Browse Articles

NuFold: end-to-end approach for RNA tertiary structure prediction with flexible nucleobase center representation

Identification of a cryptic unbalanced translocation Der(22)t(12;22)(q24.33;q13.33) in a large Chinese family with Phelan-McDermid syndrome by nanopore sequencing

Quantum machine learning with Adaptive Boson Sampling via post-selection

BMI gain and dietary characteristics are risk factors of MASLD in non-obese individuals

Abstract This longitudinal observational study aimed to evaluate whether cardiometabolic factors and dietary characteristics are determinants of metabolic dysfunction-associated steatotic liver disease (MASLD) in non-obese individuals (body mass index [BMI] < 25 kg/m²). The study was conducted at the Japanese Red Cross Society Kyoto Daiichi Hospital. Clinical data were longitudinally recorded at annual health checks. The diagnosis of MASLD was based on the results of abdominal ultrasonography and cardiometabolic criteria. Lifestyle behaviors and dietary characteristics were assessed using a self-administered questionnaire. A total of 4,100 non-obese middle-aged and older participants (1,636 men and 2,464 women) were followed up for an average of 6.44 ± 4.16 years. During the follow-up period, there were 410 new cases of MASLD in men (25.1%) and 484 in women (19.6%). The incidence rate was higher for men (39.7 per 1,000 person-years) than for women (30.1 per 1,000 person-years). Multivariable-adjusted logistic regression analyses using the rate of change per year with standardized values found that BMI gain was strongly associated with the onset of MASLD for both men (OR: 1.90, 95% CI: 1.64–2.19) and women (OR: 1.95, 95% CI: 1.72–2.21). Increased waist circumference and triglycerides were also associated with MASLD onset for both men and women. Lowering of high-density lipoprotein cholesterol was identified as a risk factor for MASLD in both men and women. Regarding dietary characteristics, the onset of MASLD was significantly and negatively associated with “often eating vegetables” for men (OR: 0.73, 95% CI: 0.57–0.93) and “often eating soy products” for women (OR: 0.71, 95% CI: 0.58–0.88), even after adjusting for BMI change and other covariates. These findings suggest that maintaining body weight and favorable dietary characteristics are key factors in the prevention of MASLD in non-obese individuals.

Lactobacillus reuteri ZJ617 attenuates metabolic syndrome via microbiota-derived spermidine

Peptide nucleic acid-immobilised paper combined with multiplex recombinase polymerase amplification for the ultrasensitive and rapid detection of rifampicin-resistant tuberculosis

Anomalous entropy-driven kinetics of dislocation nucleation

Abstract The kinetics of dislocation reactions, such as dislocation multiplication, controls the plastic deformation in crystals beyond their elastic limit, therefore critical mechanisms in a number of applications in materials science. We present a series of large-scale molecular dynamics simulations that shows that one such type of reactions, the nucleation of dislocation at free surfaces, exhibit unconventional kinetics, including unexpectedly large nucleation rates under compression, very strong entropic stabilization under tension, as well as strong non-Arrhenius behavior. These unusual kinetics are quantitatively rationalized using a variational transition state theory approach coupled with an efficient numerical scheme for the estimation of vibrational entropy changes. These results highlight the need for a variational treatment of the kinetics to quantitatively capture dislocation reaction kinetics, especially at low-to-moderate strains where large deformations are required to activate reactions. These observations suggest possible explanations to previously observed unconventional deformation kinetics in both molecular dynamics simulations and experiments.

Impact of 17-alpha ethinyl estradiol (EE2) and diethyl phthalate (DEP) exposure on microRNAs expression and their target genes in differentiated SH-SY5Y cells

Abstract Environmental endocrine disruptor chemicals (EDCs) have raised significant concerns due to their potential adverse effects on human health, particularly on the central nervous system (CNS). This study provides a comparative analysis of the effects of 17-alpha ethinyl estradiol (EE2) and diethyl phthalate (DEP) on neuronal cell proliferation and neurotoxicity. Using differentiated SH-SY5Y human neuronal cells, we evaluated cell viability, microRNA (miRNA) regulation, and RNA expression following exposure to subtoxic concentrations of EE2 and DEP. Our results show that both EDCs downregulated specific miRNAs—miR-18b-5p, miR-200a-3p, and miR-653-5p—affecting key processes such as cell proliferation, survival, and apoptosis. Gene expression analysis revealed the upregulation of EGFR, IGF1R, BTG2, and SH3BP4, implicating these miRNAs in the regulation of the Ras and PI3K/Akt/mTOR pathways. Our findings highlight distinct cellular responses: DEP disrupts PTEN activity, while EE2 enhances phosphorylation within the PI3K/Akt/mTOR pathway, promoting pro-survival and anti-apoptotic signals. This study emphasizes the urgent need for regulatory measures to mitigate the neurotoxic effects of EDCs and offers valuable insights into their molecular impacts on brain health.

Noise amplification and ill-convergence of Richardson-Lucy deconvolution

Abstract Richardson-Lucy (RL) deconvolution optimizes the likelihood of the object estimate for an incoherent imaging system. It can offer an increase in contrast, but converges poorly, and shows enhancement of noise as the iteration progresses. We have discovered the underlying reason for this problematic convergence behaviour using a Cramér Rao Lower Bound (CRLB) analysis. An analytical expression for the CRLB diverges for spatial frequency components that approach the diffraction limit from below. The resulting mean noise variance per pixel diverges for large images. These results imply that a regular optimum of the likelihood does not exist, and that RL deconvolution is necessarily ill-convergent.

Relationship Between Body Mass Index and Low Skeletal Muscle Mass in Adults Based on NHANES 2011–2018

Correction for Gadea et al., The smallest electrochemical bubbles

CD133+PD-L1+ cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanoma

Retraction Note: Confidence level based complex polytopic fuzzy Einstein aggregation operators and their application to decision-making process

Taming large-scale genomic analyses via sparsified genomics

Abstract Searching for similar genomic sequences is an essential and fundamental step in biomedical research. State-of-the-art computational methods performing such comparisons fail to cope with the exponential growth of genomic sequencing data. We introduce the concept of sparsified genomics where we systematically exclude a large number of bases from genomic sequences and enable faster and memory-efficient processing of the sparsified, shorter genomic sequences, while providing comparable accuracy to processing non-sparsified sequences. Sparsified genomics provides benefits to many genomic analyses and has broad applicability. Sparsifying genomic sequences accelerates the state-of-the-art read mapper (minimap2) by 2.57-5.38x, 1.13-2.78x, and 3.52-6.28x using real Illumina, HiFi, and ONT reads, respectively, while providing comparable memory footprint, 2x smaller index size, and more correctly detected variations compared to minimap2. Sparsifying genomic sequences makes containment search through very large genomes and large databases 72.7-75.88x (1.62-1.9x when indexing is preprocessed) faster and 723.3x more storage-efficient than searching through non-sparsified genomic sequences (with CMash and KMC3). Sparsifying genomic sequences enables robust microbiome discovery by providing 54.15-61.88x (1.58-1.71x when indexing is preprocessed) faster and 720x more storage-efficient taxonomic profiling of metagenomic samples over the state-of-the-art tool (Metalign).

DKN-01 in Combination With Tislelizumab and Chemotherapy as First-Line Therapy in Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: DisTinGuish

PURPOSE The outcomes of anti–PD-1 agents plus fluoropyrimidine/platinum in frontline advanced gastroesophageal adenocarcinomas (aGEAs) remain poor. We investigated the safety, tolerability, and activity of fluoropyrimidine/oxaliplatin and tislelizumab with the DKK1-neutralizing antibody DKN-01 in aGEAs in a phase IIa open-label study. PATIENTS AND METHODS Patients had untreated human epidermal growth factor receptor 2–negative aGEAs, RECIST v1.1 measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and adequate organ function. Patients received intravenous DKN-01 300 mg once every 2 weeks, tislelizumab 200 mg once every 3 weeks, oxaliplatin 130 mg/m 2 once every 3 weeks, and capecitabine 1,000 mg/m 2 twice daily on days 1-15 of each 21-day cycle. The primary end point was safety and tolerability. Key secondary end points included objective response rate (ORR) by RECISTv1.1, progression-free survival (PFS), and overall survival (OS). RESULTS Between September 18, 2020, and April 8, 2021, 25 patients were enrolled. All patients who received at least one dose of DKN-01 were included in the safety analysis. Most patients had gastroesophageal junction tumors, median age was 61 years, 76% were male, and 55% were ECOG of 0. All patients reported at least one treatment-emergent adverse event. The ORR was 73% (95% CI, 49.8 to 89.3), with a disease control rate of 95%. The ORR was 90% (95% CI, 55.5 to 99.7) in the DKK1-high tumor patients and 67% (95% CI, 29.9 to 92.5) in the DKK1-low tumor patients. The median PFS was 11.3 months (95% CI, 5.8 to 12.0) and the 12-month PFS rate was 33%. The median OS was 19.5 months (95% CI, 15.2 to 24.4) with a 12-month OS rate of 76% and an 18-month OS rate of 55%. CONCLUSION DKN-01 can be safely combined with frontline fluoropyrimidine/oxaliplatin and tislelizumab and demonstrates encouraging activity independent of PD-L1 expression levels. A randomized phase II trial is ongoing (ClinicalTrials.gov identifier: NCT04363801 ).

Phase Ib Study for the Combination of Doxorubicin, Dacarbazine, and Nivolumab as the Upfront Treatment in Patients With Advanced Leiomyosarcoma: A Study by the Spanish Sarcoma Group (GEIS)

PURPOSE Doxorubicin, alongside a select group of cytotoxic agents, is capable of inducing an adaptive immune response via a well-established peculiar type of tumor cell death called immunogenic cell death (ICD). We hypothesize that combining doxorubicin and dacarbazine with nivolumab may enhance therapeutic efficacy by exerting synergy in the ICD circuit. We hereby present a phase Ib trial with this combination. PATIENTS AND METHODS Patients with advanced leiomyosarcoma and anthracycline-naïve were eligible. The initial dose level consisted of doxorubicin 75 mg/m 2 once on day 1, once every three weeks, followed by dacarbazine 400 mg/m 2 once on days 1 and 2, once every three weeks, plus nivolumab 360 mg once on day 2, once every 3 weeks, for six courses and then 1 year of nivolumab. A (–1) dose level was the same regimen but with nivolumab 240 mg. A classic 3 + 3 phase-I design was used to determine the recommended phase-II dose (RP2D). Secondary end points included overall response rate, safety profile, survival, and translational research. RESULTS From January 2002 to July 2023, 24 patients were enrolled and 23 were evaluable for efficacy, excluding one patient because of noncompliant dose. All patients were treated with the initial dose level, then the RP2D. Toxicity was mild, with the most frequent being grade 4 toxicity neutropenia (16.7%) and thrombocytopenia (8.3%), while no grade 5 toxicity occurred. The centrally reviewed objective response rate was as follows: partial response 56.5%, stable disease 39.1%, and progression 4.4%. The 6-month progression-free survival (PFS) rate was 80% (95% CI, 63 to 98). Dynamic increases of HMGB1 in blood significantly correlated with longer PFS. CONCLUSION This scheme of doxorubicin, dacarbazine, and nivolumab is feasible and well tolerated. Clinical activity is encouraging and the prognostic impact of HMGB1 supports the relevance of ICD activation. Further clinical research is already underway with this concept in leiomyosarcoma.

Can We Find a Place for Trophoblast Cell Surface Antigen 2–Targeted Antibody-Drug Conjugates in Lung Cancer?

Pembrolizumab or Placebo Plus Adjuvant Chemotherapy With or Without Radiotherapy for Newly Diagnosed, High-Risk Endometrial Cancer: Results in Mismatch Repair-Deficient Tumors

Mismatch repair-deficient (dMMR) endometrial cancer (EC) is an inflamed phenotype with poor outcomes when meeting high-risk criteria and limited treatment options in the adjuvant setting. We report protocol-prespecified subgroup analysis of patients with dMMR tumors from the phase III ENGOT-en11/GOG-3053/KEYNOTE-B21 study (ClinicalTrials.gov identifier: NCT04634877 ) in newly diagnosed, high-risk EC after surgery with curative intent. Patients were randomly assigned to pembrolizumab 200 mg or placebo (six cycles) plus carboplatin-paclitaxel (four to six cycles) once every 3 weeks, then pembrolizumab 400 mg or placebo once every 6 weeks (six cycles), respectively. MMR status was a stratification factor. Patients received radiotherapy at investigator discretion. Investigator-assessed disease-free survival (DFS) was a primary end point. No formal hypothesis testing was performed for subgroup analysis. In the intention-to-treat population, 141 patients in the pembrolizumab arm and 140 in the placebo arm had dMMR tumors. At this interim analysis, hazard ratio for DFS favored pembrolizumab (0.31 [95% CI, 0.14 to 0.69]); median DFS was not reached in either group. Two-year DFS rates were 92.4% (95% CI, 84.4 to 96.4) and 80.2% (95% CI, 70.8 to 86.9), respectively. No new safety signals occurred. Longer-term follow-up of outcomes will be evaluated at final analysis. Preplanned subgroup analysis on the basis of the study's stratification factors suggests that pembrolizumab plus chemotherapy improves DFS and is clinically relevant for patients with dMMR tumors in the curative-intent setting.

Air Pollution and Breast Cancer Incidence in the Multiethnic Cohort Study

PURPOSE Recent studies suggested fine particulate matter (PM 2.5 ) exposure increases the risk of breast cancer, but evidence among racially and ethnically diverse populations remains sparse. MATERIALS AND METHODS Among 58,358 California female participants of the Multiethnic Cohort (MEC) Study followed for an average of 19.3 years (1993-2018), we used Cox proportional hazards regression to examine associations of time-varying PM with invasive breast cancer risk (n = 3,524 cases; 70% African American and Latino females), adjusting for sociodemographics and lifestyle factors. Subgroup analyses were conducted for race and ethnicity, hormone receptor status, and breast cancer risk factors. RESULTS Satellite-based PM 2.5 was associated with a statistically significant increased incidence of breast cancer (hazard ratio [HR] per 10 μg/m 3 , 1.28 [95% CI, 1.08 to 1.51]). We found no evidence of heterogeneity in associations by race and ethnicity and hormone receptor status. Family history of breast cancer showed evidence of heterogeneity in PM 2.5 -associations ( P heterogeneity = .046). In a meta-analysis of the MEC and 10 other prospective cohorts, breast cancer incidence increased in association with exposure to PM 2.5 (HR per 10 μg/m 3 increase, 1.05 [95% CI, 1.00 to 1.10]; P = .064). CONCLUSION Findings from this large multiethnic cohort with long-term air pollutant exposure and published prospective cohort studies support PM 2.5 as a risk factor for breast cancer. As about half of breast cancer cannot be explained by established breast cancer risk factors and incidence is continuing to increase, particularly in low- and middle-income countries, our results highlight that breast cancer prevention should include not only individual-level behavior-centered approaches but also population-wide policies and regulations to curb PM 2.5 exposure.

The Retrofit: Lessons From Sotorasib's Dosing Conundrum