Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( ...NCT02977052 ) studies
. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma.
Genera of phytopathogenic fungi: GOPHY 2 Marin-Felix, Y.; Hernández-Restrepo, M.; Wingfield, M.J. ...
Studies in mycology,
03/2019, Volume:
92, Issue:
1
Journal Article
Peer reviewed
Open access
This paper represents the second contribution in the Genera of Phytopathogenic Fungi (GOPHY) series. The series provides morphological descriptions and information regarding the pathology, ...distribution, hosts and disease symptoms for the treated genera. In addition, primary and secondary DNA barcodes for the currently accepted species are included. This second paper in the GOPHY series treats 20 genera of phytopathogenic fungi and their relatives including: Allantophomopsiella, Apoharknessia, Cylindrocladiella, Diaporthe, Dichotomophthora, Gaeumannomyces, Harknessia, Huntiella, Macgarvieomyces, Metulocladosporiella, Microdochium, Oculimacula, Paraphoma, Phaeoacremonium, Phyllosticta, Proxypiricularia, Pyricularia, Stenocarpella, Utrechtiana and Wojnowiciella. This study includes the new genus Pyriculariomyces, 20 new species, five new combinations, and six typifications for older names.
Neoadjuvant ipilimumab plus nivolumab has yielded high response rates in patients with macroscopic stage III melanoma. These response rates translated to high short-term survival rates. However, data ...on long-term survival and disease recurrence are lacking.
In OpACIN, 20 patients with macroscopic stage III melanoma were randomized to ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w four cycles of adjuvant or split two cycles of neoadjuvant and two adjuvant. In OpACIN-neo, 86 patients with macroscopic stage III melanoma were randomized to arm A (2× ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w; n = 30), arm B (2× ipilimumab 1 mg/kg plus nivolumab 3 mg/kg q3w; n = 30), or arm C (2× ipilimumab 3 mg/kg q3w plus 2× nivolumab 3 mg/kg q2w; n = 26) followed by surgery.
The median recurrence-free survival (RFS) and overall survival (OS) were not reached in either trial. After a median follow-up of 69 months for OpACIN, 1/7 patients with a pathologic response to neoadjuvant therapy had disease recurrence. The estimated 5-year RFS and OS rates for the neoadjuvant arm were 70% and 90% versus 60% and 70% for the adjuvant arm. After a median follow-up of 47 months for OpACIN-neo, the estimated 3-year RFS and OS rates were 82% and 92%, respectively. The estimated 3-year RFS rate for OpACIN-neo was 95% for patients with a pathologic response versus 37% for patients without a pathologic response (P < 0.001). In multiple regression analyses, pathologic response was the strongest predictor of disease recurrence. Of the 12 patients with distant disease recurrence after neoadjuvant therapy, 5 responded to subsequent anti-PD-1 and 8 to targeted therapy, although 7 patients showed progression after the initial response.
Updated data confirm the high survival rates after neoadjuvant combination checkpoint inhibition in macroscopic stage III melanoma, especially for patients with a pathologic response. Pathologic response is the strongest surrogate marker for long-term outcome.
•Updated data of neoadjuvant combination therapy show high survival rates for patients with macroscopic stage III melanoma.•Pathologic response strongly predicted disease recurrence in multiple regression analyses.•Most patients with disease recurrence after neoadjuvant combination therapy responded to subsequent systemic therapy.
Abstract
Porcine epidemic diarrhea virus (PEDV) is a heat-sensitive virus that has devastated the U.S. swine industry. Because of its heat sensitivity, we hypothesized that a steam conditioner and ...pellet mill mimicking traditional commercial thermal processing may mitigate PEDV infectivity. Pelleting, a common feed processing method, includes the use of steam and shear forces, resulting in increased temperature of the processed feed. Two thermal processing experiments were designed to determine if different pellet mill conditioner retention times and temperatures would impact PEDV quantity and infectivity by analysis of quantitative reverse transcription PCR and bioassay. In Exp. 1, a 3 · 3 · 2 factorial design was used with 3 pelleting temperatures (68.3, 79.4, and 90.6°C), 3 conditioning times (45, 90, or 180 s), and 2 doses of viral inoculation (low, 1 · 102 tissue culture infectious dose50 (the concentration used to see cytopathic effect in 50% of the cells)/g, or high, 1 · 104 tissue culture infectious dose50/g). Noninoculated and PEDV-inoculated unprocessed mash were used as controls. The low-dose PEDV–infected mash had 6.8 ± 1.8 cycle threshold (Ct) greater (P < 0.05) PEDV than the high-dose mash. Regardless of time or temperature, pelleting reduced (P < 0.05) the quantity of detectable viral PEDV RNA compared with the PEDV-inoculated unprocessed mash. Fecal swabs from pigs inoculated with the PEDV-positive unprocessed mash, regardless of dose, were clinically PEDV positive from 2 to 7 d (end of the trial) after inoculation. However, if either PEDV dose of inoculated feed was pelleted at any of the 9 tested conditioning time · temperature combinations, no PEDV RNA was detected in fecal swabs or cecum content. Based on Exp. 1 results, a second experiment was developed to determine the impact of lower processing temperatures on PEDV quantity and infectivity. In Exp. 2, PEDV-inoculated feed was pelleted at 1 of 5 conditioning temperatures (37.8, 46.1, 54.4, 62.8, and 71.1°C) for 30 s. The 5 increasing processing temperatures led to feed with respective mean Ct values of 32.5, 34.6, 37.0, 36.5, and 36.7, respectively. All samples had detectable PEDV RNA. However, infectivity was detected by bioassay only in pigs from the 37.8 and 46.1°C conditioning temperatures. Experiment 2 results suggest conditioning and pelleting temperatures above 54.4°C could be effective in reducing the quantity and infectivity of PEDV in swine feed. However, additional research is needed to prevent subsequent recontamination after pelleting as it is a point-in-time mitigation step.
New and Interesting Fungi. 2 Crous, P W; Schumacher, R K; Akulov, A ...
Fungal Systematics and Evolution,
06/2019, Volume:
3, Issue:
1
Journal Article
Peer reviewed
Open access
One order, seven families, 28 new genera, 72 new species, 13 new combinations, four epitypes, and 21 interesting new host and / or geographical records are introduced in this study. ...Pseudorobillardaceae is introduced for Pseudorobillarda (based on P. phragmitis).
New genera include: Jeremyomyces (based on J. labinae) on twigs of Salix alba (Germany); Neodothidotthia (based on N. negundinicola) on Acer negundo (Ukraine); Neomedicopsis (based on N. prunicola) on fallen twigs of Prunus padus
(Ukraine); Neophaeoappendicospora (based on N. leucaenae) on Leucaena leucocephala (France) (incl.Phaeoappendicosporaceae); Paradevriesia (incl. Paradevriesiaceae) (based on P .americana) from air (USA); Phaeoseptoriella (based
on P. zeae) on leaves of Zea mays (South Africa); Piniphoma (based on P. wesendahlina) on wood debris of Pinus sylvestris (Germany); Pseudoconiothyrium (based on P. broussonetiae) on branch of Broussonetia papyrifera (Italy);Sodiomyces
(based onS .alkalinus) from soil (Mongolia), and Turquoiseomyces (incl. Turquoiseomycetales and Turquoiseomycetaceae) (based on T. eucalypti) on leaves of Eucalyptus leptophylla (Australia); Typhicola (based on T. typharum) on
leaves of Typha sp. (Germany);Xenodevriesia (incl.Xenodevriesiaceae) (based on X . strelitziicola) on leaves of Strelitzia sp. (South Africa). New species include: Bacillicladium clematidis on branch of Clematis vitalbae (Austria);
Cercospora gomphrenigena on leaves of Gomphrena globosa (South Africa); Cyphellophora clematidis on Clematis vitalba (Austria); Exophiala abietophila on bark of Abies alba (Norway); Exophiala lignicola on fallen decorticated trunk of Quercus
sp. (Ukraine); Fuscostagonospora banksiae on Banksia sp. (Australia); Gaeumannomycella caricicola on dead leaf of Carex remota (Germany); Hansfordia pruni on Prunus persica twig (Italy) (incl. Hansfordiaceae); Microdochium rhopalostylidis
on Rhopalostylis sapida (New Zealand); Neocordana malayensis on leaves of Musa sp. (Malaysia); Neocucurbitaria prunicola on fallen twigs of Prunus padus (Ukraine); Neocucurbitaria salicis-albae on Salix alba twig (Ukraine); eohelicomyces
deschampsiae on culm base of dead leaf sheath of Deschampsia cespitosa (Germany); Pararoussoella juglandicola on twig of Juglans regia (Germany); Pezicula eucalyptigena on leaves of Eucalyptus sp. (South Africa); Phlogicylindrium dunnii on leaves
of Eucalyptus dunnii (Australia); Phyllosticta hagahagaensis on leaf litter of Carissa bispinosa (South Africa); Phyllosticta austroafricana on leaf spots of unidentified deciduous tree host (South Africa); Pseudosigmoidea alnicola on Alnus glutinosa
leaf litter (Germany); Pseudoteratosphaeria africana on leaf spot on unidentified host (Angola); Porodiplodia vitis on canes of Vitis vinifera (USA); Sodiomyces alkalinus from soil (Mongolia), Sodiomyces magadiensis and Sodiomyces tronii from soil
(Kenya), Sympodiella quercina on fallen leaf of Quercus robur (Germany) and Zasmidium hakeicola on leaves of Hakea corymbosa (Australia). Epitypes are designated for: Cryptostictis falcata on leaves of E. alligatrix (Australia), Hendersonia phormii
on leaves of Phormium tenax (New Zealand), Sympodiella acicola on needles of Pinus sylvestris (Netherlands), and Sphaeria scirpicola var. typharum on leaf of Typha sp. (Germany). Several taxa originally described from rocks are validated in this study.
New taxa include: Extremaceae fam. nov., and new genera, Arthrocatena, Catenulomyces, Constantinomyces, Extremus, Hyphoconis, Incertomyces, Lapidomyces, Lithophila, Monticola, Meristemomyces, Oleoguttula, Perusta, Petrophila, Ramimonilia, Saxophila and Vermiconidia.
New species include: Arthrocatena tenebrosa, Catenulomyces convolutus, Constantinomyces virgultus, C. macerans, C. minimus, C. nebulosus, C. virgultus, Exophiala bonariae, Extremus adstrictus, E. antarcticus, Hyphoconis sterilis, Incertomyces perditus, Knufia karalitana, K. marmoricola,
K. mediterranea, Lapidomyces hispanicus, Lithophila guttulata, Monticola elongata, Meristemomyces frigidus, M. arctostaphyli, Neodevriesia bulbillosa, N. modesta, N. sardiniae, N. simplex, Oleoguttula mirabilis, Paradevriesia compacta, Perusta inaequalis, Petrophila incerta, Rachicladosporium
alpinum, R. inconspicuum, R. mcmurdoi, R. monterosanum, R. paucitum, Ramimonilia apicalis, Saxophila tyrrhenica, Vermiconidia antarctica, V. calcicola, V. foris, and V. flagrans.
The Staphylococcus aureus multidrug binding protein QacR represses transcription of the qacA multidrug transporter gene and is induced by structurally diverse cationic lipophilic drugs. Here, we ...report the crystal structures of six QacR-drug complexes. Compared to the DNA bound structure, drug binding elicits a coil-to-helix transition that causes induction and creates an expansive multidrug-binding pocket, containing four glutamates and multiple aromatic and polar residues. These structures indicate the presence of separate but linked drug-binding sites within a single protein. This multisite drug-binding mechanism is consonant with studies on multidrug resistance transporters.
Organoid cultures derived from colorectal cancer (CRC) samples are increasingly used as preclinical models for studying tumor biology and the effects of targeted therapies under conditions capturing ...in vitro the genetic make-up of heterogeneous and even individual neoplasms. While 3D cultures are initiated from surgical specimens comprising multiple cell populations, the impact of tumor heterogeneity on drug effects in organoid cultures has not been addressed systematically. Here we have used a cohort of well-characterized CRC organoids to study the influence of tumor heterogeneity on the activity of the KRAS/MAPK-signaling pathway and the consequences of treatment by inhibitors targeting EGFR and downstream effectors. MAPK signaling, analyzed by targeted proteomics, shows unexpected heterogeneity irrespective of RAS mutations and is associated with variable responses to EGFR inhibition. In addition, we obtained evidence for intratumoral heterogeneity in drug response among parallel "sibling" 3D cultures established from a single KRAS-mutant CRC. Our results imply that separate testing of drug effects in multiple subpopulations may help to elucidate molecular correlates of tumor heterogeneity and to improve therapy response prediction in patients.
Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision ...oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I-IV) and developed a pre-clinical platform generating a compendium of drug sensitivity data totalling >4,000 assays testing 16 clinical drugs on patient-derived in vivo and in vitro models. This large biobank of 106 tumours, 35 organoids and 59 xenografts, with extensive omics data comparing donor tumours and derived models provides a resource for advancing our understanding of CRC. Models recapitulate many of the genetic and transcriptomic features of the donors, but defined less complex molecular sub-groups because of the loss of human stroma. Linking molecular profiles with drug sensitivity patterns identifies novel biomarkers, including a signature outperforming RAS/RAF mutations in predicting sensitivity to the EGFR inhibitor cetuximab.
In clinical trials, sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and testosterone replacement therapy (TRT) were shown to stimulate red blood cell production. Little is known if combination ...therapy poses risk of erythrocytosis in real world clinical practice.
This was a retrospective nationwide cohort study of US Veterans with type 2 diabetes (T2D) and baseline hematocrit between 38 and 50% who were prescribed SGLT-2i and/or TRT between 3/2013 and 10/2022 and had adequate adherence based on the proportion of days covered > 80%. Patients were divided into 3 groups: SGLT-2i only, TRT only, or combination therapy. Odds Ratio (OR) of new erythrocytosis defined as hematocrit level > 54% within 365 days of therapy initiation was calculated by logistic regression model adjusted for baseline hematocrit, age, BMI, obstructive sleep apnea, diuretic use, and smoking status.
Of the entire cohort of 53,971 people with T2D, total of 756 (1.4%) patients developed erythrocytosis. In unadjusted analyses, the OR of new onset erythrocytosis was higher in the combined SGLT-2i and TRT group compared with the SGLT-2i or TRT group alone (4.99, 95% CI (3.10-7.71) and 2.91, 95% CI (1.87-4.31), respectively). In the models adjusted for baseline characteristics, patients on combination therapy had significantly higher odds of erythrocytosis compared to those on SGLT-2i (OR 3.80, 95% CI (2.27-6.11)) or TRT alone (OR 2.49, 95% CI (1.51-3.59)). Testosterone delivery route (topical vs injectable) did not modify increased odds of erythrocytosis.
For the first time, we demonstrated that in large cohort of patients combined therapy with SGLT-2i and TRT is associated with increased erythrocytosis risk compared with either treatment alone. Given rising prevalence of SGLT-2i use, providers should consider periodic hematocrit assessment in persons receiving both SGLT-2i and TRT.
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