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Demographic predictors of multi-target stool DNA test completion in an underserved primary care population: A retrospective analysis.

30 Background: Colorectal cancer screening remains crucial for early detection, with multi-target stool DNA(Exact Sciences, Madison, WI, USA) serving as a non-invasive option. However, adherence to test completion may vary across different demographic groups. This study aims to assess the association between patient demographics and the completion of Cologuard testing in an underserved primary care population in order to further explore the disparities that exist. Methods: We conducted a retrospective analysis of 12071 eligible patients, aged 45-75, across Hartford Healthcare Primary Care Clinics across Connecticut, USA, between November 2022 and April 2024 for whom an order for this test was placed. Demographic data including gender, age, English proficiency, and insurance status(public/private vs no insurance) were analyzed. The outcome of interest was whether patients had results available within 120 days of placing the order. Logistic regression was used to examine the relationship between these variables and the likelihood of Cologuard test completion. Results: 11704(96.9%) of all patients were insured. Among insured patients, 6945 (59.9%) had results available, while 4759 (41.1%) did not have results at the 120 day mark. Among uninsured patients, 46 (12.5%) had results, while 321 (87.5%) did not. Insured patients were more likely to have test results available compared to uninsured patients (OR = 10.184, 95% CI: 7.460-13.901, p < 0.01). 10977(90.9%) patients were English proficient. They were more likely to have results compared to Non-English proficient patients (OR = 3.474, 95% CI: 3.038-3.972, p < 0.01). Gender was not a significant predictor of test completion (OR = 0.964, 95%CI: 0.895-1.039, p = 0.341), and older age demonstrated a small, non-significant effect (OR = 1.004, p = 0.094), with a test for non-linearity confirming a linear relationship between age and test completion (p = 0.162). Conclusions: Insured status and English proficiency are significant predictors of Cologuard test completion in this primary care cohort and are more likely complete testing. These findings underscore the need for targeted interventions to increase colorectal cancer screening adherence, particularly among this population.

Prevalence of extracolonic malignancies in patients with familial adenomatous polyposis.

103 Background: Familial adenomatous polyposis (FAP) is an autosomal-dominant inherited colorectal cancer syndrome resulting from mutations in the adenomatous polyposis coli ( APC ) gene. Patients with FAP have nearly 100% lifetime risk of colorectal cancer, typically managed with prophylactic colectomies. As patient survival has improved, the incidence of extracolonic tumors, including thyroid malignancies and desmoid tumors, has increased. However, limited research exists on the prevalence of extracolonic malignancies in FAP patients. Methods: We prospectively enrolled 219 patients with FAP in the Hereditary Gastrointestinal Cancers Cohort at the MD Anderson Cancer Center between December 2015 and July 2024. Inclusion criteria included either a clinical or molecular diagnosis of FAP. Data on demographics, cancer history (including cancers diagnosed both prior to and during the study period), BMI, tobacco use, medications, endoscopy results, thyroid ultrasound findings, and abdominal/pelvic CT results were collected. Screening for thyroid and desmoid tumors was provider-dependent, with additional screenings as deemed appropriate. Descriptive and inferential statistics were used to identify associations between demographic and clinical factors and the prevalence of extracolonic malignancies. Results: Among 219 patients, 20.5% developed desmoid tumors, 18.7% developed colorectal cancer, and 6.8% developed well-differentiated thyroid cancer (6.4% papillary thyroid cancer, 0.4% follicular thyroid cancer). Prophylactic colorectal surgery was performed in 151 patients (68.9%). Per chart review, benign thyroid disease and hypothyroidism were present in 21% and 11.4% of patients, respectively. Female sex was significantly associated with hypothyroidism (p=0.007) and thyroid cancer (p=0.009). BMI > 30 was also linked to increased thyroid cancer risk (p=0.046). Desmoid tumors were found in 20.5% of patients, most commonly in the abdominal wall. Female sex, BMI > 30, and history of colorectal surgery were significantly associated with desmoid tumor development (p=0.004, 0.0064, 0.0038). Conclusions: FAP patients exhibit a higher prevalence of benign thyroid disease, thyroid cancer, and desmoid tumors compared to the general population. Given these findings, adherence to existing surveillance guidelines, such as those outlined by the National Comprehensive Cancer Network (NCCN), is essential. Our findings further support the importance of these established surveillance strategies in the management of FAP patients.

Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen

Abstract T cell receptor-engineered T cells (TCR-T) could be advantageous in glioblastoma by allowing safe and ubiquitous targeting of the glioblastoma-derived peptidome. Protein tyrosine phosphatase receptor type Z1 (PTPRZ1), is a clinically targetable glioblastoma antigen associated with glioblastoma cell stemness. Here, we identify a therapeutic HLA-A*02-restricted PTPRZ1-reactive TCR retrieved from a vaccinated glioblastoma patient. Single-cell sequencing of primary brain tumors shows PTPRZ1 overexpression in malignant cells, especially in glioblastoma stem cells (GSCs) and astrocyte-like cells. The validated vaccine-induced TCR recognizes the endogenously processed antigen without off-target cross-reactivity. PTPRZ1-specific TCR-T (PTPRZ1-TCR-T) kill target cells antigen-specifically, and in murine experimental brain tumors, their combined intravenous and intracerebroventricular administration is efficacious. PTPRZ1-TCR-T maintain stem cell memory phenotype in vitro and in vivo and lyse all examined HLA-A*02 + primary glioblastoma cell lines with a preference for GSCs and astrocyte-like cells. In summary, we demonstrate the proof of principle to employ TCR-T to treat glioblastoma.

Experimental and Theoretical Force Constants as Meaningful Indicator for Interatomic Bonding Characteristics and the Specific Case of Elemental Antimony

AbstractStable Sb exhibits a rhombohedral structure, often referred to as distorted primitive cubic, with each Sb atom having three short and three longer first neighbor bonds. However, this crystal structure can also be interpreted as being layered, putting emphasis on only three short first neighbor bonds. Therefore, temperature‐dependent extended X‐ray absorption fine structure (EXAFS) spectroscopy is carried out at the Sb K‐edge in order to obtain more detailed information on local structural and vibrational properties. Evaluation of the temperature‐dependent bond lengths provides the temperature‐dependent Peierls distortion while the temperature dependence of the variance of the interatomic distance distribution yields the EXAFS force constants. Ab initio density functional theory (DFT) calculations are used for determining projected force constants. Both EXAFS and DFT force constants are compared to those of other materials with different bonding characteristics, including two‐center covalently bonded semiconductors, multicenter bonded IV–VI and V2VI3 compounds, and metallic Cu. Clearly, Sb exhibits characteristics of both localized covalent bonding and delocalized multicenter bonding. This suggests a continuous transition between these two bonding scenarios and adds to the understanding of bonding in elemental Sb in particular and in IV–VI and V2VI3 materials in general.

Influence of MRP4 levels on clinical outcomes in biliary tract cancer.

624 Background: Biliary tract cancer (BTC) are rare tumors with a poor prognosis.Multidrug resistance protein 4 (MRP4) is a transmembrane efflux transporter that influences on cellular growth and differentiation. Recent studies have linked high MRP4 levels to increased aggressiveness in pancreatic cancer and other tumor types. This study aimed to evaluate the role of MRP4 in BTC and its association with clinical outcomes in a real-world cohort from endemic areas in Argentina. Methods: We conducted a retrospective analysis of clinical outcomes and MRP4 expression in paraffin-embedded tissue samples from 78 patients with BTC. Immunohistochemistry staining was performed, and MRP4 expression was scored based on staining intensity and the percentage of positive cells. A score exceeding 100 was classified as high MRP4 levels. Statistical analyses included Chi-square, Kaplan-Meier survival curves, and log-rank tests, with significance set as p <0.05 (two-tailed). Results: High MRP4 levels were observed in 46 out of the 78 samples (59%). Patients with gallbladder cancer (n=64) and elevated MRP4 levels had significantly poorer overall survival (OS) compared to those with low MRP4 levels (median 11.3 and 14.5 months, high and low, p =0.038). In the broader BTC cohort evaluable for survival (n=73; 64 gallbladder, 7 cholangiocarcinoma, 1 ampulla of Vater, and 1 biliary undefined) patients with elevated MRP4 levels had non-significant shorter OS (median 12.4 and 13.5 months, high and low, p =0.17). Poorly differentiated tumors were more likely to express high MRP4 levels ( p =0.06). High MRP4 expression was found in 59% of localized stages (0-II) and in 57% of advanced stages (III, IV and relapsed). Conclusions: High MRP4 expression is common in BTC, particularly gallbladder cancer, and could be a marker of poor prognosis. MRP4 levels appear more elevated in poorly differentiated tumors, and are similar in both, early and advanced stages, suggesting its involvement in early tumor progression. Further prospective studies are needed to confirm MRP4 as a biomarker. If MRP4 is a driver gene, targeting with inhibitors could represent a promising therapeutic strategy for these challenging tumors.

Impact of long-term chemotherapy (CTx) on outcomes in pancreatic ductal adenocarcinoma (PDAC): A real-world UK multi-centre study.

687 Background: PDAC is associated with poor outcomes with limited treatment options. Here, we present a multi-institutional review evaluating outcomes following short and long-term CTx with or without treatment breaks in PDAC patients (pts). Methods: All consecutive PDAC pts receiving > 3 CTx cycles between 2019 – 2023 at University College London Hospitals and Oxford University Hospitals were included. Treatment response, survival outcomes and predictors of clinical benefit were evaluated. Wilcoxon test, Kaplan-Meier and multivariate Cox regression models were performed. Results: Of the 213 screened pts, 127 eligible subjects met the study criteria. 1 st , 2 nd and 3 rd line CTx were received by 127, 40 and 2 pts, respectively. 21 pts had resectable disease (9 remained relapse-free after adjuvant CTx and 8 pts alive at post 2 years follow-up surveillance). 106 pts had unresectable or metastatic disease and were selected for final analyses (12% borderline resectable (BR), 19% locally advanced (LA), 9% localised disease who developed metastases and 60% de novo metastatic pts). 7 pts (7%) pts underwent genetic profiling on pt request or previous clinical trial screening; KRAS aberrations (N = 4), actionable PLAB2 / BRCA2 mutations (N = 2). BR and LA pts (N = 33) achieved a median PFS1 (Progression Free Survival while on 1 st line CTx) of 8.28 (95% Confidence Interval (CI), 5.49 – 15.11) and Overall Survival (OS) of 15.15 (95% CI, 9.46 – 26.41) months (mos). De novo metastatic pts (N = 64) attained a PFS1 of 6.64 (95% CI, 5.98 – 8.18) and OS of 9.30 (95% CI, 8.05 – 12.81) mos. Patient-specific factors in both cohorts comprising of age, gender, performance status, smoking history, co-morbidities were not associated with PFS1 and OS. Improved PFS was associated with ≥ 6 cycles of 1 st line CTx (P = < 0.001), median duration of 1 st CTx of ≥ 3.58 mos (P = < 0.001) and best response to 1 st CTx (P = 0.007). A favourable OS was associated with > 1 line of CTx (P = < 0.001), ≥ 6 cycles of 1 st line CTx (P = 0.009), median duration of 1 st CTx of ≥ 3.58 mos (P = < 0.001) and best response to 1 st CTx (P = 0.002). Subjects receiving ≥ 6 cycles of 1 st CTx were younger than pts tolerating fewer cycles (median age 62.41 vs 72.25 years) (P = 0.04). In the localised disease group, improved PFS was associated with ≥ 6 cycles of 1 st line CTx (P = 0.003), median duration of 1 st CTx of ≥ 2.99 mos (P = 0.008) and local treatment after commencing 1 st line CTx (P = < 0.001). These three factors were also associated with OS; P = 0.02, P = 0.02 and P = < 0.001, respectively. Median number and duration of 1 st line CTx interruptions were not associated with PFS1 or OS in both cohorts. Conclusions: Despite challenges associated with long-term CTx, survival outcomes may be better in pts receiving CTx for longer periods and multiple treatment lines. Genetic profiling currently offers limited value but in carefully selected pts, localised treatment options may be associated with improved survival outcomes.

Zimberelimab platform study: Safety and efficacy of zimberelimab in combination with futibatinib and chemotherapy in patients with first-line advanced or metastatic esophageal carcinoma.

409 Background: Zimberelimab: AB122 (Zim) platform study is a Phase 1 a/b study with multiple cohorts designed to evaluate the safety and efficacy of Zim, an anti-PD-1 antibody. Futibatinib (Futi) is an FGFR inhibitor that covalently binds FGFR1–4; FGFR inhibitors have been reported to modulate the tumor immune microenvironment, including reducing MDSCs and inhibiting CAFs. These immunomodulatory effects are expected to enhance the efficacy of the anti-PD-1 antibodies. The safety and efficacy of the combination of Zim, Futi, and chemotherapy were evaluated in patients (pts) with first-line advanced or metastatic esophageal cancer (EC) in Japan. Methods: Key eligibility criteria included age ≥ 18 years, histologically confirmed advanced or metastatic EC with measurable lesions by RECIST v1.1 regardless of FGFR and PD-L1 status, previously untreated, adenocarcinoma or squamous cell carcinoma, and ECOG PS 0 or 1. Patients received Zim 360 mg on day 1, Futi 20 mg QD, fluorouracil 800 mg/m2 on days 1–5, and cisplatin 80 mg/m2 on day-1 of a three-week cycle. The primary endpoint was dose-limiting toxicity (DLT). The secondary endpoints included adverse events, antitumor activity, pharmacokinetics, pharmacodynamics, and pharmacogenomics. Results: As of May 10, 2024, 43 pts were enrolled. At the data cutoff date for this analysis (July 15, 2024), treatment was ongoing in 23 pts. Safety and efficacy were evaluated in 43 and 41 pts, respectively. The median age of the pts was 61 years (53–70). An ECOG PS score of 0 was observed in 31 pts. DLTs were evaluated in the first three pts, and none were reported. Common treatment-emergent adverse events (TEAEs)were hyperphosphatemia (81.4%), diarrhea (67.4%), nausea (62.8%), decreased appetite (62.8%), constipation (55.8%), anemia (53.5%), stomatitis (51.2%), neutrophil count decreased (37.2%), alanine aminotransferase increased (34.9%), and palmar-plantar erythrodysaesthesia syndrome (30.2%). Grade ≥ 3 TEAEs occurred in 31 pts (72.1%), and common events (≥ 30%) were anaemia (30.2%) and neutrophil count decreased (30.2%). The objective response rate was 70.7% (95% CI: 54.5–83.9), and the confirmed overall response rate was 58.5% (95% CI: 42.1–73.7). The disease control rate was 92.7% (95% CI: 80.1–98.5). Median duration of response was 5.6 months (95% CI: 4.1–5.6), and median progression-free survival was 4.9 months (95% CI: 3.4–6.7). Conclusions: The combination of Zim, Futi, and chemotherapy has a manageable safety profile without new safety signals and shows promising antitumor activity in pts with advanced or metastatic EC. As more than half of the enrolled pts are still undergoing treatment, these are preliminary data; follow-up is needed to evaluate the viability of this combination appropriately. Clinical trial information: NCT04999761 .

Nutrient status alters developmental fates via a switch in mitochondrial homeodynamics

Permanent Electride Magnets Induced by Quasi‐Atomic Non‐Nucleus‐Bound Electrons

AbstractInterstitial quasi‐atomic electrons (IQEs) in the quantized energy levels of positively charged cavities possess a substantial own magnetic moment and control the magnetism of crystalline electrides depending on the interaction with surrounding cations. However, weak spin‐orbit coupling and gentle exchange interaction restricted by the IQEs preclude a large magnetic anisotropic, remaining a challenge for a hard magnetism. It is reported that 2D [Re2C]2+·2e− electrides (Re = Er, Ho, Dy, and Tb) show the permanent magnetism in a ferrimagnetic ground state, mimicking the ferrites composed of magnetic sublattices with different spin polarizations. Magnetic interaction between Re‐spin lattice and IQE‐spin lattice in the [Re2C]2+·2e− electrides results in a large magnetocrystalline anisotropy and high coercivity, giving a maximum energy product of 15 MGOe. It is demonstrated that the spontaneous breaking of magnetic IQE‐sublattice through substitution with paramagnetic elements produces a crossover into an antiferromagnetic spin ordering of Re‐sublattice, implying that the magnetic sublattice of IQEs drives the permanent magnetism.

A phase IIa clinical trial of first-line cyclical therapy alternating gemcitabine, cisplatin, and durvalumab with pemigatinib for advanced biliary tract cancers with <i>FGFR2</i> -alterations.

TPS645 Background: Unresectable biliary tract cancer (BTC) has a poor prognosis. Frontline chemo-immunotherapy (C-IO) for advanced BTC leads to ~25% overall survival (OS) at 24-month, but 93-99% of patients reported adverse events (AEs), and 13-19% of patients stopped treatment drugs due to AEs. FGFR kinase inhibitors (FGFRi) are second-line therapy for 10% of BTC with FGFR2 fusions. However, clinical trials of upfront FGFRi have not accrued well. Cumulative toxicities frequently interrupt treatment and limit feasibility of concurrent C-IO + FGFRi. Over time, side effects from each of therapies have a negative impact on patients’ quality of life (QoL). We previously treated two FGFR2 -altered BTC patients with cyclical chemotherapy (CT) and FGFRi and observed prolonged survival with better QoL. By monitoring serial circulating tumor DNA (ctDNA), we observed development of FGFRi-resistant subclones while on FGFRi and their subsequent clearance after resuming CT. Thus, we have developed a clinical trial to validate our hypothesis that upfront cyclical therapy alternating between C-IO and FGFRi can improve therapeutic efficacy and QoL. Alternating therapy is hypothesized to avoid accumulating toxicities and treat emerging resistance subclones. Methods: In this single-center, single-arm, Phase IIa trial, all treatment-naive patients with FGFR2 -altered advanced BTCs, PS ≤ 1, are eligible. Patients will receive cyclical therapy alternating between two therapy-blocks, starting from C-IO block (2 cycles of gemcitabine, cisplatin and durvalumab, 28-day/cycle), then FGFRi block (3 cycles of pemigatinib on day 1-14 of 21-day/cycle). Block-switch continues until progressive disease (PD), and then we will continue alternated block until the next PD. A sample size of 30 is calculated based on an expected 12-month OS rate of ≥ 55%. The trial is anticipated to enroll the first patient in early 2025. Results: The primary objective is 12-month OS rate. Secondary objectives are overall response rate, progression-free survival, AEs. We will stratify patients to PD-L1 CPS &lt;1 or ≥ 1 to assess if cyclical therapy can enhance IO. Exploratory objectives are (1) assessing dynamics of FGFR2 -ctDNA variants throughout therapy correlating with clinical outcomes, using a custom liquid biopsy (FGFR-Dx) developed at the Ohio State University; (2) assessing QoL scores with EORTC-QLQ-C30 and -BIL21 questionnaires, correlating with clinical outcomes. Results will be compared to historical controls from TOPAZ-1 trial. Conclusions: Cyclical therapy will be one of the first to combine alternating C-IO and targeted therapy in cancer. This strategy can be validated in other tumors if it is proven effective in our trial. Cyclical therapy holds great promise to introduce FGFRi earlier into treatment for BTC and improve both efficacy and QoL.

Adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommendations and overall mortality among adults with colorectal cancer in a multiethnic cohort study.

29 Background: High adherence to AICR recommendations on diet, adiposity, and physical activity is associated with improved survival among adults with colorectal cancer (CRC). However, over 80% of participants in existing studies self-reported as non-Hispanic White (NHW). We studied the association between adherence to AICR recommendations and overall mortality among adults with CRC in a multiethnic cohort. Methods: This prospective analysis used data from the Multiethnic Cohort (MEC) study. The MEC is a racially/ ethnically diverse cohort of over 200,000 participants residing in Hawaii and Los Angeles. Lifestyle behaviors in the MEC were assessed by questionnaire at enrolment/Q1 (1993-1996) and periodically over follow-up. We included those with incident CRC before completing Q3 (2003-2008). Follow-up was from Q3 survey completion to December 2019. The main exposure was the standardized AICR score [0-7 points] at Q3. The primary outcome was overall mortality; CRC-specific mortality was secondary. We used multivariable Cox proportional hazards regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CIs). Results: There were 1127 adults diagnosed with CRC prior to Q3. Of these, 1079 (95.7%) had non-missing data on the AICR score and comprised our study population. Median (IQR) age at diagnosis was 69 (62-75); median (IQR) follow-up was 12.2 (0.1-16.4) years. There were 489 (45.3%) women. By self-reported race/ethnicity, there were: 153 (14.2%) Black/African Americans, 453 (42.0%) Japanese Americans, 79 (7.3%) Latinos, 165 (15.3%) Native Hawaiians, and 229 (21.2%) NHWs. Only 48 (4.4%) adults had high adherence (AICR≥5 points). Those in the highest category of AICR scores (AICR≥4.5) had statistically significant lower risk of overall mortality relative to those in the lowest category (AICR≤2.5) (HR: 0.64, 95% CI, 0.47-0.89). A similar (but non-statistically significant) association was observed with CRC-specific mortality [HR (high vs low): 0.70, 95% CI, 0.31-1.60]. Those who increased their score between Q1&amp;Q3 had lower overall mortality (HR: 0.87, 95% CI,0.79 - 0.96). Similar trends were observed in stratified analysis by race/ethnicity; however, statistical power was limited. Conclusions: High adherence to AICR recommendations was associated with lower risk of overall mortality in this multiethnic population of adults with CRC. Efforts to increase adherence to AICR recommendations in this population are needed.

Real-world excess costs associated with hematologic adverse events (hAEs) during first-line (1L) treatment of metastatic pancreatic adenocarcinoma (mPDAC) with FOLFIRINOX (FFX), FFX without 5FU bolus, and gemcitabine+nab-paclitaxel (GnP).

693 Background: During 1L treatment of mPDAC with FFX and GnP, hAEs can harm patients (pts) and accrue excess costs to the health system, i.e., costs beyond those of a treated pt without the hAE. This study examined excess total cost of care (TCoC) and components (total inpatient; outpatient transfusion, granulocyte colony-stimulating factor [G-CSF], and thrombopoietic growth factor [TGF]) for three key hAEs (anemia, neutropenia, thrombocytopenia) during 1L FFX, FFX without 5FU bolus (FFXnb), and GnP. Methods: This retrospective observational study utilized Optum Market Clarity claims + EHR linked data. Inclusion criteria were: adult pts diagnosed with mPDAC between 1/1/2015 and 5/31/2023; initiated 1L FFX, FFXnb, or GnP within -14 to +90 days (index date); ≥6 months pre-index enrollment. hAEs during 1L were detected from lab values and grouped all grades combined. Pts were divided into “hAE groups” and “ref. groups” with and without any of the three hAEs of interest, respectively. Pts were matched 1:1 without replacement based on follow-up time. Costs were measured from the day a lab value indicated an hAE until 30 days later and during the corresponding times for ref. pts, then standardized to per-pt-per-month (PPPM). This study did not adjust for differences in pt characteristics. Results: Means and differences (95% CI) in TCoC following hAE detection for each regimen and hAE of interest are presented (Table). PPPM TCoC was greater for all three regimens and hAEs, driven by 1.6–4.9 times higher inpatient costs. Inpatient costs were $5,614 and $5,665 higher for FFX and FFXnb neutropenia pts vs. ref. groups. Use of outpatient G-CSF at any time during 1L was lower for FFX and FFXnb neutropenia pts, at 76% and 63% vs. 83% and 75% in the ref. groups, respectively. Outpatient TGF and transfusions were rare. Conclusions: All hAEs showed excess PPPM TCoC across regimens, driven by inpatient costs. FFX and FFXnb neutropenia pts had lower overall utilization of outpatient G-CSF but higher inpatient costs following detection of neutropenia, which may represent an opportunity for improved pt management. Excess TCoC of hAEs. AE (any grade) FFX, hAE group(N=199, 127, 157) FFX, ref. group(N=199, 127, 157) Diff. (95% CI) FFXnb, hAE group(N=202, 106, 137) FFXnb, ref. group (N=202, 106, 137) Diff. (95% CI) GnP, hAE group (N=406, 268, 270) GnP, ref. group (N=406, 268, 270) Diff. (95% CI) AnemiaTCoC, mean 30,561 22,310 8,251 (4,396–12,106) 31,866 23,380 8,487(4,007–12,966) 32,662 27,697 4,965(1,320–8,610) NeutropeniaTCoC, mean 30,382 24,952 5,430(-31–10,891) 26,588 22,571 4,017(-1,288–9,322) 32,975 31,051 1,924(-4,629–8,477) ThrombocytopeniaTCoC, mean 30,566 22,535 8,031 (3,895–12,166) 31,434 22,958 8,476(2,962–13,991) 33,863 30,751 3,113(-3,310–9,536)

Sustainable synthesis of α-ketoglutaric and methanetriacetic acids from biomass feedstocks

Emerging 0D Hybrid Metal Halide Luminescent Glasses

Abstract 0D hybrid metal halide (HMH) luminescent glasses have garnered significant attentions for its chemical diversity in optoelectronic applications and it also retains the skeleton connectivity and coordination mode of the crystalline counterparts while exhibiting various physics/chemistry characteristics distinct from the crystalline states. However, understanding of the glass‐forming ability and the specific structural origins underpinning the luminescent properties of 0D HMH glasses remains elusive. In this review, it is started from the solid‐liquid phase transition and thermodynamic analysis of 0D HMHs formed through melt‐quenching, and summarize the current compounds capable of stably forming glassy phases via chemical structural design. The structural characterization methods are further discussed and highlight the exceptional transparency, specific luminescent properties, and glass crystallization behaviors. Moreover, the application prospects demonstrated by these 0D HMH glasses have been presented accordingly in X‐ray detection and imaging, anti‐counterfeiting, and information encryption. Finally, perspective is offered into the future development of this emerging family of 0D HMH glasses and their applications.

Personalized oncogenomic analysis of metastatic squamous cell carcinoma of the anus: Utilizing whole-genome sequencing to guide clinical decision-making.

11 Background: Metastatic squamous cell carcinoma of the anus (SCCA) is associated with significant morbidity and mortality. Due to its relative rarity, there is limited evidence to support systemic therapy regimens informed by genomic data. This study aims to utilize whole-genome and transcriptome sequencing to enhance the understanding of the genetic alterations driving metastatic SCCA and to identify potentially actionable therapeutic targets. Methods: This report examines nine cases of metastatic SCCA in patients enrolled in the Personalized Oncogenomics (POG) Program at the BC Cancer Agency. Comprehensive genomic profiling, including whole-genome and transcriptome analysis (WGTA) was conducted on fresh tumor biopsy or formalin fixed paraffin embedded (FFPE) tissue. Tumor genomic alterations were analyzed in detail including: SNVs, indels, copy number alterations, structural variants, mutation signatures, viral presence, tumor mutation burden (TMB), expression outliers, and immune cell scores. The somatic alterations were integrated with existing knowledge of drug-target interactions to identify actionable therapeutic targets. Results: Of the nine patients, eight were found to be HPV-positive, with one exhibiting high tumor mutational burden (TMB&gt;10mut/Mb). Mutation signatures included seven cases with AID/APOBEC signatures (commonly seen with HPV), and one case with an ID2 DNA replication slippage signature. The PI3K/AKT/mTOR pathway was the most commonly affected signaling pathway (n=4), followed by FGFR amplification and overexpression (n=3), and RAS/RAF alterations ( BRAF mutation and KRAS overexpression, n=2). EGFR amplification was identified in two cases, one of which also exhibited EGFR overexpression. Additionally, FBXW7 mutations were present in two cases. Immunotherapy was recommended for all nine patients: eight based on HPV positivity, either alone or in combination with other alterations, such as high TMB, SWI/SNF complex alterations, and presence of immune infiltrating cells, and the remaining case based on a SWI/SNF complex mutation. Only two patients ultimately received immunotherapy, both of whom derived clinical benefit. One patient, treated with atezolizumab as part of the phase II CAPTIV-8 trial (NCT04273061), demonstrated progression-free survival (PFS) of 10 months (ongoing), while the other, treated with nivolumab, achieved a PFS of 6 months. Conclusions: Genomic analysis using WGTA supported the recommendation of immunotherapy for all patients in this cohort. Although only two patients received immunotherapy, both experienced clinical benefit, underscoring the potential of personalized genomic-guided treatment in metastatic SCCA.

Clinical and genomic features of the morphological subtypes in advanced pancreatic cancer.

765 Background: In resected pancreatic cancer (PDA), morphology from routine histopathology slides provides a rapid inexpensive biomarker that predicts overall survival and correlates with transcriptomic subtypes. In this study, we evaluated clinical and genomic associations of morphological subtypes in resected and advanced disease and validated the consistency of subtypes in patient-derived organoids (PDO) and mouse xenografts (PDXs) during in vitro and in vivo modeling. Methods: Our cohort included PDA tumor tissues from 152 resectable (stage I/II) and 228 advanced cases (Stage III/IV). Hematoxylin and eosin-stained slides were blindly reviewed by two pathologists and classified into subtypes based on Kalimuthu (1). Morphological subtypes were correlated with clinical and genomic data from whole-genome and transcriptome sequencing. Histological preparations from PDOs and PDXs obtained from pancreatic resections and metastases were reviewed using the same criteria. Results: Morphological subtypes were significantly associated with clinical patterns. Locally advanced PDA exhibited the highest proportion of glandular tumors. Metastatic tumors were enriched for non-glandular morphologies. The non-glandular morphologies were significantly associated with lower survival rates in both resected and advanced tumors. Furthermore, morphological subtypes were significantly associated with unique genomic alterations. Compared to glandular tumors, non-glandular tumors were associated with increased KRAS copy number, KRAS imbalances, and polyploid genomes. In advanced settings, glandular and non-glandular tumors mostly exhibited classical and basal-like transcriptional subtypes, respectively. Squamous tumors had the highest mutation burden and the highest proportion of Basal A signature (2). Using differential gene expression, we identified transcriptional signatures of the morphological subtypes. PDOs and PDXs maintained the morphological subtypes, although non-glandular tumors had a lower success rate for PDO establishment. Conclusions: Morphological subtypes have distinct clinical and genomic associations across all stages of pancreatic cancer, which can be consistently modeled both in vitro and in vivo . These results demonstrate that morphological subtyping offers a rapid and biologically-relevant classification of PDA that could be used for drug development and stratification to predict therapy selection. 1. Gut; 69:317-328 (2020). 2. Nat Gen; 52:231-240 (2020).

p53 pathway genes' mutations as prognostic factors in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC): A single center study.

771 Background: Mutations (muts) in oncosuppressor genes have been associated with poor prognosis in different solid tumors. This study aims to evaluate the prognostic impact of p53 pathway muts in mPDAC pts. Methods: For each mPDAC pt enrolled in this study a FFPE tumor tissue specimen was collected and Next Generation Sequencing (NGS) was performed by TSO500HT assay (DNA [523 genes], RNA [55 genes]). Primary endpoint was overall survival (OS). The Kaplan–Meier method was used to estimate efficacy outcome; log-rank test, Peto-Peto test and Cox-regression model were used to compare the differences, considering a statistically significant p value &lt; 0.05. Results: A total of 149 mPDAC pts were enrolled; TP53 was mutated in 115/149 (77.2%) pts, CDKN2A in 28 (24.3%), CDKN2B in 8 (5.3%), ATM in 6 (4%), TP53BP1 and MDM2 in 2 pts each (1.3%) and ATR in 1 (0.7%). No mutations were found in MDM4, CHEK1 and CHEK2 genes. Overall, 121 (81.2%) pts had at least one mutation in a gene of p53 signaling pathway (p53sigmut) and 28 pts (19.8%) had none (p53sigwt). The most frequent TP53 alterations were single nucleotide variations (SNVs): R175 (10 pts-8.7%), R248 (9 pts-7.8%) and R273 (8 pts-7%); 27 TP53 muts (18.1%) occurred in exon 7, 26 (17.4%) in exon 5, 19 (12.8%) in exon 8 and 13 (8.7%) in exon 4. Median OS (mOS) was 15 months (mos) (CI 95%: 12.8-18.2) in TP53 mutated pts vs 24.3 mos (CI 95%: 17.3-Not reached) in TP53 wt pts, p=0.03. The site of TP53 alteration was correlated with pts’ survival: mOS was 34.9 mos (CI 95%: 31-Nr) in exon 4-mutated pts, 16.9 mos (CI 95%: 11.2-21.2) in exon 7-mut, 13.8 mos (CI 95%: 11.2-17.8) in exon 5-mut and 10.7 mos (CI 95%: 8.2-Nr) in exon 8-mut, p= 0.018. CDKN2A mutations were also associated with survival: mOS was 17.9 mos (CI 95%: 15.9-24.1) in wt pts vs 13.4 (CI 95%: 10.7-22.2) in mutated pts, p= 0.04. CDKN2B, ATM, TP53BP1, MDM2 and ATR mutations were not associated with OS. Overall, patients with at least one mutation in one of the genes of p53 pathway had a mOS of 15 mos (CI 95%: 12.8-18.2) vs 19.6 months (mos) (CI 95%: 17.3-Not reached) in p53sigwt patients. In terms of comutations, TP53 wt pts had a higher frequency of KRAS mutations: 94% vs 64.5%, p&lt;0.001. Conclusions: Our study suggests an important prognostic role of p53 signaling muts in mPDAC pts; wt pts resulted in a longer OS than mutated pts, although some mutations seem to be associated with a longer survival. Further studies are needed to investigate these findings, including an in-depth analysis of structural proteogenomic.

Transcriptome size matters for single-cell RNA-seq normalization and bulk deconvolution

Abstract The variation of transcriptome size across cell types significantly impacts single-cell RNA sequencing (scRNA-seq) data normalization and bulk RNA-seq cellular deconvolution, yet this intrinsic feature is often overlooked. Here we introduce ReDeconv, a computational algorithm that incorporates transcriptome size into scRNA-seq normalization and bulk deconvolution. ReDeconv introduces a scRNA-seq normalization approach, Count based on Linearized Transcriptome Size (CLTS), which corrects differential expressed genes typically misidentified by standard count per 10 K normalization, as confirmed by orthogonal validations. By maintaining transcriptome size variation, CLTS-normalized scRNA-seq enhances the accuracy of bulk deconvolution. Additionally, ReDeconv mitigates gene length effects and models expression variances, thereby improving deconvolution outcomes, particularly for rare cell types. Evaluated with both synthetic and real datasets, ReDeconv surpasses existing methods in precision. ReDeconv alters the practice and provides a new standard for scRNA-seq analyses and bulk deconvolution. The software packages and a user-friendly web portal are available.

Soft, Modular Power for Composing Robots with Embodied Energy

Abstract The adaptable, modular structure of muscles, combined with their confluent energy storage allows for numerous architectures found in nature: trunks, tongues, and tentacles to name some more complex ones. To provide an artificial analog to this biological soft muscle, a self‐powered, soft hydrostat actuator is presented. As an example of how to use these modules, a worm robot is assembled where the near totality of the body stores electrochemical potential. The robot exhibits an extremely high system energy density (51.3 J g −1 ), using a redox flow battery motif, with a long theoretical operational range of more than 100 m on a single charge. The innovation lies in the battery pouch, fabricated with a dry‐adhesion method, automatically bonding Nafion separators to a silicone‐urethane copolymer body. These pouches contain anolyte within a hydrostat pod filled with catholyte, increasing current density per pod. Each pod has a motor and tendon actuator for radial compression and expansion. By linking these self‐contained pods in series, the robot worm is created that automatically navigates an enclosed, curved path. This high‐capacity soft worm also climbs up and down a vertical pipe, using a two‐anchor crawling gait, with an extra payload equivalent to 1.5 times its body weight.

Disparities in liver cancer risk and outcomes in the LGBTQ community: A literature review.

528 Background: Liver cancer continues to be a significant public health concern, particularly among high-risk groups such as individuals with hepatitis infections, alcohol use disorders, and metabolic diseases. While liver cancer disparities have been well-documented among racial and ethnic minority groups, emerging research highlights significant health inequities within the LGBTQ community, including higher rates of risk factors and limited access to screening and care. This literature review aims to assess the extent of liver cancer disparities within the LGBTQ community and identify gaps in prevention, screening, and treatment. Methods: We performed a systematic search across PubMed, Scopus, and Google Scholar for peer-reviewed studies published between 2000 and 2024. The inclusion criteria focused on studies addressing liver cancer risk, prevalence, or outcomes in LGBTQ populations. Data on key liver cancer risk factors such as hepatitis B and C prevalence, alcohol use, obesity, and access to healthcare services were extracted and synthesized. Additionally, we reviewed public health reports and clinical guidelines relevant to LGBTQ health disparities. Results: The review identified significant disparities in liver cancer incidence and mortality among LGBTQ individuals. Hepatitis B infection rates were about 1.5 times higher, and hepatitis C rates up to 1.7 times higher among LGBTQ populations, particularly among gay and bisexual men. Alcohol use disorder was about 30-40% more prevalent in LGBTQ individuals, which further increases the risk of liver cancer. Screening for liver cancer in LGBTQ populations is underutilized, with rates approximately 20% lower than the general population. There were reported delays in diagnosis in LGBTQ community due to stigma, discrimination, and lack of culturally competent healthcare services. While some interventions targeting LGBTQ health have shown promise, the overall lack of targeted liver cancer prevention and treatment strategies remains a significant barrier. Conclusions: LGBTQ individuals face increased liver cancer risk due to a higher prevalence of key risk factors and inadequate healthcare access. Current screening and preventive strategies are insufficient for addressing these disparities. Targeted interventions, including enhanced screening efforts, hepatitis vaccination and treatment programs, and the development of LGBTQ-specific healthcare protocols, are needed to reduce the liver cancer burden in this underserved population. Policymakers and healthcare providers must address the unique needs of LGBTQ individuals to achieve equitable cancer outcomes. Prevalence of liver cancer risk factors in LGBTQ vs. general population. Risk Factor LGBTQ Population (%) General Population (%) Hepatitis B Infection 15 10 Hepatitis C Infection 18 12 Alcohol Use Disorder 25 16 Metabolic Syndrome 22 18 Screening Rate 40 60