Large-pore mesoporous silica supports with different structure and pore sizes distribution have been tested for glyoxyl multipoint covalent immobilization of Pectinex Ultra SP-L, a commercial ...preparation including the enzyme β-galactosidase from Aspergillus aculeatus. The prepared biocatalysts have been assayed in the production of galacto-oligosaccharides (GOS) from lactose as prebiotic functional food, aiming to optimize the yield to the GOS having the highest presumed prebiotic effect, tri- and tetra- GOS (high-GOS). Immobilization of β-galactosidase over glyoxyl-modified silica supports, with pores, large enough to accommodate the enzyme within their structure, led to an enhancement of the enzyme activity in terms of high-GOS production relative to the free enzyme under the same reaction conditions. Remarkably, such an improvement was achieved without previous purification of β-galactosidase from the commercial source. An enhancement of the transgalactosylation activity over the hydrolytic activity, due to the relatively hydrophobic nature of organically modified silica surface of the supports, led to an increase in the selectivity to high-GOS. The best biocatalyst in the series was that based in hexagonal ultra-large-pore SBA-15 (ULP-SBA-15), which presents the most adequate balance between confinement effect within its pore framework and transgalactosylation activity leading to a remarkable yield to high-GOS of 20.2% vs. 11.2% for the enzyme in free conditions. Furthermore, reusability of these silica-based biocatalysts in three consecutive 24 h reaction-cycles has been successfully performed at 50 °C, temperature that minimizes the thermal deactivation of the enzyme.
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•Large-pore mesoporous supports for covalent immobilization of β-galactosidase.•ULP-SBA-15 provides the best catalytic results.•Yield to high-GOS of 20.2% supported enzyme vs. 11.2% with the free enzyme.•Biocatalysts is reusable in three consecutive 24 h-reaction cycles.
Bioko is one of the few islands that exist around Africa, the most genetically diverse continent on the planet. The native Bantu-speaking inhabitants of Bioko, the Bubi, are believed to have ...colonized the island about 2000 years ago. Here, we sequenced the genome of thirteen Bubi individuals at high coverage and analysed their sequences in comparison to mainland populations from the Gulf of Guinea.
We found that, genetically, the closest mainland population to the Bubi are Bantu-speaking groups from Angola instead the geographically closer groups from Cameroon. The Bubi possess a lower proportion of rainforest hunter-gatherer (RHG) ancestry than most other Bantu-speaking groups. However, their RHG component most likely came from the same source and could have reached them by gene flow from the mainland after island settlement. By studying identity by descent (IBD) genomic blocks and runs of homozygosity (ROHs), we found evidence for a significant level of genetic isolation among the Bubi, isolation that can be attributed to the island effect. Additionally, as this population is known to have one of the highest malaria incidence rates in the world we analysed their genome for malaria-resistant alleles. However, we were unable to detect any specific selective sweeps related to this disease.
By describing their dispersal to the Atlantic islands, the genomic characterization of the Bubi contributes to the understanding of the margins of the massive Bantu migration that shaped all Sub-Saharan African populations.
Abstract Objective PF-04691502 and gedatolisib (PF-05212384) are potent, dual PI3K/mTOR inhibitors. This phase II study (B1271004) was conducted in patients with recurrent endometrial cancer ...following platinum-containing chemotherapy. The primary endpoint was to assess clinical benefit response (complete or partial response, or stable disease for ≥ 16 weeks) following treatment with PF-04691502 or gedatolisib. Methods The main study consisted of four independent arms based on a Simon two-stage design. Patients were assigned to putative PI3K-basal (PF-04691502 or gedatolisib) or PI3K-activated (PF-04691502 or gedatolisib) arms based on stathmin-low or stathmin-high tumor expression, respectively. Japanese patients were also enrolled in a separate lead-in cohort. Results In stage 1 (main study), eighteen patients were randomized to PF-04691502 and 40 to gedatolisib. The two PF-04691502 arms were discontinued early due to unacceptable toxicity, including pneumonia and pneumonitis. The most common treatment-related adverse events associated with gedatolisib were nausea (53%), mucosal inflammation (50%), decreased appetite (40%), diarrhea (38%), fatigue (35%), and dysgeusia and vomiting (each 30%). Clinical benefit response rate was 53% (10/19) in the gedatolisib/stathmin-low arm and 26% (5/19) in the gedatolisib/stathmin-high arm. Safety profile and pharmacokinetic characteristics of both drugs in the Japanese lead-in cohort were comparable to the Western population. Conclusions Gedatolisib administered by weekly intravenous infusion demonstrated acceptable tolerability and moderate activity in patients with recurrent endometrial cancer. PF-04691502 daily oral dosing was not well tolerated. Clinical benefit response criteria for proceeding to stage 2 were only met in the gedatolisib/stathmin-low arm. Stathmin-high expression did not correlate with greater treatment efficacy. ClinicalTrials.gov registration ID: NCT01420081.
Abstract
Background
Although pneumococcal conjugate vaccines (PCVs) effectively prevent invasive pneumococcal disease (IPD), serotype replacement has occurred.
Objectives
We studied the pangenome, ...antibiotic resistance mechanisms and presence of mobile elements in predominant non-PCV13 serotypes causing adult IPD after PCV13 vaccine introduction in Spain.
Methods
We conducted a multicentre study comparing three periods in six Spanish hospitals and analysed through whole genome sequencing representative strains collected in the pre-PCV13, early-PCV13 and late-PCV13 periods.
Results
Among 2197 cases of adult IPD identified, 110 pneumococci expressing non-PCV13 capsules were sequenced. Seven predominant serotypes accounted for 42.6% of IPD episodes in the late-PCV13 period: serotypes 8 (14.4%), 12F (7.5%), 9N (5.2%), 11A (4.1%), 22F (3.9%), 24F (3.9%) and 16F (3.6%). All predominant non-PCV13 serotypes were highly clonal, comprising one or two clonal complexes (CC). In general, CC538, CC4048, CC3016F, CC43322F and CC669N, related to predominant non-PCV13 serotypes, were antibiotic susceptible. CC15611A was associated with resistance to co-trimoxazole, penicillin and amoxicillin. CC23024F was non-susceptible to penicillin and resistant to erythromycin, clindamycin, and tetracycline. Six composite transposon structures of the Tn5252-family were found in CC23024F, CC98912F and CC3016F carrying different combinations of erm(B), tet(M), and cat. Pangenome analysis revealed differences in accessory genomes among the different CC, with most variety in CC3016F (23.9%) and more conservation in CC15611A (8.5%).
Conclusions
We identified highly clonal predominant serotypes responsible for IPD in adults. The detection of not only conjugative elements carrying resistance determinants but also clones previously associated with vaccine serotypes (CC15611A and CC23024F) highlights the importance of the accessory genome.
•10 polymorphic gene variants of pesticide-metabolizing enzymes were analyzed.•Allelic frequency, linkage disequilibrium and haplotype analysis were studied.•SNPs and CNVs frequencies were broadly ...consistent with European populations.•Adverse genotype combinations conferring a greater genetic risk were suggested.•These combinations can be used in future studies to predict adverse health effects.
Polymorphisms in genes encoding xenobiotic-metabolizing enzymes (XME) are important parameters accounting for the wide inter-individual variability to environmental exposures. Paraoxonase-1 (PON1), butyrylcholinesterase (BChE) and Cytochrome-P450 constitute major classes of XME involved in the detoxification of pesticide chemicals, in particular organophosphates. This study explored the allelic frequency, linkage disequilibrium and haplotype analysis of ten common polymorphic variants of seven key genes involved in organophosphate metabolism (BCHE-K, BCHE-A, PON1 Q192R, PON1 L55M, PON1 −108C/T, CYP2C19 G681A, CYP2D6 G1846A, CYP3AP1 −44G/A, GSTM1∗0 and GSTT1∗0) in a children population living near an intensive agriculture area in Spain. It was hypothesized that individuals with unfavorable combinations of gene variants will be more susceptible to adverse effects from organophosphate exposure. Genomic DNA from 496 healthy children was isolated and amplified by PCR. Hydrolysis probes were used for the detection of eight specific SNPs and two copy number variants (CNVs) by using TaqMan® Assay-based real-time PCR. Frequencies of SNPs and CNVs in the target genes were in Hardy–Weinberg equilibrium and broadly consistent with European populations. Linkage disequilibrium was found between the three PON1 genetic polymorphisms studied and between BCHE-K and BCHE-A. The adverse genotype combination (unusual BCHE variants, PON1 55MM/−108TT and null genotype for both GSTM1 and GSTT1) potentially conferring a greater genetic risk from exposure to organophosphates was observed in 0.2% of our study population. This information allows broadening our knowledge about differential susceptibility toward environmental toxicants and may be helpful for further research to understand the inter-individual toxicokinetic variability in response to organophosphate pesticides exposure.
Summary Background Patients with progressive disease after two or more HER2-directed regimens for recurrent or metastatic breast cancer have few effective therapeutic options. We aimed to compare ...trastuzumab emtansine, an antibody–drug conjugate comprising the cytotoxic agent DM1 linked to trastuzumab, with treatment of physician's choice in this population of patients. Methods This randomised, open-label, phase 3 trial took place in medical centres in 22 countries across Europe, North America, South America, and Asia-Pacific. Eligible patients (≥18 years, left ventricular ejection fraction ≥50%, Eastern Cooperative Oncology Group performance status 0–2) with progressive HER2-positive advanced breast cancer who had received two or more HER2-directed regimens in the advanced setting, including trastuzumab and lapatinib, and previous taxane therapy in any setting, were randomly assigned (in a 2:1 ratio) to trastuzumab emtansine (3·6 mg/kg intravenously every 21 days) or physician's choice using a permuted block randomisation scheme by an interactive voice and web response system. Patients were stratified according to world region (USA vs western Europe vs other), number of previous regimens (excluding single-agent hormonal therapy) for the treatment of advanced disease (two to three vs more than three), and presence of visceral disease (any vs none). Coprimary endpoints were investigator-assessed progression-free survival (PFS) and overall survival in the intention-to-treat population. We report the final PFS analysis and the first interim overall survival analysis. This study is registered with ClinicalTrials.gov , number NCT01419197. Findings From Sept 14, 2011, to Nov 19, 2012, 602 patients were randomly assigned (404 to trastuzumab emtansine and 198 to physician's choice). At data cutoff (Feb 11, 2013), 44 patients assigned to physician's choice had crossed over to trastuzumab emtansine. After a median follow-up of 7·2 months (IQR 5·0–10·1 months) in the trastuzumab emtansine group and 6·5 months (IQR 4·1–9·7) in the physician's choice group, 219 (54%) patients in the trastuzumab emtansine group and 129 (65%) of patients in the physician's choice group had PFS events. PFS was significantly improved with trastuzumab emtansine compared with physician's choice (median 6·2 months 95% CI 5·59–6·87 vs 3·3 months 2·89–4·14; stratified hazard ratio HR 0·528 0·422–0·661; p<0·0001). Interim overall survival analysis showed a trend favouring trastuzumab emtansine (stratified HR 0·552 95% CI 0·369–0·826; p=0·0034), but the stopping boundary was not crossed. A lower incidence of grade 3 or worse adverse events was reported with trastuzumab emtansine than with physician's choice (130 events 32% in 403 patients vs 80 events 43% in 184 patients). Neutropenia (ten 2% vs 29 16%), diarrhoea (three <1% vs eight 4%), and febrile neutropenia (one <1% vs seven 4%) were grade 3 or worse adverse events that were more common in the physician's choice group than in the trastuzumab emtansine group. Thrombocytopenia (19 5% vs three 2%) was the grade 3 or worse adverse event that was more common in the trastuzumab emtansine group. 74 (18%) patients in the trastuzumab emtansine group and 38 (21%) in the physician's choice group reported a serious adverse event. Interpretation Trastuzumab emtansine should be considered as a new standard for patients with HER2-positive advanced breast cancer who have previously received trastuzumab and lapatinib. Funding Genentech.
The phase 2, multicohort, open-label LEAP-005 study evaluated lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors. We report outcomes from the ovarian cancer ...cohort.
Eligible patients had metastatic/unresectable ovarian cancer and had received 3 previous lines of therapy. Patients received lenvatinib 20 mg/day plus pembrolizumab 200 mg every 3 weeks. Treatment continued until progression, unacceptable toxicity, or (for pembrolizumab) completion of 35 cycles. Primary endpoints were objective response rate (ORR) per RECIST version 1.1 and safety. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
Thirty-one patients were enrolled. 39% had high grade serous ovarian cancer, 23% were platinum-sensitive, 55% were platinum-resistant, 23% were platinum-refractory, and 84% had tumors that had a PD-L1 combined positive (CPS) score ≥1. ORR (95% CI) was 26% (12%–45%) by investigator assessment and 35% (19%–55%) by blinded independent central review (BICR). Per BICR, median DOR was 9.2 (1.5+ to 37.8+) months. ORRs (95% CI) by BICR were 35% (9/26 patients; 17%–56%) for PD-L1 CPS ≥ 1 disease and 50% (2/4 patients; 7%–93%) for PD-L1 CPS < 1 disease. Median (95% CI) PFS by BICR and OS were 6.2 (4.0–8.5) months and 21.3 (11.7–32.3) months, respectively. Treatment-related AEs occurred in 94% of patients (grade 3–4, 77%). One patient died from treatment-related hypovolemic shock.
Lenvatinib plus pembrolizumab demonstrated antitumor activity as fourth line therapy in patients with advanced ovarian cancer, and no unanticipated safety signals were identified. Responses were observed regardless of PD-L1 status.
•We evaluated lenvatinib plus pembrolizumab as fourth-line therapy in 31 patients with advanced ovarian cancer.•Lenvatinib plus pembrolizumab had an objective response rate of 35% by blinded independent central review in this population.•Median duration of response by blinded independent central review was 9.2 (1.5+ to 37.8+) months.•Median progression-free survival was 6.2 months and median overall survival was 21.3 months.•Treatment-related adverse events occurred in 94% of patients (grade 3–4, 77%; grade 5, 3%).
Introduction
We evaluated real-world outcomes in patients with advanced ovarian cancer (AOC) based on their cumulative risk profile and maintenance therapy (MT) status following first-line (1L) ...treatment.
Methods
This retrospective observational study of a nationwide electronic health record-derived de-identified database included adult patients diagnosed with stage III/IV OC from January 1, 2011 to February 28, 2021, who received 1L therapy and had ≥ 12 weeks of follow-up after the index date (end of 1L therapy). Patients were grouped according to whether they received MT or active surveillance (AS) following 1L treatment and by the cumulative number of risk factors (RF) present (stage IV disease; no surgery/treated with neoadjuvant therapy and interval debulking surgery; had postoperative visible residual disease; and had
BRCA
wild-type disease/unknown
BRCA
status). Time to next treatment (TTNT) and overall survival (OS) were assessed with a cloning and inverse probability of censoring (IPC)-weighted Kaplan–Meier method.
Results
Among 1920 patients, 22.2% received MT and 77.8% received AS. Median IPC-weighted TTNT and OS were 13.3 months (95% CI 11.7–15.8) and 39.1 months (95% CI 32.5–48.6) in the MT cohort, respectively, and 8.6 months (95% CI 8.0–9.5) and 38.4 months (95% CI 36.4–41.0) in the AS cohort, respectively. Almost all patients had ≥ 1 RF (MT 95.3%; AS 96.7%). Median IPC-weighted TTNT was shorter among patients with more RF in both cohorts (MT: 1 RF, 19.3 months, 95% CI 13.5–37.8; 2 RF, 17.2 months, 95% CI 12.8–20.2; 3 RF, 11.0 months, 95% CI 8.2–13.8; 4 RF, 7.0 months, 95% CI 6.2–8.8; AS: 1 RF, 17.7 months, 95% CI 13.5–22.3; 2 RF, 10.2 months, 95% CI 9.1–11.5; 3 RF, 6.5 months, 95% CI 5.8–7.4; 4 RF, 4.1 months, 95% CI 3.5–4.5).
Conclusion
Regardless of RF number, MT was associated with longer TTNT in real-world patients with AOC.
Within the complex system that once formed part of the epigraphic ensemble that accompanied these amphorae, we highlight the particular study of the painted marks known as tituli picti in the delta ...position of the olive oil amphorae from Baetica, Dressel 20. Here we address a singular fact, only detectable through the visualization of large data sets, indicating the existence of the endorsement in delta of the amount expressed in alpha throughout the years of the Antonine reform. If until now it was believed to be something fortuitous, or a scribe's error, now it could be considered, due to its structure and the cases exposed, a regulated script.
In the randomized phase 3 ICON7 trial (ISRCTN91273375), adding bevacizumab to chemotherapy for newly diagnosed ovarian cancer significantly improved progression-free survival (PFS; primary endpoint) ...but not overall survival (OS; secondary endpoint) in the intent-to-treat (ITT) population. We explored treatment effect according to stage and extent of residual disease.
Patients with stage IIB–IV or high-risk (grade 3/clear-cell) stage I–IIA ovarian cancer were randomized to receive six cycles of carboplatin and paclitaxel either alone or with bevacizumab 7.5 mg/kg every 3 weeks followed by single-agent bevacizumab for 12 further cycles (total duration 12 months). Post hoc exploratory analyses of subgroups defined by stage and extent of residual disease at diagnosis within the stage IIIB–IV population (European indication) was performed.
The PFS benefit from bevacizumab was seen consistently in all subgroups explored. The PFS hazard ratio was 0.77 (95% confidence interval CI, 0.59–0.99) in 411 patients with stage IIIB–IV ovarian cancer with no visible residuum and 0.81 (95% CI, 0.69–0.95) in 749 patients with stage IIIB–IV disease and visible residuum. As in the ITT population, no OS difference was detected in any subgroup except the previously described ‘high-risk’ subgroup. Safety results in analyzed subgroups were consistent with the overall population.
Adding bevacizumab to front-line chemotherapy improves PFS irrespective of stage/residual disease. In patients with stage III with >1 cm residuum, stage IV or inoperable disease, this translates into an OS benefit. No OS benefit or detriment was seen in other subgroups explored.
•Post hoc analyses of ICON7 explored bevacizumab by stage and extent of residual disease after upfront surgery for OC.•The progression-free survival (PFS) benefit from bevacizumab was seen consistently in all subgroups explored.•The PFS hazard ratio was 0.77 (95% CI, 0.59–0.99) in 411 patients with stage IIIB–IV disease and no visible residuum.•No OS difference was detected overall or in any subgroup except the previously reported ‘high-risk’ subgroup.•Adding bevacizumab to front-line chemotherapy improves PFS irrespective of stage/residual disease.
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