Summary
What is known and Objective: Mycophenolate mofetil (MMF) has been reported recently to be effective in the treatment of systemic lupus erythematosus (SLE). The therapeutic range of ...mycophenolic acid (MPA) in SLE in the remission‐maintenance phase remains to be clarified. The aim of this study was to evaluate the therapeutic efficacy of MMF and predose plasma concentrations of MPA and its phenolic glucuronide (MPAG) in patients with SLE in the remission‐maintenance phase.
Methods: Thirty‐one patients with SLE receiving a fixed dosage regimen of MMF (median and interquartile range, 1500 and 1000–2000 mg/day) for at least 1 month and who had not experienced any adverse drug reactions for more than 3 months were enrolled.
Results: Significant improvement was observed after MMF administration in total haemolytic complement CH50 and its fractions C3 and C4, immunoglobulins IgG, IgA and IgM, anti‐dsDNA antibody, serum concentration of albumin and red blood cell count, even though the mean daily dose of prednisolone was significantly reduced (P = 0·02). Median predose plasma concentrations of MPA and MPAG were 1·95 and 26·2 μg/mL (interquartile ranges, 0·94–2·96 and 18·6–53·7 μg/mL). Predose plasma concentrations of MPA and MPAG correlated significantly with MMF dose (r = 0·64, P < 0·01 and r = 0·39, P = 0·03).
What is new and Conclusions: MMF improved clinical laboratory markers and reduced prednisolone dosage in SLE patients with predose plasma concentration of MPA and MPAG in the interquartile ranges of 0·94–2·96 and 18·6–53·7 μg/mL, respectively.
The Americas were the last inhabitable continents to be occupied by humans, with a growing multidisciplinary consensus for entry 15–25 thousand years ago (kya) from northeast Asia via the former ...Beringia land bridge 1–4. Autosomal DNA analyses have dated the separation of Native American ancestors from the Asian gene pool to 23 kya or later 5, 6 and mtDNA analyses to ∼25 kya 7, followed by isolation (“Beringian Standstill” 8, 9) for 2.4–9 ky and then a rapid expansion throughout the Americas. Here, we present a calibrated sequence-based analysis of 222 Native American and relevant Eurasian Y chromosomes (24 new) from haplogroups Q and C 10, with four major conclusions. First, we identify three to four independent lineages as autochthonous and likely founders: the major Q-M3 and rarer Q-CTS1780 present throughout the Americas, the very rare C3-MPB373 in South America, and possibly the C3-P39/Z30536 in North America. Second, from the divergence times and Eurasian/American distribution of lineages, we estimate a Beringian Standstill duration of 2.7 ky or 4.6 ky, according to alternative models, and entry south of the ice sheet after 19.5 kya. Third, we describe the star-like expansion of Q-M848 (within Q-M3) starting at 15 kya 11 in the Americas, followed by establishment of substantial spatial structure in South America by 12 kya. Fourth, the deep branches of the Q-CTS1780 lineage present at low frequencies throughout the Americas today 12 may reflect a separate out-of-Beringia dispersal after the melting of the glaciers at the end of the Pleistocene.
•We sequenced 20 Native American Y chromosomes chosen for their genetic diversity•A Beringian Standstill of <4,600 years led to both Siberian and American Y-lineages•Y-lineage split times rule out occupation of the Americas before 19,500 years ago•Present-day male population structure in South America arose before 12,000 years ago
Pinotti et al. provide a genetic analysis of male history in the Americas that reveals three or four founding lineages, an occupation of Beringia for no longer than 4,600 years, entry south of the ice sheets after 19,500 years ago, and the establishment of the present-day male population structure in South America by 12,000 years ago.
Over the past decades, consistent studies have shown that race/ethnicity have a great impact on cancer incidence, survival, drug response, molecular pathways and epigenetics. Despite the influence of ...race/ethnicity in cancer outcomes and its impact in health care quality, a comprehensive understanding of racial/ethnic inclusion in oncological research has never been addressed. We therefore explored the racial/ethnic composition of samples/individuals included in fundamental (patient-derived oncological models, biobanks and genomics) and applied cancer research studies (clinical trials). Regarding patient-derived oncological models (n = 794), 48.3% have no records on their donor's race/ethnicity, the rest were isolated from White (37.5%), Asian (10%), African American (3.8%) and Hispanic (0.4%) donors. Biobanks (n = 8,293) hold specimens from unknown (24.56%), White (59.03%), African American (11.05%), Asian (4.12%) and other individuals (1.24%). Genomic projects (n = 6,765,447) include samples from unknown (0.6%), White (91.1%), Asian (5.6%), African American (1.7%), Hispanic (0.5%) and other populations (0.5%). Concerning clinical trials (n = 89,212), no racial/ethnic registries were found in 66.95% of participants, and records were mainly obtained from Whites (25.94%), Asians (4.97%), African Americans (1.08%), Hispanics (0.16%) and other minorities (0.9%). Thus, two tendencies were observed across oncological studies: lack of racial/ethnic information and overrepresentation of Caucasian/White samples/individuals. These results clearly indicate a need to diversify oncological studies to other populations along with novel strategies to enhanced race/ethnicity data recording and reporting.
Abstract
STUDY QUESTION
Can maternal plasma cell-free DNA (cfDNA) detect chromosomal anomalies in early pregnancy loss (EPL) and recurrent pregnancy loss (RPL)?
SUMMARY ANSWER
Genome-wide cfDNA ...testing can serve as an alternative to cytogenetic analysis in products of conception (POCs) in RPLs and can guide further management.
WHAT IS KNOWN ALREADY
Random chromosomal anomalies are the single most common cause for EPL and RPL. Cytogenetic analysis in POCs may be used to direct management in RPL because the detection of random chromosomal anomalies can eliminate further unwarranted testing.
STUDY DESIGN, SIZE, DURATION
This was a prospective diagnostic test study from March 2018 to January 2019 of 109 patients experiencing pregnancy loss before 14 weeks gestation at a tertiary-care academic medical center.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Blood samples were drawn for genome-wide cfDNA testing prior to chorionic villous sampling for cytogenetic analysis of POCs with both short-term cultures (STCs) and long-term cultures (LTCs). Final analysis included 86 patients with non-mosaic cytogenetic results in POCs and available cfDNA results. Aneuploidy detection rates by cfDNA testing and POC cytogenetic analysis were compared. The first 50 samples served as the Training Set to establish pregnancy loss-specific log-likelihood ratio (LLR) thresholds using receiver-operator characteristic (ROC)-like analyses. These were then used for the entire cohort.
MAIN RESULTS AND THE ROLE OF CHANCE
Seventy-eight samples (71.5%) had results available from both STC and LTC; 12 samples (11%) had a result from STC only, and 7 samples (6.4%) had a result from LTC only. A chromosomal anomaly was detected in 55/86 (64%). The rates of chromosomal anomalies were 61, 72, 73 and 44% in patients undergoing their first, second, third and ≥4th pregnancy losses, respectively. The median cfDNA fetal fraction was 5%. With standard LLR thresholds used for noninvasive prenatal screening, the sensitivity of cfDNA in detecting aneuploidy was 55% (30/55) and with a specificity of 100% (31/31). Using pregnancy loss-specific LLR thresholds, the sensitivity of cfDNA in detecting aneuploidy was 82% (45/55), with a specificity of 90% (28/31). The positive and negative likelihood ratios were 8.46 and 0.20, respectively. Fetal sex was correctly assigned in all cases.
LIMITATIONS, REASONS FOR CAUTION
Cases with a false-positive result by cfDNA analysis would not receive the indicated RPL workup. Specificity could be improved by using a fetal fraction (FF) cutoff of 4%, but this would result in exclusion of more than a quarter of cases.
WIDER IMPLICATIONS OF THE FINDINGS
cfDNA-based testing can serve as an alternative to POC cytogenetic analysis and can guide further RPL management: if cfDNA demonstrates aneuploidy, no further action is taken and if no abnormality is detected, the recommended RPL workup is performed.
STUDY FUNDING/COMPETING INTEREST(S)
Cell-free DNA testing was funded by Illumina, Inc., San Diego, CA. Y.Y. is a member of Illumina’s Clinical Expert Panel and has received travel grants. A.B. has received travel grants from Illumina. All authors have no competing interest to declare.
Entamoeba histolytica is one of the least understood protists in terms of taxa, clone, and kin discrimination/recognition ability. However, the capacity to tell apart same or self (clone/kin) from ...different or nonself (nonclone/nonkin) has long been demonstrated in pathogenic eukaryotes like Trypanosoma and Plasmodium, free-living social amebas (Dictyostelium, Polysphondylium), budding yeast (Saccharomyces), and in numerous bacteria and archaea (prokaryotes). Kin discrimination/recognition is explained under inclusive fitness theory; that is, the reproductive advantage that genetically closely related organisms (kin) can gain by cooperating preferably with one another (rather than with distantly related or unrelated individuals), minimizing antagonism and competition with kin, and excluding genetic strangers (or cheaters = noncooperators that benefit from others' investments in altruistic cooperation). In this review, we rely on the outcomes of in vitro pairwise discrimination/recognition encounters between seven Entamoeba lineages to discuss the biological significance of taxa, clone, and kin discrimination/recognition in a range of generalist and specialist species (close or distantly related phylogenetically). We then focus our discussion on the importance of these laboratory observations for E. histolytica's life cycle, host infestation, and implications of these features of the amebas' natural history for human health (including mitigation of amebiasis).
Summary
Background and objectives: Fentanyl has been used for cancer pain in transdermal formulation. The aim of the present study was to establish an analytical method for fentanyl in human plasma ...and in an applied transdermal reservoir patch (Reservoir‐TTS), as well as for therapeutic monitoring of fentanyl in cancer patients.
Method: Electro‐spray ionization mass spectrometric (ESI‐MS/MS) analysis followed solid phase extraction (SPE) from human plasma and drug reservoir extraction from an applied Reservoir‐TTS. Each separation was completed within 9 min using an ODS column (particle size, 3 μm, 2·0 mm i.d. × 75 mm) with 25% acetonitrile containing 5 mm ammonium acetate at pH 3·5. In the ESI‐MS/MS analysis, the calibration curve for fentanyl was linear over a concentration range of 0·05–7·2 ng/mL in human plasma. The extraction efficiency of fentanyl in the human plasma was more than 95%. The intra‐ and interassay precision and accuracy were within 7% and 97·3–101·2%, respectively. The lower LOQ for fentanyl was 0·05 ng/mL in the human plasma. The extraction of the 25 μg/h and 50 μg/h Reservoir‐TTS gave reproducible recoveries of 88·3% and 90·9%, respectively. The plasma concentration of fentanyl showed large interindividual variation in 31 patients with cancer pain.
Conclusion: The method described is simple, accurate, and reproducible, and should be helpful for the therapeutic monitoring of fentanyl in cancer patients.
Prostate cancer (PC) is the most frequently diagnosed cancer in Ecuador (15.6%). The androgen receptor gene codes for a protein that has an androgen‑binding domain, DNA‑binding domain and N‑terminal ...domain, which contains two polymorphic trinucleotide repeats (CAG and GGC). The aim of the present study was to determine whether variations in the number of repetitions of CAG and GGC are associated with the pathological features and the risk of developing PC. The polymorphic CAG and GGC repeat lengths in 108 mestizo patients with PC, 148 healthy mestizo individuals, and 78 healthy indigenous individuals were examined via a retrospective case‑control study. Genotypes were determined by genomic sequencing. The results demonstrated that patients with ≤21 CAG repeats have an increased risk of developing PC odds ratio (OR)=2.99, 95% confidence interval (CI) =1.79‑5.01; P<0.001. The presence of ≤21 CAG repeats was also associated with a tumor stage ≥T2c (OR=4.75; 95% CI=1.77‑12.72; P<0.005) and a Gleason score ≥7 (OR=2.9; 95% CI=1.1‑7.66; P=0.03). In addition, the combination of ≤21 CAG and ≥17 GGC repeats was associated with the risk of developing PC (OR=2.42; 95% CI=1.38‑4.25; P=0.002) and with tumor stage ≥T2c (OR=2.77; 95% CI=1.13‑6.79; P=0.02). In conclusion, the histopathological characteristics and PC risk in Ecuadorian indigenous and mestizo populations differs in association with the CAG repeats, and the combination of CAG and GGC repeats.
PDF
