Abstract
Paecilomyces lilacinus was described more than a century ago and is a commonly occurring fungus in soil. However, in the last decade this fungus has been increasingly found as the causal ...agent of infections in man and other vertebrates. Most cases of disease are described from patients with compromised immune systems or intraocular lens implants. In this study, we compared clinical isolates with strains isolated from soil, insects and nematodes using 18S rRNA gene, internal transcribed spacer (ITS) and partial translation elongation factor 1-α (TEF) sequences. Our data show that P. lilacinus is not related to Paecilomyces, represented by the well-known thermophilic and often pathogenic Paecilomyces variotii. The new genus name Purpureocillium is proposed for P. lilacinus and the new combination Purpureocillium lilacinum is made here. Furthermore, the examined Purpureocillium lilacinum isolated grouped in two clades based on ITS and partial TEF sequences. The ITS and TEF sequences of the Purpureocillium lilacinum isolates used for biocontrol of nematode pests are identical to those causing infections in (immunocompromised) humans. The use of high concentrations of Purpureocillium lilacinum spores for biocontrol poses a health risk in immunocompromised humans and more research is needed to determine the pathogenicity factors of Purpureocillium lilacinum.
We evaluated the safety, tolerability, pharmacokinetics and antitumor activity of barecetamab monotherapy and combination cetuximab therapy in patients with advanced solid cancers, especially head ...and neck cancer (HNC). Part 1 was a 3 + 3 dose‐escalation study in which 15 patients received barecetamab at 1, 3, 5, 10 and 20 mg/kg intravenously (IV) on days 1 and 28 and weekly in patients with advanced solid cancer. Part 2 was a dose‐expansion study including two patient groups with advanced HNC, including six patients receiving barecetamab at 20 mg/kg IV every 3 weeks and 12 patients receiving barecetamab and cetuximab (400 mg/m2 on day 1 followed by 250 mg/m2 every week). No dose‐limiting toxicities (DLTs) were observed. Maximum serum target engagement was reached with trough levels of doses ≥3 mg/kg IV weekly. Common adverse drug reactions were diarrhea, stomatitis, dermatitis acneiform and decreased appetite. One durable complete response of more than 17 months was observed, and the overall response and disease control rates were 36.4% (4/11) and 81.1% (9/11), respectively, in the combination therapy group. In conclusion, DLT was not observed in barecetamab at 1 to 20 mg/kg. The recommended phase II dose was determined to be 20 mg/kg triweekly. Barecetamab and in cetuximab combination was well tolerated and demonstrated meaningful antitumor effects.
What's new?
While immune checkpoint inhibitors have improved outcomes for head and neck cancer patients, additional options are needed for those whose disease doesen't respond or progresses after ICI treatment. Here, the authors conducted a first‐in‐human, phase I study of a highly selective monoclonal antibody against ErbB3 called barecetamab. The drug was well tolerated, with no dose‐limiting toxicity, and the established recommended phase 2 dose was 20 mg/kg triweekly. When given in combination with cetuximab, the treatment achieved an overall response rate of 36% (4 patients out of 11) and a disease control rate of 81%.
The aim of our study is to evaluate the clinical efficacy of durvalumab in patients with microsatellite instability‐high/mismatch repair‐deficient (MSI‐H/dMMR) or polymerase epsilon (POLE)‐mutated ...metastatic or unresectable colorectal cancer (mCRC) who had disease progression after standard chemotherapy. This prospective, open‐label, multicenter, phase II study enrolled patients with mCRC harboring MSI‐H/dMMR or POLE mutations treated with at least one prior line of therapy. The participants received durvalumab (1500 mg) every 4 weeks intravenously. The primary endpoint was the objective response rate (ORR). Of the 33 patients, 30 had MSI‐H/dMMR and 3 had POLE‐mutated microsatellite stable (MSS) CRC. With a median follow‐up duration of 11.2 months (95% confidence interval CI: 7.3‐15.0), the ORR was 42.4% (95% CI: 25.5‐60.8). Among three patients with POLE‐mutated CRC, one patient who had an exonuclease domain mutation (EDM) achieved an objective response, but the others with mutations in the non‐exonuclease domain had progressive disease. Overall, the median duration of response was not reached and 85.7% of the responses were ongoing at data cutoff. The progression‐free survival rate of 12 months was 58.2% (95% CI: 39.0‐73.1) and the 12‐month overall survival rate was 68.3% (95% CI: 48.8‐81.7). Grade 3 treatment‐related adverse events occurred in 36.4% of the patients and were manageable. In conclusion, durvalumab showed promising clinical activity with encouraging response rates and satisfactory survival outcomes in mCRC patients with MSI‐H/dMMR or POLE EDM. In patients with POLE‐mutated mCRC, clinical response to durvalumab may be restricted to those with EDM.
What's new?
Tumor mutational burden can predict the efficacy of immune checkpoint inhibitors in various types of cancer. Here, the authors performed a prospective, open‐label, multicenter, phase II trial evaluating the efficacy of the anti‐PD‐L1 monoclonal antibody, durvalumab in patients with metastatic or unresectable colorectal cancer harboring MSI‐H/dMMR or POLE‐mutations treated with at least one prior line of chemotherapy. Durvalumab showed encouraging anti‐tumor activity with tolerable toxicity in these patient groups. The results provide clinical evidence that an anti‐PD‐L1 agent could be a reasonable option in the treatment of metastatic or unresectable colorectal cancer patients with MSI‐H/dMMR or POLE mutations.
Sclerotinia stem rot is a common disease found in Brassica rapa that is caused by the necrotic plant pathogen Sclerotinia sclerotiorum. Melatonin (MT) has known biological activity and effectively ...relieved this type of Sclerotinia stem rot in B. rapa. To better understand the mechanisms behind MT-induced S. sclerotiorum resistance in B. rapa, we performed both proteomic and metabolomic analysis. Our results showed that during S. sclerotiorum infection, thiamine synthesis was activated and defended against it. In infected leaves, ribosomal synthesis-related proteins responded positively to MT treatment. Integrated proteomic and metabolomic analysis showed that amino acid metabolism was activated by MT treatment. After MT treatment, adenosine-triphosphate (ATP) content and the activity of antioxidant enzymes were both increased in B. rapa infected leaves. Cysteine synthase, sulfur transfer-related proteins, and glucosinolate (GS) were all increased after MT treatment in infected B. rapa leaves. Taken together, these results indicated that B. rapa leaves promoted thiamine formation to defend against S. sclerotiorum infection. Moreover, MT helped further induce antioxidant activation in B. rapa in an ATP-dependent manner and stimulating GS biosynthesis to well inhibit the S. sclerotiorum infection.
Melatonin (MT) has biological activity and effectively relieved the Sclerotinia stem rot of Brassica rapa caused by the necrotic plant pathogen Sclerotinia sclerotiorum. In order to reveal the molecular mechanisms of MT-induced S. sclerotiorum resistance in B. rapa, comprehensive proteomic and metabolomic analyses were conducted. The integration analysis of omic-data illustrated that the modulation of ATP and glucosinolate biosynthesis induced by MT administration helped to defend the infection of S. sclerotiorum in B. rapa. Our results will provide insights into MT-induced anti-fungal mechanism and therapeutic strategies to mitigate Sclerotinia stem rot of B. rapa, thereby increasing plant yield and decreasing economic losses.
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•Amino acid metabolism related proteins and thiamine increased after the infection.•Ribosomal synthesis was activated by melatonin treatment in infected leaves.•Melatonin increased ATP and antioxidant enzymes levels to resist the fungal.•Melatonin treatment induced GS biosynthesis to enhance S. sclerotiorum resistance.
Aflatoxins (AFs) are a group of carcinogenic and immunosuppressive mycotoxins that threaten global food safety. Globally, over 4.5 billion people are exposed to unmonitored levels of AFs. Aspergillus ...flavus is the major source of AF contamination in agricultural crops. One approach to reduce levels of AFs in agricultural commodities is to apply a non-aflatoxigenic competitor, e.g., Afla-Guard, to crop fields. In this study, we demonstrate that the food fermenting Aspergillus oryzae M2040 strain, isolated from Korean Meju (a brick of dry-fermented soybeans), can inhibit aflatoxin B1 (AFB1) production and proliferation of toxigenic A. flavus in lab culture conditions and peanuts. In peanuts, 1% inoculation level of A. oryzae M2040 could effectively displace the toxigenic A. flavus and inhibit AFB1 production. Moreover, cell-free culture filtrate of A. oryzae M2040 effectively inhibited AFB1 production and A. flavus growth, suggesting A. oryzae M2040 secretes inhibitory compounds. Whole genome-based comparative analyses indicate that the A. oryzae M2040 and Afla-Guard genomes are 37.9 and 36.4 Mbp, respectively, with each genome containing ~100 lineage specific genes. Our study establishes the idea of using A. oryzae and/or its cell-free culture fermentate as a potent biocontrol agent to control A. flavus propagation and AF contamination.
Background
Dalcinonacog alfa (DalcA), a next‐generation, recombinant human factor IX (FIX) variant, was developed using a rational design approach for increased procoagulant activity and longer ...duration of action to be administered subcutaneously (SC) for prophylaxis of hemophilia B bleeding episodes.
Objectives
To investigate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of DalcA.
Methods
This multicenter, phase 1/2a study (NCT03186677) was conducted in 11 males aged 12 to 65 years with severe hemophilia B. In cohort 1, subjects received intravenous (IV) 75 IU/kg BeneFIX and DalcA. Cohorts 2 and 3 had DalcA IV 75 IU/kg and SC 75 IU/kg or 150 IU/kg. Cohort 4 was omitted. Cohort 5 received daily SC 150 IU/kg DalcA for 6 days and cohort 6 received IV 75 IU/kg and daily SC 150 IU/kg DalcA for 9 days. Blood sampling was performed for chemistry, hematology, PK, PD, and anti‐drug antibody measurement. Subjects were monitored for safety endpoints for 30 days postdosing.
Results
DalcA demonstrated a 24‐fold greater potency over BeneFIX and longer mean residence time (33.8 h). SC bioavailability 8.2% to 20.3%, beta half‐life 53.9 to 106.9 h and Tmax 24 to 48 h. A median 15.7% FIX activity level (interquartile range, 14.9%‐16.6%) was reached after 6 daily doses. Neutralizing antibodies to ISU304, but not wild‐type FIX, occurred in two cousins.
Conclusions
The data demonstrated that DalcA achieved protective FIX activity levels between 11% and 18%, corresponding to a reduced chance of spontaneous bleeds. Based on the results, a phase 2b trial to assess the safety and efficacy of 28 daily SC doses of DalcA was performed.
An aerobic, Gram-stain-positive, rod-shaped, endospore-forming bacterial strain, designated BB3-R1
, was isolated from cow faeces sampled in Daejeon, Republic of Korea. Growth was observed at 25-45 ...°C (optimum, 35-40 °C) and pH 7.0-9.0 (optimum, pH 8.0), with up to 3 % (w/v) NaCl (optimum, 0 % NaCl). blast analysis of 16S rRNA gene sequences revealed the highest sequence similarity of strain BB3-R1
to
NRRL NRS-818
(98.8 %) followed by
JCM 15085
(97.5 %). According to 16S rRNA gene and whole-genome based phylogenetic trees, strain BB3-R1
clustered with
FJAT-54423
and
NRRL NRS-818
. OrthoANI and dDDH values of strain BB3-R1
with the closely related strains were lower than 77.5 and 26.8 %, respectively. The major menaquinones and polar lipids of the strain were MK-7 and phosphatidylmonomethylethanolamine, diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine, respectively. The major fatty acids (>10 %) were C
iso, C
iso, C
anteiso and C
7
alcohol. The cell-wall peptidoglycan contained cross-linked
-diaminopimelic acid (type A1 gamma). The phenotypic, chemotaxonomic and genotypic data obtained in this study showed that the strain represents a novel species of the genus
, for which the name
sp. nov. (type strain BB3-R1
=KACC 22663
=NBRC 115962
) is proposed.
Aspergilli known as black- and white-koji molds which are used for awamori, shochu, makgeolli and other food and beverage fermentations, are reported in the literature as A. luchuensis, A. awamori, ...A. kawachii, or A. acidus. In order to elucidate the taxonomic position of these species, available ex-type cultures were compared based on morphology and molecular characters. A. luchuensis, A. kawachii and A. acidus showed the same banding patterns in RAPD, and the three species had the same rDNA-ITS, β-tubulin and calmodulin sequences and these differed from those of the closely related A. niger and A. tubingensis. Morphologically, the three species are not significantly different from each other or from A. niger and A. tubingensis. It is concluded that A. luchuensis, A. kawachii and A. acidus are the same species, and A. luchuensis is selected as the correct name based on priority. Strains of A. awamori which are stored in National Research Institute of Brewing in Japan, represent A. niger (n = 14) and A. luchuensis (n = 6). The neotype of A. awamori (CBS 557.65 = NRRL 4948) does not originate from awamori fermentation and it is shown to be identical with the unknown taxon Aspergillus welwitschiae. Extrolite analysis of strains of A. luchuensis showed that they do not produce mycotoxins and therefore can be considered safe for food and beverage fermentations. A. luchuensis is also frequently isolated from meju and nuruk in Korea and Puerh tea in China and the species is probably common in the fermentation environment of East Asia. A re-description of A. luchuensis is provided because the incomplete data in the original literature.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A bacterial strain designated SC2-9
was isolated from the dust collector of a pigpen located in Wanju-gun, Jeollabuk-do, Republic of Korea. Cells were strictly aerobic, Gram-stain-negative, ...flagellated and rod-shaped. The strain was catalase- and oxidase-positive, and grew optimally 28-30 °C, pH 8.0 and 0 % NaCl (w/v). Phylogenetic analysis based on 16S rRNA gene sequences showed 99.1 and 98.3 % similarities to
KBB12
and
CY1
, and revealing less than 97 % similarity to other validly named species. The genomic DNA G+C content of strain SC2-9
was 68.2 %. The orthologous average nucleotide identity and dDDH values of strain SC2-9
with the closest species
KCTC 32230
were 85.6 and 29.3 %, respectively. The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, three unidentified aminolipids and one unidentified lipid. The major fatty acids (>10 %) were summed feature 3 (C
6
and/or C
7
), C
and summed feature 8 (C
6
and/ or C
7
). The predominant isoprenoid quinone was ubiquinone-8. Based on phenotypic, chemotaxonomic and phylogenetic data, strain SC2-9
should be assigned as a novel species of the genus
, for which the name
sp. nov. is proposed. The type strain is SC2-9
(=KACC 19310
=NBRC 113103
).
Birt–Hogg–Dubé syndrome (BHD) is an inherited disorder associated with a germline mutation of the folliculin gene (FLCN). The affected families have a high risk for developing multiple renal cell ...carcinomas (RCC). Diagnostic markers that distinguish between FLCN‐related RCC and sporadic RCC have not been investigated, and many patients with undiagnosed BHD fail to receive proper medical care. We investigated the histopathology of 27 RCCs obtained from 18 BHD patients who were diagnosed by genetic testing. Possible somatic mutations of RCC lesions were investigated by DNA sequencing. Western blotting and immunohistochemical staining were used to compare the expression levels of FLCN and glycoprotein non‐metastatic B (GPNMB) between FLCN‐related RCCs and sporadic renal tumors (n = 62). The expression of GPNMB was also evaluated by quantitative RT‐PCR. Histopathological analysis revealed that the most frequent histological type was chromophobe RCC (n = 12), followed by hybrid oncocytic/chromophobe tumor (n = 6). Somatic mutation analysis revealed small intragenic mutations in six cases and loss of heterozygosity in two cases. Western blot and immunostaining analyses revealed that FLCN‐related RCCs showed overexpression of GPNMB and underexpression of FLCN, whereas sporadic tumors showed inverted patterns. GPNMB mRNA in FLCN‐related RCCs was 23‐fold more abundant than in sporadic tumors. The distinctive expression patterns of GPNMB and FLCN might identify patients with RCCs who need further work‐up for BHD.
We investigated pathological features and the expression of FLCN and glycoprotein nonmetastatic B (GPNMB) in renal tumors of BHD patients. We showed that renal tumors with FLCN germline mutations overexpress GPNMB and that they lose the intact form of FLCN.
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