Early Post-treatment Prostate-specific Antigen at 4 Weeks and Abiraterone and Enzalutamide Treatment for Advanced Prostate Cancer: An International Collaborative Analysis.

Background Declines in prostate-specific antigen (PSA) levels at 12wk are used to evaluate treatment response in metastatic castration-resistant prostate cancer (mCRPC). PSA fall by ≥30% at 4wk (PSA4w30) has been reported to be associated with better outcome in a single-centre cohort study.Objective To evaluate clinical relevance of early PSA decline in mCRPC patients treated with next-generation hormonal treatments (NGHTs) such as abiraterone and enzalutamide.Design, setting, and participants This was a retrospective multicentre analysis. Eligible patients received NGHT for mCRPC between 6 January 2006 and 31 December 2017 in 13 cancer centres worldwide, and had PSA levels assessed at baseline and at 4 and/or 12wk after treatment. PSA response was defined as a ≥30% decline (progression as a ≥25% increase) from baseline.Outcome measurements and statistical analysis Association with overall survival (OS) was analysed using landmark multivariable Cox regression adjusting for previous chemotherapy, including cancer centre as a shared frailty term.Results and limitations We identified 1358 mCRPC patients treated with first-line NGHT (1133 had PSA available at 4wk, and 948 at both 4 and 12wk). Overall, 583 (52%) had a PSA4w30; it was associated with longer OS (median: 23; 95% confidence interval [CI]: 21-25) compared with no change (median: 17; 95% CI: 15-18) and progression (median: 13; 95% CI: 10-15). A PSA12w30 was associated with lower mortality (median OS 22 vs 14; hazard ratio=0.57; 95% CI=0.48-0.67; p<0.001). PSA4w30 strongly correlated with PSA12w30 (ρ=0.91; 95% CI=0.90-0.92; p<0.001). In total, 432/494 (87%) with a PSA4w30 achieved a PSA12w30. Overall, 11/152 (7%) patients progressing at 4wk had a PSA12w30 (1% of the overall population).Conclusions PSA changes in the first 4wk of NGHT therapies are strongly associated with clinical outcome from mCRPC and can help guide early treatment switch decisions.Patient summary Prostate-specific antigen changes at 4wk after abiraterone/enzalutamide treatment are important to determine patients' outcome and should be taken into consideration in clinical practice

Serum immunoglobulin G, M and A response to Cryptosporidium parvum in Cryptosporidium-HIV co-infected patients

<p>Abstract</p> <p>Background</p> <p><it>Cryptosporidium parvum</it>, the protozoan parasite, causes a significant enteric disease in immunocompromised hosts such as HIV patients. The present study was aimed to compare serum IgG, IgM and IgA responses to crude soluble antigen of <it>C. parvum </it>in HIV seropositive and seronegative patients co-infected with <it>Cryptosporidium </it>and to correlate the responses with symptomatology.</p> <p>Methods</p> <p><it>Cryptosporidium parvum </it>specific serum antibody (IgG, IgM and IgA) responses were assessed by ELISA in 11 HIV seropositive <it>Cryptosporidium </it>positive (Group I), 20 HIV seropositive <it>Cryptosporidium </it>negative (Group II), 10 HIV seronegative <it>Cryptosporidium </it>positive (Group III), 20 HIV seronegative <it>Cryptosporidium </it>negative healthy individuals (Group IV) and 25 patients with other parasitic diseases (Group V).</p> <p>Results</p> <p>A positive IgG and IgA antibody response was observed in significantly higher number of <it>Cryptosporidium </it>infected individuals (Gp I and III) compared to <it>Cryptosporidium </it>un-infected individuals (Gp II, IV and V) irrespective of HIV/immune status. Sensitivity of IgG ELISA in our study was found to be higher as compared to IgM and IgA ELISA. The number of patients with positive IgG, IgM and IgA response was not significantly different in HIV seropositive <it>Cryptosporidium </it>positive patients with diarrhoea when compared to patients without diarrhoea and in patients with CD4 counts <200 when compared to patients with CD4 counts >200 cells/μl.</p> <p>Conclusion</p> <p>The study showed specific serum IgG and IgA production in patients infected with <it>Cryptosporidium</it>, both HIV seropositive and seronegative as compared to uninfected subjects suggesting induction of <it>Cryptosporidium </it>specific humoral immune response in infected subjects. However, there was no difference in number of patients with positive response in HIV seropositive or seronegative groups indicating that HIV status may not be playing significant role in modulation of <it>Cryptosporidium </it>specific antibody responses. The number of patients with positive IgG, IgM and IgA response was not significantly different in patients with or without history of diarrhoea thereby indicating that <it>Cryptosporidium </it>specific antibody responses may not be necessarily associated with protection from symptomatology.</p

A study of association between common variation in the growth hormone-chorionic somatomammotropin hormone gene cluster and adult fasting insulin in a UK Caucasian population

BACKGROUND: Reduced growth during infancy is associated with adult insulin resistance. In a UK Caucasian cohort, the CSH1.01 microsatellite polymorphism in the growth hormone-chorionic somatomammotropin hormone gene cluster was recently associated with increases in adult fasting insulin of approximately 23 pmol/l for TT homozygote males compared to D1D1 or D2D2 homozygotes (P = 0.001 and 0.009; n = 206 and 92, respectively), but not for females. TT males additionally had a 547-g lower weight at 1 year (n = 270; P = 0.008) than D2D2 males. We sought to replicate these data in healthy UK Caucasian subjects. We genotyped 1396 subjects (fathers, mothers and children) from a consecutive birth study for the CSH1.01 marker and analysed genotypes for association with 1-year weight in boys and fasting insulin in fathers. RESULTS: We found no evidence for association of CSH1.01 genotype with adult male fasting insulin concentrations (TT/D1D1 P = 0.38; TT/D2D2 P = 0.18) or weight at 1 year in boys (TT/D1D1 P = 0.76; TT/D2D2 P = 0.85). For fasting insulin, our data can exclude the previously observed effect sizes as the 95 % confidence intervals for the differences observed in our study exclude increases in fasting insulin of 9.0 and 12.6 pmol/l for TT relative to D1D1 and D2D2 homozygotes, respectively. Whilst we have fewer data on boys' 1-year weight than the original study, our data can exclude a reduction in 1-year weight greater than 557 g for TT relative to D2D2 homozygotes. CONCLUSION: We have not found association of the CSH1.01 genotype with fasting insulin or weight at 1 year. We conclude that the original study is likely to have over-estimated the effect size for fasting insulin, or that the difference in results reflects the younger age of subjects in this study relative to those in the previous study

Malaria is a cause of iron deficiency in African children

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID1. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334), a genetic variant that confers specific protection against malaria2, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%

FRAX (R): Prediction of Major Osteoporotic Fractures in Women from the General Population: The OPUS Study

Purposes: The aim of this study was to analyse how well FRAXH predicts the risk of major osteoporotic and vertebral fractures over 6 years in postmenopausal women from general population. Patients and methods: The OPUS study was conducted in European women aged above 55 years, recruited in 5 centers from random population samples and followed over 6 years. The population for this study consisted of 1748 women (mean age 74.2 years) with information on incident fractures. 742 (43.1%) had a prevalent fracture; 769 (44%) and 155 (8.9%) of them received an antiosteoporotic treatment before and during the study respectively. We compared FRAXH performance with and without bone mineral density (BMD) using receiver operator characteristic (ROC) c-statistical analysis with ORs and areas under receiver operating characteristics curves (AUCs) and net reclassification improvement (NRI). Results: 85 (4.9%) patients had incident major fractures over 6 years. FRAXH with and without BMD predicted these fractures with an AUC of 0.66 and 0.62 respectively. The AUC were 0.60, 0.66, 0.69 for history of low trauma fracture alone, age and femoral neck (FN) BMD and combination of the 3 clinical risk factors, respectively. FRAXH with and without BMD predicted incident radiographic vertebral fracture (n = 65) with an AUC of 0.67 and 0.65 respectively. NRI analysis showed a significant improvement in risk assignment when BMD is added to FRAXH. Conclusions: This study shows that FRAXH with BMD and to a lesser extent also without FN BMD predict major osteoporotic and vertebral fractures in the general population

Poly(ADP-ribose) polymerase inhibition: a new direction for BRCA and triple-negative breast cancer?

Inhibitors of poly(ADP-ribose) polymerase (PARP)-mediated DNA repair have shown promise in early clinical studies in the treatment of specific subgroups of breast cancer. Notably, phase II trials indicate that olaparib, an oral PARP inhibitor, has activity as a single agent in BRCA-related tumours, and that a combination of iniparib, an intravenous PARP inhibitor, and chemotherapy offers a survival advantage, compared with chemotherapy alone, in triple-negative breast cancer. Phase III data on the latter indication are expected in 2011. Intriguingly, iniparib does not increase toxicity when used as a chemo-potentiating agent, suggesting that it differs in its mechanism of action from other agents in this class. Overall, PARP inhibitors represent a potentially important new class of anti-cancer agents with two potential modes of action, as single agents causing synthetic lethality and as chemo-potentiating agents

Improving the biopharmaceutical attributes of mangiferin using vitamin E-TPGS co-loaded self-assembled phosholipidic nano-mixed micellar systems

The current research work encompasses the development, characterization, and evaluation of self-assembled phospholipidic nano-mixed miceller system (SPNMS) of a poorly soluble BCS Class IV xanthone bioactive, mangiferin (Mgf) functionalized with co-delivery of vitamin E TPGS. Systematic optimization using I-optimal design yielded self-assembled phospholipidic nano-micelles with a particle size of  80% of drug release in 15 min. The cytotoxicity and cellular uptake studies performed using MCF-7 and MDA-MB-231 cell lines demonstrated greater kill and faster cellular uptake. The ex vivo intestinal permeability revealed higher lymphatic uptake, while in situ perfusion and in vivo pharmacokinetic studies indicated nearly 6.6- and 3.0-folds augmentation in permeability and bioavailability of Mgf. In a nutshell, vitamin E functionalized SPNMS of Mgf improved the biopharmaceutical performance of Mgf in rats for enhanced anticancer potency