Detection of circulating highly expanded T-cell clones in at-risk individuals for rheumatoid arthritis before the clinical onset of the disease.

OBJECTIVES: To quantitatively profile the T-cell repertoire in the peripheral blood of individuals genetically at risk for RA, namely first-degree relatives of RA patients (RA-FDR) at different phases of disease development. METHODS: Next-generation sequencing of the TCR CDR3ß repertoire was performed on genomic DNA isolated from whole blood samples of RA-FDR selected at three different pre-clinical stages and of matched RA patients (n = 20/group). T-cell clones were identified by their unique sequence and their degree of expansion (frequency) within each sample was characterized. Clones with a frequency over 0.5% were considered highly expanded clones (HEC). RESULTS: The absolute number of HEC was significantly higher in established RA patients (mean 4.65) and tended to be higher in symptomatic RA-FDR (mean 3.4) compared with asymptomatic RA-FDR (mean 1.55, P =0.003 and P =0.07, respectively). Asymptomatic individuals with high levels of ACPA did not differ from asymptomatic RA-FDR in terms of absolute number and frequency of clones. The number of HEC tended to be slightly higher at the time of RA onset (P =0.055). Neither clones shared by several patients, nor clones previously associated with RA, were preferentially present within or between the different groups. Finally, a longitudinal analysis did not allow to uncover a kinetic expansion of RA-specific clones closely correlated with disease development. CONCLUSIONS: HEC were detected in the peripheral blood before the clinical onset of RA, in particular in the later pre-clinical phase of RA development, and their presence increased over time.

Genetic alterations and clinical dimensions of oral cancer: a review.

Oral cancer ranks sixth most prevalent type of cancer worldwide due to its alarming increase every year. Progression of oral cancer depends on various heterogeneity pathways, but their exact mechanism remains unclear. Genetic aberrations on oral cancer cells set back the effectiveness of existing therapies and make it more challenging by triggering drug resistance. To understand the intricate details of oral cancer pathogenesis and for advancing current therapies, genetic modifications are the most promising approach. In this review, we tabulated the information on genetic alterations, microbial associations, aberrant signalling pathways and their clinicopathological characters on the pathogenesis of oral cancer. We primarily discussed the pitfalls of the current treatment regimen and its associated drug resistance pattern, which will provide a clear insight into developing new drugs. We also highlighted the genetic-molecular targets with their current clinical status on drug development and its outcome.

Differential expression of innate immune response genes in clinical phases of chronic hepatitis B infection.

We investigated innate immune gene expression in clinical phases of chronic hepatitis B infection, including immune tolerant (IT), immune active (IA), inactive carrier (IC) and hepatitis B e antigen (HBeAg)-negative phases, as well as healthy controls. Expression levels of interferon types I, II and III, their receptor subunits, IRFs, TLRs and other IFN-induced genes in peripheral blood mononuclear cells were compared. Forty HBsAg-positive treatment-naïve subjects without co-infection with HIV, HCV or HDV were enrolled. To complement the viral load, the expression levels of 37 innate immune genes were measured by qPCR. The highest response of the innate immune system was observed in the IT and HBeAg-negative phases, and the IC phase had the lowest response; 31 of the 37 studied genes reached their maximum mRNA expression levels in the IT and HBeAg-negative phases, and the minimum expression levels of 23 genes were found in the IC phase. The highest mRNA expression levels of IFNs, IFN receptor subunits, IRFs and TLRs genes in all clinical phases were IFN-λ2 and 3, IFN-γR2, IRF7 and TLR7, and the lowest levels of mRNA expression were observed for IFN-α, IFN-λR1, IRF8 and TLR2. We conclude that innate immune response genes are expressed differentially among chronic HBV phases, and this difference may help to develop new precise and noninvasive methods to determine the progression of disease in chronic HBV patients.

Analyzing the Influence of Video Game and Music Engagement on Technical Skills Acquisition in Dental Students in Preclinical Phase: Protocol for a Prospective, Controlled, Longitudinal Study.

BACKGROUND: The practice of dental surgery requires a few different skills, including mental rotation of an object, precision of movement with good hand-eye coordination, and speed of technical movement. Learning these different skills begins during the preclinical phase of dental student training. Moreover, playing a musical instrument or video game seems to promote the early development of these skills. However, we found that studies specifically addressing this issue in the field of dental education are lacking. OBJECTIVE: The main aims of this study are to evaluate whether the ability to mentally represent a volume in 3D, the precision of gestures with their right and left hand, or the speed of gesture execution is better at baseline or progresses faster for players (video games or music or both). METHODS: A prospective monocentric controlled and longitudinal study will be conducted from September 2023 and will last until April 2025 in the Faculty of Dental Surgery of Nantes. Participants were students before starting their preclinical training. Different tests will be used such as Vandenberg and Kuse's mental rotation test, the modified Precision Manual Dexterity (PMD), and performing a pulpotomy on a permanent tooth. This protocol was approved by the Ethics, Deontology, and Scientific Integrity Committee of Nantes University (institutional review board approval number IORG0011023). RESULTS: A total of 86 second-year dental surgery students were enrolled to participate in the study in September 2023. They will take part in 4 iterations of the study, the last of which will take place in April 2025. CONCLUSIONS: Playing video games or a musical instrument or both could be a potential tool for initiating or facilitating the learning of certain technical skills in dental surgery. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55738.

Proposed clinical phases for the improvement of personalized treatment of checkpoint inhibitor-related pneumonitis.

Background: Checkpoint inhibitor-related pneumonitis (CIP) is a lethal immune-related adverse event. However, the development process of CIP, which may provide insight into more effective management, has not been extensively examined. Methods: We conducted a multicenter retrospective analysis of 56 patients who developed CIP. Clinical characteristics, radiological features, histologic features, and laboratory tests were analyzed. After a comprehensive analysis, we proposed acute, subacute, and chronic phases of CIP and summarized each phase's characteristics. Results: There were 51 patients in the acute phase, 22 in the subacute phase, and 11 in the chronic phase. The median interval time from the beginning of CIP to the different phases was calculated (acute phase: ≤4.9 weeks; subacute phase: 4.9~13.1 weeks; and chronic phase: ≥13.1 weeks). The symptoms relieved from the acute phase to the chronic phase, and the CIP grade and Performance Status score decreased (P<0.05). The main change in radiologic features was the absorption of the lesions, and 3 (3/11) patients in the chronic phase had persistent traction bronchiectasis. For histologic features, most patients had acute fibrinous pneumonitis in the acute phase (5/8), and most had organizing pneumonia in the subacute phase (5/6). Other histologic changes advanced over time, with the lesions entering a state of fibrosis. Moreover, the levels of interleukin-6, interleukin-10 and high-sensitivity C-reactive protein (hsCRP) increased in the acute phase and decreased as CIP progressed (IL-6: 17.9 vs. 9.8 vs. 5.7, P=0.018; IL-10: 4.6 vs 3.0 vs. 2.0, P=0.041; hsCRP: 88.2 vs. 19.4 vs. 14.4, P=0.005). Conclusions: The general development process of CIP can be divided into acute, subacute, and chronic phases, upon which a better management strategy might be based devised.

Current Status of HIV-1 Vaccines.

HIV-1 infection and its progression to AIDS remains a significant global health challenge, particularly for low-income countries. Developing a vaccine to prevent HIV-1 infections has proven to be immensely challenging with complex biological acquisition and infection, unforeseen clinical trial disappointments, and funding issues. This paper discusses important landmarks of progress in HIV-1 vaccine development, various vaccine strategies, and clinical trials.

Lung cancer pathogenesis and poor response to therapy were dependent on driver oncogenic mutations.

AIMS: Lung cancer was the most fatal malignancy, dominated the cancer related mortality list for years, and we tried to distinguish the lung adenocarcinoma patients at higher risk from those bearing lower therapy resistance and recurrence risk. MATERIALS: Patients information from clinical Sequencing Cohorts and from the Regional Medical Center of the Middle-West China were included. The whole-exome sequencing was analyzed for risk evaluation. KEY FINDINGS: We found that Smoking stimulated the oncogenic genes mutations, and the most frequently mutated genes of EGFR, KRAS, and TP53 (E/K/P) were identified. Different N stage affected the survival prognosis of patients bearing E/K/P mutations, but the T stage and AJCC stage did not. Radiation failed to prolong survival of phase II/III patients who didn't receive surgery. In those received surgery, radiation also failed to prolong survival of phase II/III patients. Radiation did not improve the prognosis in patients bearing E/K/P mutation burdens, whose differences were identified in gender or smoking-history classified groups. SIGNIFICANCE: Smoking status and history contributed to oncogenic mutation burdens associated therapy resistance, and the aggressive treatment, especially to radiation, may lead to worse therapy response to current and past smoking behavior.

Coronavirus disease 2019 vaccine: An overview of the progression and current use.

On December 31, 2019; unidentified pneumonia cases were reported from China. It was soon announced that these cases were of viral origin and the cause was a new coronavirus (CoV). Initially, the virus was called "novel CoV " and then defined as "severe acute respiratory syndrome CoV 2 (SARS-CoV-2)" after more detailed investigations. The disease caused by SARS-CoV-2 was named CoV disease 2019 (COVID-19) by the World Health Organization. The rapid spread of the disease in a few months has resulted in a global pandemic and it continues. However, there are no specific effective anti-viral drugs for SARS-CoV-2 infection, some antiviral drugs are using in the therapy of COVID-19 with limited success. Currently, for the prevention of the pandemic, global vaccination seems to be important. Antiviral protection of vaccines is provided by the development of antibodies that can neutralize the virus. Antibody response develops against spike protein and nucleocapsid protein but neutralizing antibodies are formed against the receptor-binding domain of the spike protein. It has also been shown that most viral proteins are recognized in T-cell responses. Vaccine discovery trials for COVID-19 have begun all over the world since the outbreak began. More than 100 vaccine studies against COVID-19 have been published in the last year. Some of them were urgently approved and used worldwide. The current study aimed to review the progression and current use of COVID-19 vaccines.

Insights of tankyrases: A novel target for drug discovery.

Tankyrases are the group of enzymes belonging to a class of Poly (ADP-ribose) polymerase (PARP) recently named ADP-ribosyltransferase (ARTD). The two isoforms of tankyrase i.e. tankyrase1 (TNKS1) and tankyrase2 (TNKS2) were abundantly expressed in various biological functions in telomere regulation, Wnt/ß-catenin signaling pathway, viral replication, endogenous hormone regulation, glucose transport, cherubism disease, erectile dysfunction, and apoptosis. The structural analysis, mechanistic information, in vitro and in vivo studies led identification and development of several classes of tankyrase inhibitors under clinical phases. In the nutshell, this review will drive future research on tankyrase as it enlighten the structural and functional features of TNKS 1 and TNKS 2, different classes of inhibitors with their structure-activity relationship studies, molecular modeling studies, as well as past, current and future perspective of the different class of tankyrase inhibitors.

Characterization of the "a" determinant region of the hepatitis B virus genome in Iranian patients at different clinical phases of chronic infection.

AIM: To determine the distribution of important mutations of the "a" determinant region in the HBV genome among patients in different clinical phases of HBV infection. BACKGROUND: Variations in Hepatitis B infection not only change the outcome of the disease but also the symptoms from which the chronic HBV patients are suffering. METHODS: We have meticulously selected a total of 40 chronic HBV patients from four different subclasses of chronic HBV clinical phases including immune tolerant (IT), immune active (IA), inactive carrier (IC) and hepatitis B e antigen (HBeAg)-negative (ENEG); 10 samples per each phase. Mutations of the "a" determinant region were identified using PCR-Direct sequencing method. RESULTS: 17 amino-acid substitutions at 12 positions inside the "a" determinant were identified in all forty samples; 3 mutations in the IT group, 6 mutations in the IA phase, 3 mutations in the IC patients and 5 mutations in the ENEG phase. Different substitutions were observed in all four clinical phases. The IA phase was the most variant group with the highest number of amino-acid substitutions. CONCLUSION: These results did not reveal a strong pattern to distinguish different clinical phases of Chronic HBV infection, but there are some obvious differences regarding the number and position of mutations between these four clinical phases.

NK cell phenotypic and functional shifts coincide with specific clinical phases in the natural history of chronic HBV infection.

BACKGROUND: Chronic HBV infection can be divided into 4 distinct clinical phases: immune tolerant, immune active, inactive carrier, and HBeAg-negative hepatitis. Using a systems biology approach, we recently identified innate immune response components, specifically NK cells as a distinctive factor of specific HBV clinical phases. To expand on this study and identify the underlying immunological mechanisms, we performed a comprehensive profiling of NK cells in chronic HBV infection. METHODS: Peripheral blood from untreated chronic HBV patients was used to analyze phenotypic markers, as well as cytokine production and cytoxicity of NK cells. RESULTS: The overall composition, phenotype, and cytolytic activity of the NK cells remained constant across all clinical phases, with the exception of a few specific markers (KIRs, NKp46). CD56bright NK cells of chronic HBV patients differed in their ability to produce IFN-γ between the clinical phases pre- and post-HBeAg seroconversion. CONCLUSION: This depicts a shift in NK cell characteristics between the immune active, under heavy viral or immune pressure, and inactive carrier phases, that coincides with HBeAg seroconversion. Although these changes in NK cells do not appear to be completely responsible for differences in liver damage characteristic of specific clinical phases, they could provide a step toward understanding immune dysregulation in chronic HBV infection.

Metabolic characterization of the natural progression of chronic hepatitis B.

BACKGROUND: Worldwide, over 350 million people are chronically infected with the hepatitis B virus (HBV) and are at increased risk of developing progressive liver diseases. The confinement of HBV replication to the liver, which also acts as the central hub for metabolic and nutritional regulation, emphasizes the interlinked nature of host metabolism and the disease. Still, the metabolic processes operational during the distinct clinical phases of a chronic HBV infection-immune tolerant, immune active, inactive carrier, and HBeAg-negative hepatitis phases-remains unexplored. METHODS: To investigate this, we conducted a targeted metabolomics approach on serum to determine the metabolic progression over the clinical phases of chronic HBV infection, using patient samples grouped based on their HBV DNA, alanine aminotransferase, and HBeAg serum levels. RESULTS: Our data illustrate the strength of metabolomics to provide insight into the metabolic dysregulation experienced during chronic HBV. The immune tolerant phase is characterized by the speculated viral hijacking of the glycerol-3-phosphate-NADH shuttle, explaining the reduced glycerophospholipid and increased plasmalogen species, indicating a strong link to HBV replication. The persisting impairment of the choline glycerophospholipids, even during the inactive carrier phase with minimal HBV activity, alludes to possible metabolic imprinting effects. The progression of chronic HBV is associated with increased concentrations of very long chain triglycerides together with citrulline and ornithine, reflective of a dysregulated urea cycle peaking in the HBV envelope antigen-negative phase. CONCLUSIONS: The work presented here will aid in future studies to (i) validate and understand the implication of these metabolic changes using a thorough systems biology approach, (ii) monitor and predict disease severity, as well as (iii) determine the therapeutic value of the glycerol-3-phosphate-NADH shuttle.

Vascular endothelial growth factor-A mRNA gene expression in clinical phases of multiple sclerosis.

BACKGROUND: Vascular endothelial growth factor A stimulates angiogenesis, but is also pro-inflammatory and plays an important role in the development of neurological disease. This study aimed to investigate whether vascular endothelial growth factor A mRNA expression could be used as a marker for the prediction of susceptibility to multiple sclerosis and relate vascular endothelial growth factor to the clinical phases of multiple sclerosis. METHODS: This was a cross-sectional study, consisting of a total of 60 subjects with multiple sclerosis and 20 healthy controls. Subjects were subjected to history taking, neurological examination and peripheral blood sampling for vascular endothelial growth factor A mRNA gene expression. Vascular endothelial growth factor A gene expression was measured by real-time polymerase chain reaction using the SYBR Green technique. RESULTS: Vascular endothelial growth factor A mRNA gene expression level was significantly lower in the multiple sclerosis group than in the healthy control group (P < 0.001). Vascular endothelial growth factor A mRNA gene expression level was higher in relapsing remitting multiple sclerosis (RRMS) patients than in those in remission (P < 0.001) and in relapsing remitting multiple sclerosis compared with secondary progressive multiple sclerosis (P < 0.001). There was no correlation between vascular endothelial growth factor A gene expression levels and duration of disease, multiple sclerosis progression index or expanded disability status scale. CONCLUSIONS: A lower vascular endothelial growth factor A mRNA gene expression level was independently associated with a higher risk of multiple sclerosis.