Subtype 1b Research Articles

Research on Anatomical Types and Variations of Lung Segment Bronchi Based on Artificial Intelligence 3D Reconstruction Technology

Aims: To investigate the anatomic type and variation of segmental bronchus based on artificial intelligence 3D reconstruction technology. Methods: The image data of 200 patients who underwent thin-layer enhanced chest CT examination in the Department of Thoracic Surgery of Shandong Public Health Clinical Center from December 2021 to December 2022 were selected. The bronchi and blood vessels of the affected side of the lung were reconstructed according to the CT scanning data of the patients, and the anatomic types and anatomic variations of the bronchi of each lung segment on the affected side were observed and statistically analyzed. Results: There were basically four anatomical types of the right superior lobar bronchus, of which the three branching subtypes B1, B2 and B3 are the most common anatomical types. There are two types of right middle lobe bronchus, of which the B4 and B5 subtypes are the most common anatomic types. For the left lung, 4 types of segmental bronchus were found and (B1+2a+b, B1+2c), (B3a, B3b+c) was the most common anatomical type. Two types of bronchus were found in the left superior lobe of the lung. Type B4 and type B5 were the most common anatomical types. In addition, there were 3 types of bronchi in the dorsal segment of the left inferior lobe, and 3 types in the anterior, external and posterior basal segment bronchi of the left inferior lobe, among which B8, B9+B10 (57.6%) were the most common. Conclusion: The anatomical types of segmental and subsegmental bronchus are complex and varied, and there may be rare anatomical variations. Therefore, before performing relevant operations, it is necessary to be familiar with the relevant operations and the branch types of corresponding bronchus in advance to ensure the smooth operation.

Genetic diversity of hepatitis C virus and the prevalence of resistance mutations to NS5A inhibitors in the Krasnoyarsk region

To research the molecular genetic characteristics of the HCV population circulating among HIV‐infected residents of the Krasnoyarsk Territory, including analysis of resistance‐associated mutations to NS5A inhibitors. Total RNA was isolated from 94 blood plasma samples from HIV/HCVinfected residents of the region and the nucleotide sequences of the Core/E1 gene and NS5A gene regions were obtained and deciphered, which were used for genotyping and searching for resistance mutations.In the HCV samples studied, the circulation of five virus subtypes was recorded: 1b (47,9 %), 3a (37,2 %), 1a (10,6 %), 2a (3,2 %) and 2k (1,1 %). Phylogenetic analysis of HCVs revealed partial clustering within subtypes 1a and 3a on a territorial basis. HCV subtypes 1b, 2a and 2k were grouped with other HCVs previously isolated in Russia, Armenia and Kyrgyzstan. Among the HCVs studied, no clusters were found that were common to HIV‐infected individuals with the same route of infection. Among patients who had no experience of taking DAAs, HCV resistance mutations in the NS5A region were found in 42,3 % of cases for those infected with subtype 3a virus and in 75,6 % of cases for those infected with HCV subtype 1b.The analysis of the diversity and occurrence of mutations of HCV drug resistance to direct antiviral drugs is extremely important for the development of tactics for effective treatment of CHC. The high prevalence of polymorphic mutations that affect sensitivity to DAAs indicates the relevance of introducing HCV resistance analysis into clinical practice.

A Combined Approach for the Characterization of Small Ruminant Lentivirus Strains Circulating in the Islands and Mainland of Greece.

Small ruminant lentiviruses are a group of viruses infecting goat and sheep worldwide. These viruses exhibit an extraordinary degree of genetic and antigenic variability that severely influence in vivo and in vitro features, as well as diagnostic test results. Small ruminant farming is the most important animal farming business in Greece, with a high impact on the Greek primary economy. Although SRLV infection and its impact on animal production are well established in the country, little is known about the circulating SRLV strains and their prevalence. The aim of this study was to characterize SRLVs circulating in Greece with a combined serological and molecular approach, using the bulk milk matrix collected from 60 farms in different municipalities. This study allowed us to estimate a seroprevalence of around 52% at the herd level. The B1, B2 and A3 subtypes and a novel A viral cluster were identified. Moreover, the amplicon sequencing method allowed us to identify more than one viral subtype in a sample. These results again confirm the high variability of these viruses and highlight the importance of the constant monitoring of viral evolution, in particular in antigens of diagnostic interest.

GSD1 Subtype 1B: Timeline and progression of clinical symptoms in a patient with juvenile idiopathic arthritis

GSD1 Subtype 1B: Timeline and progression of clinical symptoms in a patient with juvenile idiopathic arthritis

Genetic Characterization of Small Ruminant Lentiviruses Isolated from Dairy Sheep in Greece.

The high genetic heterogeneity of small ruminant lentiviruses (SRLV) renders the genetic characterization of the circulating strains crucial for the epidemiological investigation and the designation of effective diagnostic tools. In Greece, research data regarding the genetic diversity of the circulating SRLV strains is scarce, hindering the implementation of efficient surveillance and control programs. The objective of the study was to genetically characterize SRLV strains isolated from intensive dairy sheep farms in Greece and evaluate the variability of the immunodominant regions of the capsid protein. For this reason, a total of 12 SRLV-infected animals from four intensive dairy sheep farms with purebred Chios and Lacaune ewes were used for the amplification and sequencing of an 800 bp gag-pol fragment. The phylogenetic analyses revealed a breed-related circulation of strains; Chios ewes were infected with strains belonging exclusively to a separate group of genotype A, whereas strains belonging to subtype B2 were isolated from Lacaune ewes. Immunodominant epitopes of capsid protein were quite conserved among the strains of the same genotype, except for the Major Homology Region which showed some unique mutations with potential effects on viral evolution. The present study contributes to the extension of the current knowledge regarding the genetic diversity of SRLV strains circulating in sheep in Greece. However, broader genetic characterization studies are warranted for the exploration of possible recombinant events and the more comprehensive classification of the circulating strains.

Rare HCV subtypes and retreatment outcomes in a cohort of European DAA-experienced patients

Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort. A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively. Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n= 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n= 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure. In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed. Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.

Abstract 7653: Role of ITGB2 in patients with luminal B1 breast cancer

Abstract Purpose: Luminal-type breast cancers are the most commonly diagnosed in women. Among them, the luminal B1 subtype exhibits higher proliferation rates and a worse prognosis compared to the luminal A subtype. Despite significant advancements in detection and therapies, recurrence still occurs after primary treatment. In this study, our aim is to identify genomic alterations in early recurrent luminal B1 breast cancer. Experimental Design: In this VGHTPE cohort, we recruited a total of 42 patients diagnosed with stage I-III luminal B1 breast cancer, comprising 15 subjects who experienced recurrence within five years and 27 subjects who did not. Genomic DNA was extracted from formalin-fixed paraffin-embedded samples and subjected to targeted next-generation sequencing. We assessed cell aggressiveness through in vitro transwell migration, invasion, and sphere assays. Results: Luminal B1 breast cancer patients with advanced stage and poorly differentiated tumors were associated with recurrence within five years. Driver gene mutation analysis revealed that TP53 mutations were present in 46.7% of patients who experienced recurrence within five years, compared to 29.6% in the non-recurrence group. In the analysis of copy number variations, the most common amplifications/gains observed in luminal B1 breast cancer patients were in MCL1, MYC, and KLF6. Remarkably, patients who experienced recurrence within five years showed a higher occurrence of gain in ITGB2, the gene encoding the integrin β chain, compared to those who remained recurrence-free. Patients with ITGB2 amplifications/gains had a shorter 5-year recurrence-free survival compared to those with a neutral status. In vitro studies revealed that the knockdown of ITGB2 suppressed cell migration, invasion, and sphere formation in estrogen receptor-positive HER2-negative breast cancer cells. Conclusion: Our study has identified ITGB2 amplifications/gains as a potential biomarker for early recurrence in luminal B1 breast cancer. Citation Format: Chun-Yu Liu, Ji-Lin Chen, Yi-Fang Tsai, Ta-Chung Chao, Wan-Lun Wang, Pei-Ju Lien, Chih-Yi Hsu, Jiun-I Lai, Chi-Cheng Huang, Jen-Hwey Chiu, Ling-Ming Tseng. Role of ITGB2 in patients with luminal B1 breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7653.

Abstract 779: Functional role of TGF-beta receptor type-2 in breast cancer progression and survival

Abstract Background and Rational: Transforming growth factor β (TGFβ) signaling is pivotal in cellular proliferation and can exhibit either tumor-suppressive or promoting effects depending on cellular context and genetic alterations. TGFβ receptor type-2 (TGFβR2), the ligand-binding receptor, is implicated in various cancers. This study explores the functional role of TGFβR2 in breast cancer (BrCa) progression. Materials and Method: Genomic alterations in TGFβR2 were assessed in TCGA samples. TGFβR2 mRNA and protein expression were examined in a panel of BrCa cell lines, including MCF7, MCF12A, MDA-MB-231, and MDA-MB-468. Additionally, serum samples from BrCa patients, meticulously categorized into subtypes such as triple-negative (TN), human epidermal growth factor receptor 2-positive (Her2+), Luminal A (LA), Luminal B1 (LB1), and Luminal B2 (LB2), were analyzed. BrCa cell lines were treated with TGFβ ligand to investigate receptor expression modulation. Results: Analysis of genomic alterations in TGFβR2 from The Cancer Genome Atlas (TCGA, n=1084, BrCa samples) revealed TGFβ copy number amplification in 25% of samples, while less than 1% showed TGFβR2 amplification. Elevated TGFβR2 levels were identified in aggressive triple-negative MDA-MB-231 cells compared to other tested cell lines. Serum samples from BrCa patients (n=240) demonstrated higher TGFβR2 levels, particularly in Luminal B1 subtype and African American patients. Treatment of BrCa cell lines with TGFβ ligand induced TGFβR2 expression, suggesting ligand-induced receptor upregulation. Discussion: The findings suggest TGFβR2 as a potential biomarker for BrCa, with higher levels associated with aggressiveness and racial disparities. Ligand-induced receptor upregulation implies a potential oncogenic role. These results contribute to understanding TGFβR2's functional significance and its implications in breast cancer progression, offering insights into potential biomarkers and therapeutic targets. Citation Format: Meera Srivastava, Alakesh Bera, Harvey B. Pollard, Hai Hu, Craig D. Shriver. Functional role of TGF-beta receptor type-2 in breast cancer progression and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 779.

Detection and Phylogenetic Analysis of Caprine Arthritis Encephalitis Virus Using TaqMan-based qPCR in Eastern China.

Caprine arthritis encephalitis is an infectious disease caused by the caprine arthritis encephalitis virus that infects goats, sheep, and other small ruminants. An outbreak of CAEV could be extremely harmful to the goat farming industry and could cause severe economic losses. We designed specific primers and probes for the gag gene and established a TaqMan real-time quantitative polymerase chain reaction assay. This method's correlation coefficient (R2) was >0.999, and the sensitivity of the assay to the plasmid-carried partial gag gene was approximately 10 copies/µL, 1000 times higher than that of conventional PCR. No specific fluorescence was detected for other sheep viruses. Using this method, we tested 776 asymptomatic sheep blood samples and 4 neurodegenerative sheep brain samples from six farms in eastern China, and the positivity rate was 0.77% (6/780). The gag gene was partially sequenced in the three positive samples and compared with the sequences from other representative strains in GenBank. The results revealed that all three strains belonged to the B1 subtype and were most closely related to the strains from Shanxi and Gansu, previously isolated in China, with their homology ranging from 97.7% to 98.9%. These results suggest that the designed RT-qPCR assay can be used to detect subclinical CAEV in sheep and that the virus is still present in eastern China.

Hydrogen treatment reduces electroencephalographic activity and neuronal death in rats with refractory status epilepticus by inhibiting membrane NR2B phosphorylation and oxidative stress.

To investigate the effects of hydrogen therapy on epileptic seizures in rats with refractory status epilepticus and the underlying mechanisms. Status epilepticus was induced using pilocarpine. The effects of hydrogen treatment on epilepsy severity in model rats were then monitored using Racine scores and electroencephalography (EEG), followed by western blot of plasma membrane N-methyl-D-aspartate receptor subtype 2B (NR2B) and phosphorylated NR2B expression. We also generated a cellular epilepsy model using Mg2+-free medium and used polymerase chain reaction to investigate the neuroprotective effects of hydrogen. There were no significant differences in Racine scores between the hydrogen and control groups. EEG amplitudes were lower in the hydrogen treatment group than in the control group. In epilepsy model rats, hippocampal cell membrane NR2B expression and phosphorylation increased gradually over time. Although hippocampal cell membrane NR2B expression was not significantly different between the two groups, NR2B phosphorylation levels were significantly lower in the hydrogen group. Hydrogen treatment also increased superoxide dismutase, mitochondrial (SOD2) expression. Hydrogen treatment reduced EEG amplitudes and NR2B phosphorylation; it also decreased neuronal death by reducing oxidative stress. Hydrogen may thus be a potential treatment for refractory status epilepticus by inhibiting membrane NR2B phosphorylation and oxidative stress.

Up-to-date Epidemiology of Chronic Hepatitis C Virus Infection among Bulgarian Patients: a Single Centre Experience

Epidemiological data about chronic infection with Hepatitis C virus (HCV) are limited in Bulgaria. The aim of this study was to determine the Viremic Rate and the distribution of HCV genotypes in one centre for diagnosis and treatment of chronic liver diseases. Geographic patterns of genotype distribution and associations of genotype with viral load, gender and age were investigated. Serum samples from 1731 individuals with a positive HCV Antibody Test, collected between 2016 and 2019, were analysed. HCV RNA levels were determined by HCV quantitative RNA real time polymerase chain reaction. Individuals with detectable HCV RNA further underwent HCV genotyping analysis using the Versant HCV Genotype Assay (LiPA) 2.0. The mean age of all patients was 52.9±15.3 (17–87). Among those, 54.1% were men and 45.9% women. Most patients came from the south-western region of Bulgaria (21.7%). Viral load was proven in 1385 out of 1731 individuals (VR=80%). Genotype 1 (G1) was the predominant genotype (89.8%), followed by G3 (8.5%), G2 (0.9%), G4 (0.6%) and G5 (0.1%). Among individuals with G1, infection with subtype 1b was seen in 77.4% and with subtype 1a in 22.6%. Viral load was not found to be dependent on age or gender. Viral load was higher in patients with G1 compared to G3 ($$p=0.001$$). Finally, patients with G1b were significantly older than patients with G1a ($$p<0.001$$) and G3 ($$p<0.001$$). VR in the studied population (80%) appears to be higher than the VR reported for Central Europe (73.3%). In Bulgaria, the most prevalent genotype is G1 (89.8%). This is a higher rate in comparison to the observed G1 rate in Central Europe (70%). The second most prevalent genotype is G3 (8.5%), with fewer cases identified than in Central Europe (21%).

Non-Mutational Key Features in the Biology of Thymomas.

Thymomas (THs) are a unique group of heterogeneous tumors of the thymic epithelium. In particular, the subtypes B2 and B3 tend to be aggressive and metastatic. Radical tumor resection remains the only curative option for localized tumors, while more advanced THs require multimodal treatment. Deep sequencing analyses have failed to identify known oncogenic driver mutations in TH, with the notable exception of the GTF2I mutation, which occurs predominantly in type A and AB THs. However, there are multiple alternative non-mutational mechanisms (e.g., perturbed thymic developmental programs, metabolism, non-coding RNA networks) that control cellular behavior and tumorigenesis through the deregulation of critical molecular pathways. Here, we attempted to show how the results of studies investigating such alternative mechanisms could be integrated into a current model of TH biology. This model could be used to focus ongoing research and therapeutic strategies.

Epidemiology of Viral Hepatitis in the Indigenous Populations of the Arctic Zone of the Republic of Sakha (Yakutia).

The indigenous populations of the Arctic regions of Russia experience the lowest coverage of health-related services. We assessed the prevalence of hepatitis A, B, C, D and E viruses (HAV, HBV, HCV, HDV and HEV) among 367 healthy adult Native people of the Arctic zone of Yakutia. The HAV seroprevalence was above and increased with age. The anti-HEV IgM and IgG antibody detection rates were 4.1% and 2.5%, respectively. The average HBsAg detection rate was 4.6%, with no positive cases identified in participants aged under 30 years, confirming the effectiveness of the newborn vaccination program that began in 1998. Anti-HDV antibodies were detected in 29.4% of HBsAg-positive cases. The anti-HCV and HCV RNA detection rates peaked in the age cohort of 50-59 years (10.8% and 3.9%). No statistically significant gender differences in the prevalence of different viral hepatitis were observed. The time-scaled phylogenetic analysis demonstrated that all HBV genotype A and D strains isolated in this study were autochthonous and had an estimated most common recent ancestor (MCRA) age of around the 11th to 14th century. Unlike HBV, the HCV strains of subtypes 1b, 2a and 2k/1b were introduced from other regions of Russia in the 1980s and 1990s. The HCV 1b sequence analysis revealed a series of transmission events. In conclusion, these data emphasize the urgent need for expanded viral hepatitis screening and care programs in the indigenous populations of the Arctic zone of Yakutia.

Epidemiology of hepatitis C infection among pregnant women and parturients in Nizhny Novgorod

Hepatitis C is an urgent global health problem. The high prevalence of infection among the population leads to the involvement of women of reproductive age in the epidemic process. In order to study the prevalence of specific markers of hepatitis C virus in pregnant women and to assess the risk of intrauterine infection of the fetus, an epidemiologic analysis was conducted using information collections of statistical and analytical materials of Rospotrebnadzor, blood serum samples of pregnant and postpartum women (n = 28394) at admission to obstetric institutions for the period 2018–2022 were examined. According to statistical reporting, the average annual prevalence of anti-HCV prevalence in pregnant women was 1.7% (95% CI: 1.5–1.9%). Women aged 40–49 years were found to be most actively involved in the epidemic process (4.3% [95% CI: 3.3–5.6%]). Among anti-HCV-positive samples, HCV RNA was detected in 47.0% (95% CI: 41.7–52.9%) of cases, the prevalence of current infection confirmed by HCV RNA detection in pregnant women was 0.9% (95% CI: 0.8–1.0%). The pattern of HCV genotypes in pregnant women was as follows: subtype 1b was detected in 34.9% (95% CI: 25.6–45.7%) of cases, subtype 3a in 42.2% (95% DI: 32.1–52.9%), minor subtype 1a was 9.6% (95% CI: 5.0–17.9%) and genotype 2 was 7.0% (95% CI: 3.4–14.9%). Samples containing two genotypes simultaneously (1a/1b, 1b/3a) were 3.6% (95% CI: 1.2–10.1%) and non-genotyped samples were 2.4% (95% CI: 0.7–4.1%). The results of the assessment of the significance of risk factors for perinatal transmission of hepatitis C virus show a high degree of influence on vertical transmission of HCV RNA in the presence of active infection in the mother (RR = 6.4; [95% CI: 0.9–44.6%]: p < 0.05), no statistical significance of HCV genotypic affiliation (p > 0.05) and maternal viral load level (R = 0.00009; p > 0.05). The obtained data argue the necessity of screening examinations for molecular genetic markers of hepatitis C virus in women planning pregnancy in order to conduct antiviral therapy and, as a consequence, to reduce the risk of perinatal infection of children.

The molecular epidemiology of hepatitis E virus genotype 3 in Canada.

Autochthonous hepatitis E virus (HEV) infection is increasingly reported in industrialized countries and is mostly associated with zoonotic HEV genotype 3 (HEV-3). In this study, we examined the molecular epidemiology of 63 human clinical HEV-3 isolates in Canada between 2014 and 2022. Fifty-five samples were IgM positive, 45 samples were IgG positive and 44 were IgM and IgG positive. The majority of the isolates belong to the subtypes 3a, 3b, and 3j, with high sequence homology to Canadian swine and pork isolates. There were a few isolates that clustered with subtypes 3c, 3e, 3f, 3h, and 3g, and an isolate from chronic infection with a rabbit strain (3ra). Previous studies have demonstrated that the isolates from pork products and swine from Canada belong to subtypes 3a and 3b, therefore, domestic swine HEV is likely responsible for the majority of clinical HEV cases in Canada and further support the hypothesis that swine serve as the main reservoirs for HEV-3 infections. Understanding the associated risk of zoonotic HEV infection requires the establishment of sustainable surveillance strategies at the interface between humans, animals, and the environment within a One-Health framework.

Distribution pattern, molecular transmission networks, and phylodynamic of hepatitis C virus in China.

In China, few molecular epidemiological data on hepatitis C virus (HCV) are available and all previous studies were limited by small sample sizes or specific population characteristics. Here, we report characterization of the epidemic history and transmission dynamics of HCV strains in China. We included HCV sequences of individuals belonging to three HCV surveillance programs: 1) patients diagnosed with HIV infection at the Beijing HIV laboratory network, most of whom were people who inject drugs and former paid blood donors, 2) men who have sex with men, and 3) the general population. We also used publicly available HCV sequences sampled in China in our study. In total, we obtained 1,603 Ns5b and 865 C/E2 sequences from 1,811 individuals. The most common HCV strains were subtypes 1b (29.1%), 3b (25.5%) and 3a (15.1%). In transmission network analysis, factors independently associated with clustering included the region (OR: 0.37, 95% CI: 0.19-0.71), infection subtype (OR: 0.23, 95% CI: 0.1-0.52), and sampling period (OR: 0.43, 95% CI: 0.27-0.68). The history of the major HCV subtypes was complex, which coincided with some important sociomedical events in China. Of note, five of eight HCV subtype (1a, 1b, 2a, 3a, and 3b), which constituted 81.8% HCV strains genotyped in our study, showed a tendency towards decline in the effective population size during the past decade until present, which is a good omen for the goal of eliminating HCV by 2030 in China.

Blood flow reconstruction in portal vein anatomical variations in right lobe living donor liver transplantation

Background. Adequate restoration of blood flow through the portal vein in the graft is only possible with a clear understanding of its anatomy in the donor.The aim was to describe new and extend current data on the portal vein anatomy in a donor of the right liver lobe, to describe variants and formulate principles of portal reconstruction in right lobe living donor liver transplantation.Material and methods. 306 living donor liver transplantations were performed from 2009 to 2021 in the State Research Center – Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency. The vascular anatomy of 518 potential donors was analyzed. Portal vein variants of the anatomy of right lobe graft were assessed.Results. Nine types and 3 subtypes of portal vein branching were evaluated. A, B, C, D, E types match the types described earlier in Nakamura classification. Subtypes B1, B2 и D1 are specifications of types B and D. Types F, G, H, I have been described additionally. The incidence of types and subtypes where reconstruction was made: type A (82%), B (4.6%), B1 (3.9%), B2 (1.3%), C (3.9%), D (3.9%). The incidence of E, G, H, I types among 518 potential donors was 0.4%, 0.6%, 0.2%, 0.4%, respectively. The recipient portal vein complications were detected in 12 cases (3.9%), where 3(25%) were Class 3b according to Clavien-Dindo and 9(75%) of Clavien-Dindo Class 2. There were no correlations between portal vein complications and the method of portal vein reconstruction. (p<0.05). No complications occurred with portal vein in donors.Conclusion. The existing classification of right liver graft portal vein has been updated and detailed. A certain way of reconstruction has been proposed for each portal vein type. Anatomical types in which donation and transplantation are contraindicated have been specified.

Characterization of (R)- and (S)-[18F]OF-NB1 in Rodents as Positron Emission Tomography Probes for Imaging GluN2B Subunit-Containing N-Methyl-d-Aspartate Receptors.

The N-methyl-d-aspartate receptor (NMDAR) subtype 2B (GluN1/2B) is implicated in various neuropathologies. Given the lack of a validated radiofluorinated positron emission tomography (PET) probe for the imaging of GluN1/2B receptors, we comprehensively investigated the enantiomers of [18F]OF-NB1 in rodents. Particularly, the (R)- and (S)- enantiomers were evaluated using in silico docking, in vitro autoradiography, in vivo PET imaging, and ex vivo biodistribution studies. A select panel of GluN1/2B antagonists (CP-101,606, CERC-301, and eliprodil) and the off-target sigma-1 receptor ligands (fluspidine and SA4503) were used to determine the specificity and selectivity of the tested enantiomers. Additionally, a nonmetal-mediated radiofluorination strategy was devised that harnesses the potential of diaryliodoniums in the nucleophilic radiofluorination of nonactivated aromatic compounds. Both enantiomers exhibited known GluN1/2B binding patterns; however, the R-enantiomer showed higher GluN1/2B-specific accumulation in rodent autoradiography and higher brain uptake in PET imaging experiments compared to the S-enantiomer. Molecular simulation studies provided further insights with respect to the difference in binding, whereby a reduced ligand-receptor interaction was observed for the S-enantiomer. Nonetheless, both enantiomers showed dose dependency when two different doses (1 and 5 mg/kg) of the GluN1/2B antagonist, CP-101,606, were used in the PET imaging study. Taken together, (R)-[18F]OF-NB1 appears to exhibit the characteristics of a suitable PET probe for imaging of GluN2B-containing NMDARs in clinical studies.

Abstract A001: Reshaping the immune microenvironment after temozolomide priming in metastatic colorectal cancer patients in ARETHUSA clinical trial

Abstract Mismatch repair (MMR) proficient (MMRp) tumors, known for their weak immune response, often exhibit limited effectiveness in immunotherapy. In contrast, responsive mismatch repair deficient (MMRd) tumors, characterized by heightened immune activity, show a stronger response to immune checkpoint blockade (ICB). In the ARETHUSA clinical trial (NCT03519412), we revealed that treatment with temozolomide (TMZ) can pharmacologically deactivate the MMR machinery, as indicated by mutational signature analysis and the emergence of MMR gene mutations. We focused our investigation on a subset of initially MMRp CRC patients who experienced sustained disease stabilization with ICB after receiving TMZ priming treatment. This treatment resulted in the emergence of an inactivating MSH6 mutation and the TMZ mutational signature. Additionally, TMZ treatment induced diverse genomic changes, leading to the identification of three distinct subtypes through analysis of blood and tissue samples. Notably, we observed a dose-dependent accumulation of mutations with a specific molecular signature visible at the clonal level (subtype B2) in 10% of patients, at the subclonal level (subtype B1) in 71% of patients, and the absence of these mutations (subtype A) in 19% of patients within our cohort of 21 patients. In conjunction with previous genetic findings, in this new study we performed an analysis of T-cell receptors (TCRs) in the tumor microenvironment following TMZ treatment. Our results revealed expanded clonotypes in tumors that exhibited a clonal increase in mutations following priming treatment. Furthermore, the diversity of TCRs within the immune infiltrate confirmed the categorization of tumors into three distinct classes based on Tumor Mutational Burden (TMB) and mutational signatures. We also established a significant linear correlation (p-value 0.0048) between the diversity of T-cells in the microenvironment and the number of mutations induced by TMZ. Based on these clinically-oriented preliminary findings, we propose that increasing the number of TMZ-induced mutations could enhance the likelihood of TMZ-driven neoantigens triggering clonal expansion of specific T-cell clonotypes within the tumor. Interestingly, the subset of TMZ-treated tumors displaying an acquired MSH6 mutation, TMZ mutational signature, and increased TMB not only achieved temporary disease stabilization with ICB but also exhibited clonal expansion of T-cells in the tumor microenvironment. These clinically relevant findings suggest that the inactivation of MMR achieved through TMZ priming has the potential to reshape the immune microenvironment modulating the immune response in metastatic colorectal cancer. Citation Format: Giovanni Crisafulli, Andrea Sartore-Bianchi, Luca Lazzari, Filippo Pietrantonio, Paolo Battuello, Alice Bartolini, Federica Di Nicolantonio, Silvia Marsoni, Salvatore Siena, Alberto Bardelli. Reshaping the immune microenvironment after temozolomide priming in metastatic colorectal cancer patients in ARETHUSA clinical trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A001.

Subcategorization of suspicious non-mass-like enhancement lesions(BI-RADS-MRI Category4)

BackgroundThis study aims to providing a reliable method that has good compliance and is easy to master to improve the accuracy of NMLE diagnosis.MethodsThis study retrospectively analyzed 122 cases of breast non-mass-like enhancement (NMLE) lesions confirmed by postoperative histology. MRI features and clinical features of benign and malignant non-mass enhancement breast lesions were compared by using independent sample t test, χ2test and Fisher exact test. P < 0.05 was considered statistically significant. Statistically significant parameters were then included in logistic regression analysis to build a multiparameter differential diagnosis modelto subdivide the BI-RADS Category 4.ResultsThe distribution (odds ratio (OR) = 8.70), internal enhancement pattern (OR = 6.29), ADC value (OR = 5.56), and vascular sign (OR = 2.84) of the lesions were closely related to the benignity and malignancy of the lesions. These signs were used to build the MRI multiparameter model for differentiating benign and malignant non-mass enhancement breast lesions. ROC analysis revealed that its optimal diagnostic cut-off value was 5. The diagnostic specificity and sensitivity were 87.01% and 82.22%, respectively. Lesions with 1–6 points were considered BI-RADS category 4 lesions, and the positive predictive values of subtypes 4a, 4b, and 4c lesions were15.79%, 31.25%, and 77.78%, respectively.ConclusionsComprehensively analyzing the features of MRI of non-mass enhancement breast lesions and building the multiparameter differential diagnosis model could improve the differential diagnostic performance of benign and malignant lesions.