 +/- 1.8 to 86 +/- 0.9 mm (t=2.9, P less than 0.019). At 24% hours electrocardiographic leads with 2 mm or more deviation were reduced 86% in heparin-treated patients and 28% in control subjects. Cardiac enzymes were comparably elevated at 24 and 48 hours in both groups, with no clear trend. It is concluded that heparin in anticoagulant doses reduces the 12 lead electrocardiographic pattern of injury without discernibly modifying cardiac enzymes. The question of heparin efficacy in acute myocardial ischemic injury, reopened by findings with large dose heparin in therapy in dogs and anticoagulant dose in this study, awaits further expanded investigation.     

Elevated fetal chromosomal damage in malnourished pregnant rats

Cytogenetic studies in fetal cells from pregnant rats given a protein-restricted diet revealed a significant induction of structural chromosomal aberrations and sister chromatid exchanges.     

Mamu-B＊ 007：03及其剪切异构体Mamu-B＊ 007：03-sv1基因的表达与细胞内定位

目的 Mamu-B＊007：03-sv1是中国恒河猴主要组织相容性复合体（major histocompatibility complex,MHC）I类分子的一种剪切异构体,其α3结构域缺失。本实验初步获得其在细胞内的表达和定位信息,并与全长的Mamu-B＊007：03基因的表达情况进行比较。方法分别构建Mamu-B＊007：03-sv1-myc-pEGFPN3和Mamu-B＊007：03-myc-pEGFPN3的真核表达载体,并将这两种重组质粒分别转染293T细胞。利用Western-blot免疫印迹实验检测这两种基因在细胞内的表达情况,并利用激光共聚焦显微镜技术分别分析这两种基因在细胞内的表达定位。结果 Mamu-B＊007：03-sv1和Mamu-B＊007：03基因均能在293T细胞内正常表达。Mamu-B＊007：03-sv1发生了糖基化的修饰,Mamu-B＊007：03基因在细胞膜上表达,Mamu-B＊007：03-sv1基因在细胞内表达。结论 Mamu-B＊007：03-sv1基因的α3结构域缺失,其细胞内的表达和定位与全长Mamu-B＊007：03基因有明显差异,其功能有待于进一步探索。