Grass Carp Reovirus (GCRV) and Aeromonas hydrophila (Ah) are the causative agents of haemorrhagic disease in grass carp. This study aimed to investigate the molecular mechanisms and immune responses ...at the miRNA, mRNA, and protein levels in grass carp kidney cells (CIK) infected by Grass Carp Reovirus (GCRV, NV) and Aeromonas hydrophilus (Bacteria, NB) to gain insight into their pathogenesis. Within 48 h of infection with Grass Carp Reovirus (GCRV), 99 differentially expressed microRNA (DEMs), 2132 differentially expressed genes (DEGs), and 627 differentially expressed proteins (DEPs) were identified by sequencing; a total of 92 DEMs, 3162 DEGs, and 712 DEPs were identified within 48 h of infection with Aeromonas hydrophila. It is worth noting that most of the DEGs in the NV group were primarily involved in cellular processes, while most of the DEGs in the NB group were associated with metabolic pathways based on KEGG enrichment analysis. This study revealed that the mechanism of a grass carp haemorrhage caused by GCRV infection differs from that caused by the Aeromonas hydrophila infection. An important miRNA–mRNA–protein regulatory network was established based on comprehensive transcriptome and proteome analysis. Furthermore, 14 DEGs and 6 DEMs were randomly selected for the verification of RNA/small RNA-seq data by RT-qPCR. Our study not only contributes to the understanding of the pathogenesis of grass carp CIK cells infected with GCRV and Aeromonas hydrophila, but also serves as a significant reference value for other aquatic animal haemorrhagic diseases.
There are no standard third-line treatment options for metastatic pancreatic ductal adenocarcinoma (mPDAC). Trametinib in combination with hydroxychloroquine (HCQ) or CDK4/6 inhibitors for pancreatic ...adenocarcinoma showed promising efficacy in preclinical studies. However, the regimens have not been well examined in patients with mPDAC.
Patients with mPDAC who received the combination of trametinib and HCQ or CDK4/6 inhibitors as third- or later-line therapy were reviewed. The efficacy and prognosis were further analyzed.
A total of 13 mPDAC patients were enrolled, of whom 8 and 5 patients were treated with trametinib plus HCQ or a CDK4/6 inhibitor (palbociclib or abemaciclib), respectively. All enrolled patients had either KRAS G12D or G12V mutations and had received a median of 3 prior lines of therapy (range, 2-6). The median trametinib treatment duration was 1.4 months. Of the 10 patients with measurable disease, only 1 patient achieved stable disease, and the remaining patients had progressive disease. Moreover, in patients treated with trametinib plus HCQ and a CDK4/6 inhibitor, the median progression-free survival was 2.0 and 2.8 months, respectively, and the median overall survival was 4.2 and 4.7 months, respectively. Moreover, 5 (50%) patients experienced grade 3-4 adverse events in 10 patients with available safety data.
The combination of trametinib and HCQ or CDK4/6 inhibitors may not be an effective later-line treatment for mPDAC, and the current preliminary findings need to be confirmed by other studies with larger sample sizes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
The purpose of this study is to evaluate the diagnostic efficacy of
68
Ga-NODAGA-LM3 and
68
Ga-DOTA-LM3 and compare them with
68
Ga-DOTATATE in patients with well-differentiated ...neuroendocrine tumors.
Methods
Patients were prospectively recruited and equally randomized into two arms: Arm A, patients would undergo a whole-body
68
Ga-NODAGA-LM3 PET/CT scan on the 1st day and
68
Ga-DOTATATE PET/CT scan on the 2nd day; Arm B, patients would undergo a whole-body
68
Ga-DOTA-LM3 PET/CT scan on the 1st day and
68
Ga-DOTATATE PET/CT scan on the 2nd day. Biodistribution in normal organs, lesion detection ability, and tumor uptake were compared between antagonist and agonist in each arm.
Results
A total of 40 patients with well-differentiated NETs, 20 in each arm, were recruited in the study.
68
Ga-NODAGA-LM3 showed a similar pattern as
68
Ga-DOTATATE, while
68
Ga-DOTA-LM3 demonstrated significantly lower uptake in almost all normal organs compared to
68
Ga-DOTATATE. Both
68
Ga-NODAGA-LM3 and
68
Ga-DOTA-LM3 showed superiority in lesion detection compared to
68
Ga-DOTATATE on lesion-based and patient-based comparison.
68
Ga-NODAGA-LM3 showed a significantly higher tumor uptake (median SUVmax 29.1 versus 21.6,
P
< 0.05) and tumor-to-background ratio (median tumor-to-liver ratio 5.0 versus 2.9,
P
< 0.05) compared to
68
Ga-DOTATATE.
68
Ga-DOTA-LM3 showed comparable uptake (median SUVmax 16.1 versus 17.8,
P
= 0.714) and higher tumor-to-background ratio (median tumor-to-liver ratio 5.2 versus 2.1,
P
< 0.05).
Conclusion
Both
68
Ga-NODAGA-LM3 and
68
Ga-DOTA-LM3 are promising SSTR2 antagonists for neuroendocrine tumors. They demonstrated superiority in diagnostic efficacy compared to agonist
68
Ga-DOTATATE.
Trial registration
ClinicalTrials.gov identifier: NCT04318561
(formerly known as
) has been extensively studied for agricultural applications as a plant-growth-promoting rhizobacterium and is also an important biocontrol agent. Our team has developed the
strain ...HY96-2 from the tomato rhizosphere as the first microbial biopesticide based on
for controlling plant diseases around the world, leading to the commercialization of this microbial biopesticide in China. However, further research is essential for understanding its precise biocontrol mechanisms. In this paper, we report the complete genome sequence of HY96-2 and the results of a comparative genomic analysis between different
strains. The complete genome size of HY96-2 was found to be 5.75 Mb and 5207 coding sequences were predicted. HY96-2 was compared with seven other
strains for which complete genome sequences have been published, using phylogenetic tree, pan-genome, and nucleic acid co-linearity analysis. In addition, the genes and gene clusters involved in biofilm formation, antibiotic synthesis, and systemic resistance inducer production were compared between strain HY96-2 and two other strains, namely, SC2 and E681. The results revealed that all three of the
strains have the ability to control plant diseases via the mechanisms of colonization (biofilm formation), antagonism (antibiotic production), and induced resistance (systemic resistance inducer production). However, the variation of the corresponding genes or gene clusters between the three strains may lead to different antimicrobial spectra and biocontrol efficacies. Two possible pathways of biofilm formation in
were reported for the first time after searching the KEGG database. This study provides a scientific basis for the further optimization of the field applications and quality standards of industrial microbial biopesticides based on HY96-2. It may also serve as a reference for studying the differences in antimicrobial spectra and biocontrol capability between different biocontrol agents.
S-1 has been recognized as one of the standard adjuvant chemotherapies for pancreatic ductal adenocarcinoma (PDAC) in East Asia, but the optimal adjuvant chemotherapy regimen has not been determined. ...We aimed to compare the efficacy and safety of adjuvant gemcitabine plus S-1 (GS) with S-1 monotherapy for PDAC.
Patients with resected PDAC who received adjuvant GS or S-1 chemotherapy in Peking Union Medical College Hospital between May 2014 and May 2022 were reviewed. Data retrieved from medical records were used to evaluate efficacy and toxicity.
A total of 241 patients were included, with 167 receiving GS and 74 receiving S-1. The patients who received GS were generally younger (median range age: 62 36-78 versus 64 44-87 years, p = 0.004), but chemotherapy began later (median range interval between chemotherapy and surgery: 49 17-125 versus 40 16-100 days, p < 0.001). The median disease-free survival (DFS, 15.1 versus 15.9 months, p = 0.52) and overall survival (OS, 34.8 versus 27.1 months, p = 0.34) did not differ significantly between the GS and S-1 groups, even after adjustment for the biases. However, the chemotherapy completion rate was higher in the patients treated with S-1 (52.4% versus 75.7%, p = 0.006), while grade 3-4 neutropenia occurred more frequently in the GS group (49.5% versus 18.2%, p = 0.015).
Adjuvant S-1 monotherapy demonstrated noninferiority to the GS regimen in DFS and OS with better tolerability for PDAC following surgery.
Background: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogenous malignancies that requires well-designed trials to develop effective management strategies. This ...cross-sectional study aimed to illustrate the current landscape of clinical trials in GEP-NENs to provide insights for future research. Materials and methods: We reviewed all clinical trials registered on ClinicalTrials.gov between January 1, 2000, and December 31, 2021, with GEP-NEN in the “Condition or disease” field. Results: We included 206 eligible trials. Most trials enrolled less than 50 patients (59.8%), and were sponsored by institutions other than government or industry (67.0%). Most trials were conducted in high income countries (86.6%), and countries located in Europe (30.1%) or Northern America (29.6%). The overall result reporting rates of GEP-NEN trials was 41.4%, and the median time from primary completion to result reporting was 101 months. Characteristics that improved the reporting of results included larger sample size, tumor differentiation specification for inclusion, progression-free survival as primary endpoint, industry sponsorship, and multicenter or multinational participation (all P<0.05). Compared with trials registered between 2000 and 2011 (n=28), trials registered between 2012 and 2021 (n=178) were more likely to specify the Ki-67 index for inclusion (68.0% vs. 35.7%, P=0.002), and to be conducted outside Europe or Northern America (16.4% vs. 3.7%, P=0.02), while the sample size and the sponsorship did not change significantly. Conclusions: Novel management options have been explored for GEP-NENs with more specific inclusion criteria during the past two decades. More efforts are needed to promote international collaborations in clinical trials and enhance timely result dissemination.
Functioning tumors are usually diagnosed during the early evaluation of hormonal syndromes, whereas most non-functioning pNENs are accidentally found during imaging studies and endoscopies for other ...complaints, such as the mass effect of local growth or secondary symptoms owing to metastasis. 4,5 Although most pNENs are sporadic and likely carry somatic mutations in death domain-associated protein 6 (DAXX) and ATP-dependent helicase (ATRX),6 they may develop in patients with hereditary endocrinopathies, including multiple endocrine neoplasia type 1 (MEN1),7 von Hippel–Lindau (VHL) syndrome,8 neurofibromatosis type 1 (NF1),9 and Tuberous Sclerosis Complex (TSC). Laboratory tests Peripheral blood biomarker test Serum chromogranin A (CgA), the most critical universal biomarker for neuroendocrine tumors (NETs), is used to assist in diagnosis and to assess the response and prognosis. Percutaneous transhepatic portal vein catheterization (PT-PC), which involves placing the catheter into the splenic vein and portal vein trunk to measure VIP concentrations, facilitates qualitative assessment and localization evaluation.
Neuroendocrine neoplasms (NENs) comprise a heterogeneous collection of tumors derived from various neuroendocrine cells and are divided into functioning NEN and non-functioning NEN. Some NENs present ...with mild symptoms and can secrete somatostatin. These neoplasms are known as somatostatin-producing oligosymptomatic NENs. In this report, we describe a case of metastatic somatostatin-producing oligosymptomatic NEN with peritumoral hepatic steatosis and review the relevant literature. The patient was a 45-year-old woman who presented with mild steatorrhea and melena. A computed tomography scan revealed an enlarged pancreas protruding into the duodenum. Pathology after total pancreatectomy showed a grade 2 pancreatic NEN with positive somatostatin immunostaining. Enlarging masses on the liver were observed after the operation. Ultrasound examination revealed several lesions in the liver, with inner hypoechoic areas that showed rapid enhancement and fast washout on contrast-enhanced ultrasonography and with outer hyperechoic areas with continuous iso-enhancement. Therefore, the inner hypoechoic areas seen on contrast-enhanced ultrasonography were suspected to be true metastases. A biopsy confirmed this suspicion and indicated that the outer areas were peritumoral liver steatosis. This case highlights the importance of the imaging pattern described in this report for accurate diagnosis of metastatic NEN to avoid incorrect estimation of tumor size or a missed diagnosis on biopsy.
Digestive system neuroendocrine carcinomas (NECs) are rare neoplasms originating from neuroendocrine cells with a poor prognosis and limited effective treatments. Programmed cell death protein ...1/ligand 1 (PD-1/PD-L1) blockade has been used in the management of more than 10 solid tumors and has achieved promising clinical outcomes. PD-L1 expression, immune cell infiltration, tumor mutational burden (TMB), and microsatellite instability (MSI) are all verified biomarkers that can predict the response to anti-PD-1/PD-L1 therapy. Here, we investigated PD-L1 expression and immune cell infiltration density by immunohistochemical (IHC) staining of tumor samples from 33 patients with digestive system NECs. Tumor and paratumor normal samples from 31 of these patients underwent whole-exome sequencing to evaluate TMB and the MSI-high (MSI-H) status. In total, 29.0% of digestive system NECs had positive PD-L1 expression according to the tumor proportion score (TPS). Infiltration of CD3
, CD8
, and CD68
cells was observed in 69.7, 27.3, and 54.5% of patients, respectively. The TMB value for patients sequenced ranged from 0.57 to 11.75 mutations/Mb, with a median of 5.68 mutations/Mb. mSINGS, MSIsensor, and MSIseq were used to analyze the MSI status according to the sequencing data, and in our evaluation, no MSI-H status was detected. Our data might indicate a limited potential of anti-PD-1/PD-L1 monotherapy in digestive system NECs, although clinical trials are warranted.
Purpose
To evaluate the safety and efficacy of
177
Lu-DOTA-EB-TATE, a radiolabeled somatostatin analog modified by Evans blue, at escalating doses, was used to increase tumor retention in patients ...with progressive metastatic neuroendocrine tumors (NETs).
Methods
Thirty-three patients with metastatic NETs were prospectively enrolled into four groups: group A (
n
= 6, 43 ± 12 years) administered approximately 3.7 GBq (100 mCi)
177
Lu-DOTATATE as controls; group B (
n
= 7, 55 ± 7 years) administered approximately 1.11 GBq (30 mCi)
177
Lu-DOTA-EB-TATE; group C (
n
= 6, 55 ± 10 years) administered approximately 1.85 GBq (50 mCi)
177
Lu-DOTA-EB-TATE; group D (
n
= 14, 50 ± 10 years) administered approximately 3.7 GBq (100 mCi)
177
Lu-DOTA-EB-TATE. Treatment-related adverse events were graded according to the CTCAE v.5.0.
68
Ga-DOTATATE PET/CT were performed at baseline and 2–3 months after treatment for response evaluation.
Results
Administration was well tolerated. No CTC 3/4 hematotoxicity, nephrotoxicity, or hepatotoxicity was observed during or after treatment in groups A–C. In group D, CTC-3 hematotoxicity was recorded in 2 patients with multicourse chemotherapy previously. After one-cycle treatment, the SUVmax decreased in group C (Δ% = − 17.4 ± 29.3%) and group D (Δ% = − 15.1 ± 39.1%), but greatly increased in group B (Δ% = 30.0 ± 68.0%) and mildly increased in group A (Δ% = 5.4 ± 45.9%). Referring to EORTC criteria, 16.7% (1/6), 0% (0/7), 50% (3/6), and 50% (7/14) were evaluated as partial response in groups A, B, C, and D, respectively. When selecting lesions with comparable baseline SUVmax ranging from 15 to 40, SUVmax showed no significant decrease in group B (Δ% = − 7.3 ± 24.5%) (
P
= 0.214), significant decrease in group C (Δ% = − 34.9 ± 12.4%) (
P
= 0.001), and in group D (Δ% = − 17.9 ± 19.7%) (
P
= 0.012) as compared with group A with increased SUVmax (Δ% = 8.4 ± 48.8%). SUVmax significantly decreased in the EBTATE groups (groups B–D combined) (Δ% = − 19.0 ± 21.5%) as compared with the TATE group (
P
= 0.045).
Conclusion
177
Lu-DOTA-EB-TATE is well tolerated and is more effective than
177
Lu-DOTATATE. Both 1.85 GBq (50 mCi) and 3.7 GBq (100 mCi) doses appear to be more effective than 1.11 GBq (30 mCi) dose. Further investigation with more cycles of
177
Lu-DOTA-EB-TATE treatment and longer follow-up is warranted.
Trial registration
Treatment Using 177Lu-DOTA-EB-TATE in Patients with Advanced Neuroendocrine Tumors (NCT03478358). URL:
https://register.clinicaltrials.gov/prs/app/action/ViewOrUnrelease?uid=U0001JRW&ts=13&sid=S0007RNX&cx=y3yqv4
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