bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bacteria of healthy periodontal tissues as candidates of probiotics: a systematic review
Authors: del Pilar Angarita-Díaz María , Fong Cristian , Medina Daniela 
Published: June 2024

Abstract
Objectives
The use of probiotics could promote the balance of the subgingival microbiota to contribute to periodontal health. This study aimed to identify the potential of bacteria commonly associated with healthy periodontal tissues as probiotic candidates.

Material and methods
A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the PubMed, Scopus, Science Direct, ProQuest, and Ovid databases as well as the combination of Medical Subject Headings (MeSH) and non-MeSH terms. Based on the selection criteria, original studies published in English and identifying the microorganisms present in the periodontium of healthy individuals and patients with periodontitis using the high-throughput 16S ribosomal gene sequencing technique were included.

Results
Out of 659 articles, 12 met the criteria for this review. These articles were published from 2012 to 2020 and mainly originated from the United States, China, and Spain. Most of these studies reported adequate criteria for selecting participants, using standardized clinical criteria, and compliance with quality based on the tools used. In periodontal healthy tissue were identified species like Actinomyces viscosus, Actinomyces naeslundii, Haemophilus parainfluenzae, Rothia dentocariosa, Streptococcus sanguinis, Streptococcus mitis, Streptococcus oralis, Streptococcus gordonii, Streptococcus intermedius, and Prevotella nigrescens which have recognized strains with a capacity to inhibit periodontopathogens.

Conclusions
S. sanguinis, S. oralis, S. mitis, and S. gordonii are among the bacterial species proposed as potential probiotics because some strains can inhibit periodontopathogens and have been reported as safe for humans.
Associations between deep venous thrombosis and thyroid diseases: a two-sample bidirectional Mendelian randomization study
Authors: Zhang Lifeng , Li Kaibei , Yang Qifan , Lin Yao , Geng Caijuan , Huang Wei , Zeng Wei 
Published: June 2024

Abstract
Background
Some previous observational studies have linked deep venous thrombosis (DVT) to thyroid diseases; however, the findings were contradictory. This study aimed to investigate whether some common thyroid diseases can cause DVT using a two-sample Mendelian randomization (MR) approach.

Methods
This two-sample MR study used single nucleotide polymorphisms (SNPs) identified by the FinnGen genome-wide association studies (GWAS) to be highly associated with some common thyroid diseases, including autoimmune hyperthyroidism (962 cases and 172,976 controls), subacute thyroiditis (418 cases and 187,684 controls), hypothyroidism (26,342 cases and 59,827 controls), and malignant neoplasm of the thyroid gland (989 cases and 217,803 controls. These SNPs were used as instruments. Outcome datasets for the GWAS on DVT (6,767 cases and 330,392 controls) were selected from the UK Biobank data, which was obtained from the Integrative Epidemiology Unit (IEU) open GWAS project. The inverse variance weighted (IVW), MR-Egger and weighted median methods were used to estimate the causal association between DVT and thyroid diseases. The Cochran’s Q test was used to quantify the heterogeneity of the instrumental variables (IVs). MR Pleiotropy RESidual Sum and Outlier test (MR-PRESSO) was used to detect horizontal pleiotropy. When the causal relationship was significant, bidirectional MR analysis was performed to determine any reverse causal relationships between exposures and outcomes.

Results
This MR study illustrated that autoimmune hyperthyroidism slightly increased the risk of DVT according to the IVW [odds ratio (OR) = 1.0009; p = 0.024] and weighted median methods [OR = 1.001; p = 0.028]. According to Cochran’s Q test, there was no evidence of heterogeneity in IVs. Additionally, MR-PRESSO did not detect horizontal pleiotropy (p = 0.972). However, no association was observed between other thyroid diseases and DVT using the IVW, weighted median, and MR-Egger regression methods.

Conclusions
This study revealed that autoimmune hyperthyroidism may cause DVT; however, more evidence and larger sample sizes are required to draw more precise conclusions.
Investigating the association between blood oxidative stress markers and dementia in Egyptian elderly women
Authors: Ebrahim Lamyaa Kamel , Adel Sherihan , Hamza Sarah A. , Alsadany Mohamad A. , Ali Suzan Mounir 
Published: June 2024

Abstract
Background
The predicted increase in the senior population will have a substantial impact on mental health and dementia development, emphasizing the need to study the biochemical components related to the pathogenesis of dementia. Oxidative stress is caused by an imbalance between the production of reactive oxygen species and the antioxidant balance of the body. The brain is particularly vulnerable to oxidative stress because of the relatively low levels of antioxidants in the brain, high levels of polyunsaturated fatty acids, and increased oxygen needs. The increase of reactive oxygen species leads to the accumulation of protein oxidation by-products which has a key role in dementia pathogenesis. The aim of the study is to investigate the link between oxidative stress and dementia in Egyptian older women and its possible effect on dementia severity and types. A case–control study was conducted involving 40 elderly women with dementia, and another 40 cognitively intact controls. All participants were subjected to a comprehensive geriatric evaluation, which included cognitive assessment, depression screening, and functional assessment. Blood levels of malondialdehyde (an oxidative stress marker), glutathione peroxidase enzyme and total antioxidant capacity (an antioxidant markers) were measured.

Results
Malondialdehyde’s blood level was significantly higher in dementia cases (p < 0.001), indicating a higher oxidative stress status in dementia cases. While blood levels of both glutathione peroxidase enzyme and total antioxidant capacity were significantly lower in dementia cases (p < 0.001), indicating a lower antioxidant activity in dementia cases. We found that glutathione peroxidase enzyme at a cutoff point ≤ 122 mu/ml, total antioxidant capacity at a cutoff point ≤ 39.1 mm/l, and malondialdehyde at a cutoff point > 95 nmol/ml had perfect diagnostic value for identifying patients with dementia.

Conclusion
Oxidative stress showed a significant role in the pathogenesis of dementia, with the presence of higher levels of oxidative damage by-products and lower levels of antioxidant status. So, the role of oxidative stress in dementia should not be neglected, and more effort should be directed to prevent unnecessary exposure to oxidative stress in older adults to contribute towards dementia prevention.
Alpha-lipoic acid induced insulin autoimmune antibody syndrome
Authors: Baburaj Karthik , MP Jabir , MV Vimal 
Published: June 2024

Abstract
Background
Insulin autoimmune antibody syndrome is an uncommon cause of hypoglycemia in non-diabetic individuals. We report a case of alpha-lipoic acid-induced insulin autoimmune antibody syndrome.

Case report
A 40-year-old non-diabetic female presented with unresponsiveness due to severe hypoglycemia. Investigations revealed high fasting insulin levels, elevated C-peptide, and positive anti-insulin antibodies. Further history revealed recent ingestion of alpha-lipoic acid supplements. She was diagnosed with alpha-lipoic acid-induced insulin autoimmune antibody syndrome and managed with symptomatic measures and steroids.

Conclusions
This case highlights the importance of recognizing drug-induced insulin autoimmune antibody syndrome as a potential cause of hypoglycemia in non-diabetic individuals, especially in the context of recent supplement or medication use.
Distribution and mutational landscape of inherited cancer susceptibility syndromes in central nervous system tumors.
Authors: Gong Jie , Wang Chuanwei , Luo Ningning , Han Tiantian , Yin Xiangyu , Chen Dong-sheng 
Published: June 2024

2051 Background: Inherited cancer susceptibility syndromes (ICSS) caused approximately 5%–10% of malignancies. The fifth edition of the World Health Organization Classification of Tumors emphasized that central nervous system (CNS) tumors are associated with various ICSS. Our understanding of CNS tumors, both at the systemic and germline levels, has significantly improved with the increasing popularity of next-generation sequencing (NGS) testing. Recognizing individuals with ICSS in primary CNS tumors is crucial for optimizing proper genetic counseling and improving therapeutics and clinical care, and may further directly enhance patient outcomes. Methods: We retrospectively analyzed the ICSS of 4,828 patients with CNS tumors in a Chinese cohort, including age, cancer type, and sex distribution, and further investigated the somatic and germline mutations of cancer-related genes. Additionally, we examined the molecular characteristics of CNS tumors with ICSS and their clinical significance for diagnostic and therapeutic purposes. Results: Our study identified 258 (5.34%) patients with ICSS among 4,828 patients with CNS tumors with 265 germline P/LP variants, and identified 34 categories of ICSS, including 20 types of ICSS occurring in 28% (72/258) of patients not listed in the WHO CNS 5 classification. The gene with the highest germline P/LP mutation frequency was TP53 (9.69%), followed by MSH2 (9.30%), NF1(8.91%), and BRCA2 (7.75%). These ICSS-associated genes were significantly enriched in the DNA repair and genomic stability signaling pathways (67%, 178/265). The two-hit events mainly focused on NF1, MSH6, and MSH2. The genes with the top five somatic mutation frequencies were TP53 (42.25%), TERT (30.23%), CDKN2A (28.68%), CDKN2B (27.52%), and PTEN (25.58%). The top five ICSS in CNS tumors were Lynch syndrome, BRCA-related cancer predisposition syndrome, Li-Fraumeni syndrome, Fanconi anemia, and neurofibromatosis type 1. ICSS analysis reclassifies CNS tumors of “NOS” and 53.88% (139/258) of patients diagnosed with ICSS harboring potential precision oncology therapy target mutations. Conclusions: Our study is the first to include a large-scale cohort of patients with CNS tumors with ICSS and analyze the clinical and genomic features as well as their clinical significance. Results in our study of CNS tumors with ICSS are expected to improve disease entire process management, which is an important application of DNA-based NGS in ICSS evaluation and management and provides a reference direction for the future design of clinical trials.
Investigating peripheral blood biomarkers of immune checkpoint inhibitor associated fatigue.
Authors: Li Howard Liu , Charmsaz Soren , Alden Stephanie Leigh , Brancati Madelena , Warner Aanika , Munjal Kabeer , Tsai Hua-Ling , Gross Nicole E. , Thoburn Christopher , Lipson Evan J. , Ged Yasser , Garonce-Hediger Rachel , Bansal Sanjay , Tang Laura , Jaffee Elizabeth M. , Chandler G Scott , Mohindra Rajat , Ho Won Jin , Yarchoan Mark , Kao Chester 
Published: June 2024

2571 Background: Fatigue is the most common side effect of immune checkpoint inhibitor (ICI) therapy. Despite its prevalence, the mechanisms underlying ICI-associated fatigue are poorly understood. In this study, we characterized dynamic changes in peripheral immune cell populations and cytokines to identify biomarkers and mechanisms of ICI-associated fatigue. Methods: We prospectively collected clinical data and blood samples from patients with solid tumors at a single institution who received ICIs between July 2021 and November 2023. Blood samples were collected at baseline, early-on-treatment (month 1-2), and later-on-treatment (month 4-6). Patients were contacted on-treatment to query for worsening of fatigue compared to treatment baseline. We analyzed peripheral lymphocyte populations by Cytometry by Time-of-Flight (CyTOF) and peripheral levels of 39 cytokines with Luminex multiplex assay. Tumor response was characterized by RECIST v1.1. False discovery rate (FDR) was used for multi-testing adjustment. Results: 53 patients received ICI therapy and had fatigue assessment performed. Thirty-one patients (58.5%) reported worsening fatigue, and 22 (41.5%) did not. In patients with worsened fatigue, a cluster of cytotoxic effector CD8+CD28+TIGIT+ T-cells was significantly increased from baseline to early-on-treatment (Wilcoxon Signed-rank Test FDR adjusted p<.05). Early-on-treatment fold changes in Type 1 cytokines (IFN-gamma, IL-2, IL-12) were increased in patients with worsened fatigue compared to patients with no fatigue (Wilcoxon Rank-sum Test unadjusted p<.05; Table). There was no association between increase in fatigue and objective response to ICI therapy, although numerically high rates of fatigue were observed both in patients experiencing disease progression as well as complete responses. After excluding patients with tumor progression to account for tumor-related fatigue, early-on-treatment fold changes in IL-2 and IL-12 were still increased in worsened fatigued compared to non-fatigued patients (unadjusted p<.05). However, in patients with disease progression, changes in Type 1 cytokines were not associated with worsening fatigue. Conclusions: In a pan-tumor cohort treated with ICIs, increases in a cluster of cytotoxic effector CD8+ T cells in parallel with related Type 1 cytokines were associated with fatigue, implicating fatigue as a marker of immune activation in this population. [Table: see text]
Phase 1 dose escalation and cohort expansion study evaluating safety, PK, PD and clinical activity of STC-15, a METTL-3 inhibitor, in patients with advanced malignancies.
Authors: Moser Justin C , Papadopoulos Kyriakos P. , Rodon Ahnert Jordi , Ofir-Rosenfeld Yaara , Holz Josefin-Beate ,   STC15-22101 Study Team
Published: June 2024

2586 Background: RNA modifications are involved in cancer initiation and progression. The most abundant modification of mRNA is m6A generated by METTL3. Inhibition of METTL3 causes double-stranded RNA formation and activation of cellular T1 IFN response. IFN signaling induces IFN-stimulated gene families i.e. IFIT and OAS, characteristic of an anti-viral response, and secretion of cytokines and chemokines. STC-15, a first in class small molecule inhibitor of METTL3 developed by Storm Therapeutics, demonstrated in pre-clinical models, activation of IFN signaling and remodeling of the TME towards pro-inflammatory state. We report the dose escalation results from a FIH trial in patients with advanced malignancies. Methods: This is a multi-center, open-label, dose escalation study. STC-15 oral capsules are administered daily or t.i.w. in 21-d treatment cycles. Dose escalation follows 3+3 modified Fibonacci regimen. Primary objectives are safety and PK. Secondary objectives are preliminary evidence of anticancer activity and RP2D. Exploratory objectives are PD (i.e. target engagement and immune activation biomarkers) and correlation of primary pharmacology with observed clinical efficacy. Results: As of 02/01/2024, 31 patients enrolled across 4 dose levels and 5 cohorts: 60mg QD (6 pats), 60mg t.i.w. (3 pats), 100mg t.i.w. (14 pats), 160 mg t.i.w. (5 pats) and 200mg t.i.w. (3 pats). PK profile supports t.i.w. dosing. A total of 169 AEs were observed with 45 AEs attributed to STC-15 treatment. AEs were manageable, mostly hematology (thrombocytopenia 31%; 4% Grade 3), skin (pruritis, rash 14% G1/2) and GI (N/V and diarrhea 14% G1/2). 12 SAEs occurred; 1 pt (60mg QD) had DLT with G3 pneumonitis. Of 14 patients with at least 1 on-treatment scan, DCR is 78% with 2 confirmed PR ongoing in angiosarcoma (60mg, 32 weeks) and IO-refractory NSCLC (100mg, 33 weeks) and 9 SD. An average of 63% reduction in m6A on mRNA in peripheral blood within the first 24h post dosing was observed in 60mg cohorts, confirming target engagement. Whole blood Nanostring and pathway analysis of gene expression confirms upregulation of innate immune pathways (i.e. T1,2 IFN activation and anti-viral responses) as early as 8h after first dose and throughout the treatment cycle. Updated PK/PD and clinical data will be presented. Conclusions: Treatment with STC-15 is well tolerated across pharmacologically active dose range with encouraging signs of clinical activity. Early biomarker data provide proof of mechanism in target engagement, strong activation of innate immune responses and correlation of pharmacological activity with clinical response. The study is ongoing and expansion cohorts are underway to further evaluate PK/PD, safety and clinical efficacy at optimized pharmacologically active doses. Clinical trial information: NCT05584111 .
Safety and preliminary efficacy of EIK1001 in combination with atezolizumab in participants with advanced solid tumors.
Authors: Patel Manish R. , Rasco Drew W. , Johnson Melissa Lynne , Hamid Omid , Sommerhalder David , Cho Carolyn , Wang Meihua , Kurland Etah 
Published: June 2024

2618 Background: Immune checkpoint inhibitors (ICIs) relieve immunosuppression of tumor-reactive T cells and enhance antitumor immune response; however, not all patients benefit and some become refractory. EIK1001 is a Toll-like receptor (TLR)7/8 agonist that stimulates myeloid and plasmacytoid dendritic cells, activating immune and inflammatory responses. This dual activity provides another pathway, distinct from effects on checkpoint proteins, to enhance antitumor T-cell activity alone or in combination with ICIs. Methods: Study BDB001-102 was a Phase 1, open-label, dose-escalation/expansion study of EIK1001 combined with atezolizumab (comb Rx). Enrollment criteria included participants (pts) ≥ age 18 with confirmed, RECIST-measurable advanced solid tumors. Primary study objectives included safety and tolerability, and secondary objectives included evaluation of dose-limiting toxicities, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy by RECIST 1.1. During dose escalation, pts received a range of doses of EIK1001 (QW IV) in combination with atezolizumab (1200 mg Q3W). Results: Forty-one pts (median age 65 years [range = 32 to 79]) with multiple, distinct histological tumor types and a median of 3 prior Rx regimens were enrolled. Overall, a total of 28/41 (68.3%) receiving EIK1001 + atezolizumab experienced a treatment-related adverse event (TRAE). Of these, 4/41 (9.8%) experienced a ≥ Grade 3 TRAE, including fatigue, nausea, hyponatremia, and lymphedema. Only 1/41 (2.4%) experienced manageable cytokine release syndrome. There were no deaths due to TRAEs. Of the efficacy-evaluable pts (n = 37), complete response (CR) or partial response (PR) was observed for 3/37 (8.1%). Disease control (including CR, PR, or stable disease) was observed in 19/37 (51.4%). The median duration of response (DOR) was 13 months (range = 10 to 27). One responder was PD-L1 negative yet had a > 12-month DOR; another had a history of prior anti-PD-1 Rx yet experienced a 10-month DOR on comb Rx. EIK1001 PK was linear and dose-proportional, and was not affected by combination with atezolizumab. Conclusions: Overall, EIK1001 was well-tolerated with a manageable safety profile and showed encouraging preliminary efficacy across several tumor types in combination with atezolizumab. Responses were observed even in pts not anticipated to respond to atezolizumab monotherapy. Further development of EIK1001 is underway. Clinical trial information: NCT04196530 .
Impact of body mass index (BMI) on survival outcomes in patients with cancer treated with immune checkpoint inhibitors (ICPI): A systematic review and meta analysis.
Authors: Mishra Rahul , Sukaina Mahnoor , Batra Nitya , Kumar Madhan Srinivasan , Walia Kamalpreet Singh , Chahal Rutvi , Khosla Atulya Aman , Singh Rohit , Ahmed Shahid Sattar , Jatwani Karan 
Published: June 2024

2624 Background: With the increased adoption of ICPI in treating various cancers, there is active exploration of individual-level factors that could predict treatment responses. A high-body mass index (BMI) induces a chronic inflammatory state and could drive T-cell dysfunction through high leptin levels, which may confer better outcomes with ICPI usage. However, there are conflicting outcomes in different studies. We performed this systematic review and meta-analysis to evaluate survival outcomes with ICPI in patients with BMI ≥25 vs <25 Kg/m2. Methods: A comprehensive search was conducted across PubMed, Embase, Scopus, and web of science databases. The original studies evaluating response [overall survival (OS) and progression free survival (PFS)], to ICPI-based therapies among adult cancer patients, stratified by BMI groups (high, BMI ≥25Kg/m2 or low, BMI <25Kg/m2), were included. RevMan version 5.4.1 was used for statistical analysis. A random effect model with inverse variance as the statistical method was used for hazard ratio (HR) and 95% confidence interval (CI). Results: Of 1215 identified studies, 22 observational studies, comprising 5859 patients (60.3% males) met the inclusion criteria. ECOG performance score was reported as 0-1 for 40.3% patients, and ≥2 for 7.1% patients. In 12-studies only PD-1 and/or PD-L1 inhibitors were administered, but no CTLA-4 inhibitor. Most frequently reported cancers were non-small cell cancer of lung (40.9%), melanoma (36.6%), and renal cell cancer (31.8%) in advanced/metastatic stages. Higher BMI, compared to low BMI, favored significant improvement in PFS [HR 0.86; 95% CI (0.76, 0.99), P= 0.03, I2 47%], and OS [ HR 0.73; 95% CI (0.62, 0.85), P< 0.0001, I2 53%] with any ICPI-based regimens. Similar findings were noted for patients treated with PD-1/PDL1 inhibitors [Table]. Conclusions: This study contributes to the evidence that BMI of 25 kg/m2 or higher exerts a beneficial impact on PFS and OS among cancer patients treated with ICPI. The favorable impact underscores the significance of considering BMI as a potential prognostic factor in ICPI therapy. However, the precise underlying mechanisms responsible for this observation warrant further investigation to deepen our understanding and potentially optimize therapeutic strategies in this patient population. [Table: see text]