Neoadjuvant Immunotherapy for Patients With Microsatellite Instability-High or POLE-Mutated Locally Advanced Colorectal Cancer With Bulky Tumors: New Optimization Strategy.

OBJECTIVE: To evaluate the efficacy and safety of neoadjuvant immunotherapy for patients with microsatellite instability-high (MSI-H) or DNA polymerase ε (POLE)-mutated locally advanced colorectal cancer (LACRC) with bulky tumors.  PATIENTS: We retrospectively reviewed 22 consecutive patients with MSI-H or POLE-mutated LACRC with bulky tumors (>8 cm in diameter) who received preoperative programmed death-1 blockade, with or without CapOx chemotherapy.  MAIN OUTCOME MEASURES: Pathological complete response (pCR), clinical complete response (cCR), toxicity, R0 resection rate, and complications were evaluated. Survival outcomes were analyzed using the Kaplan-Meier method. Multiplex immunofluorescence analysis were performed before and after treatment.  RESULTS: The incidence of immune-related adverse events (irAEs) was 36.4% (8/22). Five of 22 patients presented with surgical emergencies, most commonly perforation or obstruction. The 22 patients underwent a median 4 (1-8) cycles. Two patients were evaluated as cCR and underwent a watch and wait strategy. The R0 resection rate was 100.0% (20/20) and pCR rate was 70.0% (14/20). Twelve of 14 cT4b patients (85.7%) avoided multivisceral resection, and 10 of them achieved pCR or cCR. In the two patients with POLE mutations, one each achieved pCR and cCR. No Grade III/IV postoperative complications occurred. The median follow-up was 16.0 months. Two-year event-free and overall survival for the whole cohort was both 100%.  CONCLUSIONS: Preoperative immunotherapy is the optimal option for MSI-H or POLE-mutated LACRC with bulky tumors, especially cT4b. Preoperative immunotherapy in patients with T4b CRC can reduce multivisceral resection and achieve high CR rate.

Optimizing surgical strategies for retroperitoneal liposarcoma: a comprehensive evaluation of standardized aggressive surgical policies.

BACKGROUND: Retroperitoneal liposarcoma (RLPS) constitutes the majority of retroperitoneal sarcomas. While surgical resection remains the sole curative approach, determining the optimal surgical strategy for RLPS remains elusive. This study addresses the ongoing debate surrounding the optimal surgical strategy for RLPS. METHODS: We recruited 77 patients with RLPS who underwent aggressive surgical policies. Patients were categorized into three surgical subtypes: suprapancreatic RLPS, pancreatic RLPS, and subpancreatic RLPS. Our standardized surgical strategy involved resecting macroscopically uninvolved adjacent organs according to surgical subtypes. We collected clinical, pathological and prognostic data for analyses. RESULTS: The median follow-up was 45.5 months. Overall survival (OS) and recurrence-free survival (RFS) were significantly correlated with multifocal RLPS, pathological subtype, recurrent RLPS and histological grade (P for OS = 0.011, 0.004, 0.010, and < 0.001, P for RFS = 0.004, 0.001, < 0.001, and < 0.001, respectively). The 5-Year Estimate OS of well-differentiated liposarcoma (WDLPS), G1 RLPS, de novo RLPS and unifocal RLPS were 100%, 89.4%, 75.3% and 69.1%, respectively. The distant metastasis rate was 1.4%. The morbidity rates (≥ grade III) for suprapancreatic, pancreatic, and subpancreatic RLPS were 26.7%, 15.6%, and 13.3%, respectively. The perioperative mortality rate is 2.6%. CONCLUSIONS: Standardized aggressive surgical policies demonstrated prognostic benefits for RLPS, particularly for G1 RLPS, WDLPS, unifocal RLPS, and de novo RLPS. This approach effectively balanced considerations of adequate exposure, surgical safety, and thorough removal of all fat tissue. G1 RLPS, WDLPS, unifocal RLPS, and de novo RLPS could be potential indications for aggressive surgical policies.

Landscape fragmentation and regularity lead to decreased carbon stocks in basins: Evidence from century-scale research.

Landscapes evolution have significantly altered the Earth's energy balance and biogeochemical cycles, thereby exacerbating climate change. This, in turn, affects surface characteristics and the provision of ecosystem services, especially carbon storage. While recent centuries have witnessed unprecedented landscape changes, limited long-term studies have offered insights into the comparison between present-day features and historical conditions. This study utilized historical reconstruction data and remote sensing imagery to assess landscape evolution and its consequences for carbon stocks over 300 years. Employing multiple regression and random forest models were selected to quantify the influence of key landscape metrics on carbon stocks in the Dongting Lake basin, allowing for a thorough analysis across different sub-basins and land types. The results revealed that intensified human disturbances led to increased landscape fragmentation (+82%), regularity (+56%), and diversity (+37%) within the basin. Moreover, carbon stocks decreased from 4.13 Gt to 3.66 Gt, representing an 11.4% loss, with soil carbon stock experiencing the most considerable reduction (0.24 Gt, 51%). These changes in carbon stock metrics corresponded to shifts in landscape patterns, both undergoing significant transitions at the turn of the 21st century. Meanwhile, fragmentation and regularity played a vital role in explaining carbon stock changes, as their increase contributes to greater carbon losses. Likewise, an increase in landscape diversity correlated with decreased carbon stocks, challenging the prevailing notion that enhanced diversity promotes carbon stocks. The influence of landscape patterns on carbon stocks varies notably across distinct land types. An increase in the dominance of farmland and built-up land led to decreased carbon stocks, while the opposite holds true for forestland. Similarly, a decrease in regularity for farmland, forestland, and built-up land benefits carbon storage, while grassland demonstrates the opposite trend. These findings offer insights for countries and regions in the early stages of development or approaching development, suggesting improvements in land use practices and strategies to address climate change. This involves offsetting land-based carbon emissions through changes in landscape spatial configuration.

Spatiotemporal single-cell analysis decodes cellular dynamics underlying different responses to immunotherapy in colorectal cancer.

Expanding the efficacy of immune checkpoint blockade (ICB) in colorectal cancer (CRC) presses for a comprehensive understanding of treatment responsiveness. Here, we analyze multiple sequential single-cell samples from 22 patients undergoing PD-1 blockade to map the evolution of local and systemic immunity of CRC patients. In tumors, we identify coordinated cellular programs exhibiting distinct response associations. Specifically, exhausted T (Tex) or tumor-reactive-like CD8+ T (Ttr-like) cells are closely related to treatment efficacy, and Tex cells show correlated proportion changes with multiple other tumor-enriched cell types following PD-1 blockade. In addition, we reveal the less-exhausted phenotype of blood-associated Ttr-like cells in tumors and find that their higher abundance suggests better treatment outcomes. Finally, a higher major histocompatibility complex (MHC) II-related signature in circulating CD8+ T cells at baseline is linked to superior responses. Our study provides insights into the spatiotemporal cellular dynamics following neoadjuvant PD-1 blockade in CRC.

Exploring prognostic values of DNA ploidy, stroma-tumor fraction and nucleotyping in stage II colon cancer patients.

PURPOSE: To assess the prognostic value of three novel biomarkers, DNA ploidy, stroma-tumor fraction, and nucleotyping, seeking for more accurate stratification in stage II colon cancer. METHODS: A total of 417 patients with complete follow up information were enrolled in this study and divided into three clinical risk groups. IHC was performed to examine MSI status. DNA ploidy, stroma and nucleotyping were estimated using automated digital imaging system. Kaplan-Meier survival curves, Cox proportional hazards regression models, and correlation analyses were carried out to process our data. RESULTS: In the whole cohort of stage II colon cancer, nucleotyping and DNA ploidy were significant prognostic factors on OS in univariate analyses. The combination of nucleotyping and DNA ploidy signified superior OS and DFS. Difference was not significant between low-stroma and high-stroma patients. In multivariable analyses, nucleotyping and the combination of nucleotyping and DNA ploidy were proven the dominant contributory factors for OS. In the low-risk group, we found the combination of nucleotyping and DNA ploidy as the independent prognostic factor statistically significant in both univariate and multivariable, while in the high-risk group, the nucleotyping. CONCLUSIONS: Our study has proven nucleotyping and the combination of DNA ploidy and nucleotyping as independent prognostic indicators, thus expanding the application of nucleotyping as a predictor from high risk stage II colon cancer to whole risks.

Molecular transport enhancement in pure metallic carbon nanotube porins.

Nanofluidic channels impose extreme confinement on water and ions, giving rise to unusual transport phenomena strongly dependent on the interactions at the channel-wall interface. Yet how the electronic properties of the nanofluidic channels influence transport efficiency remains largely unexplored. Here we measure transport through the inner pores of sub-1 nm metallic and semiconducting carbon nanotube porins. We find that water and proton transport are enhanced in metallic nanotubes over semiconducting nanotubes, whereas ion transport is largely insensitive to the nanotube bandgap value. Molecular simulations using polarizable force fields highlight the contributions of the anisotropic polarizability tensor of the carbon nanotubes to the ion-nanotube interactions and the water friction coefficient. We also describe the origin of the proton transport enhancement in metallic nanotubes using deep neural network molecular dynamics simulations. These results emphasize the complex role of the electronic properties of nanofluidic channels in modulating transport under extreme nanoscale confinement.

Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy.

The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8+ T cells, are important parameters for the control of tumor growth and response to immunotherapy. Here, we show in murine and human cancers that these parameters exhibit circadian oscillations, driven by both the endogenous circadian clock of leukocytes and rhythmic leukocyte infiltration, which depends on the circadian clock of endothelial cells in the tumor microenvironment. To harness these rhythms therapeutically, we demonstrate that efficacy of chimeric antigen receptor T cell therapy and immune checkpoint blockade can be improved by adjusting the time of treatment during the day. Furthermore, time-of-day-dependent T cell signatures in murine tumor models predict overall survival in patients with melanoma and correlate with response to anti-PD-1 therapy. Our data demonstrate the functional significance of circadian dynamics in the tumor microenvironment and suggest the importance of leveraging these features for improving future clinical trial design and patient care.

Driver-response relationships in a large shallow lake since the Anthropocene: Short-term abrupt perturbations versus long-term sustainable.

Lakes, as integral social-ecological systems, are hotspots for exploring climatic and anthropogenic impacts, with crucial pathways revealed by continuous sediment records. However, the response of multi-proxies in large shallow lakes to typical abrupt events and sustained drivers since the Anthropocene remains unclear. Here, we explored the driver-identification relationships between multi-proxy peaks and natural and anthropogenic events as well as the attribution of short-term perturbations and long-term pressures. To this end, sediment core records, socio-ecological data, and documented events from official records were integrated into a large shallow lake (Dongting Lake, China). Significant causal cascades and path effects (goodness-of-fit: 0.488; total effect: -1.10; p < .001) were observed among catchment environmental proxies, lake biogenic proxies, and mixed-source proxies. The peak-event identification rate (PEIR) and event-peak driving rate were proposed, and values of 28.57%-46.43% and 50%-81.25% were obtained, respectively. The incomplete accuracy of depicting event perturbations using sediment proxies was caused by various information filters both inside and outside the lake. PEIRs for compound events were 1.41 (±0.72) and 1.09 (±0.46) times greater than those for anthropogenic-dominated and natural-dominated events, respectively. Furthermore, socio-economic activity, hydrologic dynamics, land-use changes, and agriculture exerted significant and persistent pressures, cumulatively contributing 55.3%-80.9% to alterations in sediment proxies. Relatively synergistic or antagonistic trends in temporal contributions of these forces were observed after 2000, which were primarily attributed to the "Grain for Green" project and the Three Gorges Dam. This study represents one of the few investigations to distinguish the driver-response relationship of multiple proxies in large shallow lakes under typical event perturbations and long-term sustained pressures since the Anthropocene. The findings will help policymakers and managers address ecological perturbations triggered by climate change and human activities over long-term periods.

Coupled effects of human activities and river-Lake interactions evolution alter sources and fate of sedimentary organic carbon in a typical river-Lake system.

Interconnected river-lake systems record sedimentary organic carbon (OCsed) dynamics and watershed environmental changes, providing valuable information for global carbon budgets and watershed management. However, owing to the evolving river-lake interactions under global change, monitoring OCsed is difficult, thereby impeding the understanding of OCsed transport and fate. This study provided new insights into the dynamical mechanisms of OCsed in a typical river-lake system consisting of Dongting Lake and its seven inlet/outlet rivers (the three inlets of the Yangtze River and four tributaries) over the last century using stable isotope tracing and quantified the influences of climate change and human activities on OCsed. Results indicated that exogenous OC dominated the OCsed in the lake (58.2 %-89.0 %) and was lower in the west than in the east due to the differences in the material inputs and depositional conditions within the lake. Temporally, the distribution patterns of OCsed sources mainly responded to human activities in the basin rather than to climate change. Before 2005, the Yangtze River contributed the most OCsed (53.5 %-74.6 %), attributed to the high-intensity land use changes (path coefficient (r∂): 0.48, p-value < 0.01) and agriculture-industry activities (r∂: 0.44, p-value < 0.001) in the Yangtze River basin that increased soil erosion. After 2005, a large amount of Yangtze River OC was intercepted by the Three Gorges Dam, altering the OC exchange in the river-lake system and shifting OCsed dominance to the four tributaries (52.2 %-63.8 %). These findings highlight the active response of OCsed to the river-lake interaction evolution and anthropogenic control, providing critical information for regulating watershed management behavior under global change.

Mechanisms of cadmium release from manganese-rich sediments driven by exogenous DOM and the role of microorganisms.

Dissolved organic matter (DOM) is a crucial component of natural sediments that alters Cd sequestration. Nevertheless, how different types of DOM fuel Cd mobilization in Mn-rich sediments has not been elucidated. In the present study, four typical DOM, fluvic acid (FA), bovine serum albumin (BSA), sodium alginate (SA), and sodium dodecyl benzene sulfonate (SDBS), were used to amend Cd-contaminated sediment to study their effects on Cd/Mn biotransformation and microbial community response. The results demonstrated that different DOM drive microbial community shifts and enhance microbially mediated Mn oxide (MnO) reduction and Cd release. The amendment of terrestrial- and anthropogenic-derived DOM (FA and SDBS) mainly contributed to enriching Mn-reducing bacteria phylum Proteobacteria, and its abundance increased by 38.16-74.47 % and 56.41-73.98 %, respectively. Meanwhile, microbial-derived DOM (BSA and SA) mainly stimulated the abundances of metal(loid)-resistant bacteria phylum Firmicutes. Accompanied by microbial community structure, diversity, and co-occurrence network shifts, the DOM concentration and oxidation-reduction potential changed, resulting in enhanced Cd mobilization. Importantly, FA stimulated Cd release most remarkably, probably because of the decreased cooperative interactions between bacterial populations, stronger reduction of MnOs, and higher aromaticity and hydrophobicity of the sediment DOM after amendment. This study linked DOM types to functional microbial communities, and explored the potential roles of different DOM types in Cd biotransformation in lake sediments.

Total Neoadjuvant Therapy With PD-1 Blockade for High-Risk Proficient Mismatch Repair Rectal Cancer.

Importance: Total neoadjuvant therapy (TNT) is the standard treatment for locally advanced rectal cancer, especially for patients with high-risk factors. However, the efficacy of TNT combined with immunotherapy for patients with proficient mismatch repair (pMMR) rectal cancer is unknown. Objectives: To evaluate the safety and efficacy of TNT with induction chemoimmunotherapy followed by long-course chemoradiation in patients with high-risk, pMMR rectal cancer and to identify potential molecular biomarkers associated with treatment efficacy. Design, Setting, and Participants: This cohort study was a single-arm phase 2 trial conducted at Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, from June 2020 to October 2021. Biopsies and plasma were collected before treatment for whole-exome sequencing and cell-free DNA sequencing, respectively. Data were analyzed from May 2022 to September 2022. Interventions: Participants received 3 cycles of induction oxaliplatin and capecitabine combined with camrelizumab and radiotherapy (50.6 Gy in 22 fractions) with concurrent capecitabine. Patients without disease progression received 2 cycles of consolidation oxaliplatin/capecitabine. Main Outcomes and Measures: The primary end point was pathologic complete response rate. Results: Of 25 patients enrolled (19 men [76%]; 6 women [24%]; median [IQR] age, 58 [48-64] years), 22 patients (88%) completed the TNT schedule. The pathologic complete response rate was 33.3% (7/21). Twelve patients (48%) achieved clinical complete response, and 4 patients (16%) chose to watch and wait. R0 resection was achieved in 21 of 21 patients, and the major pathologic response rate was 38.1% (8/21). The most common adverse event was nausea (80%, 20/25); grade 3 toxic effects occurred in 9 of 25 patients (36%). Patients with tumor shrinkage of 50% or greater after induction oxaliplatin/capecitabine and camrelizumab or clinical complete response had higher percentages of LRP1B mutation. Mutation of LRP1B was associated with high tumor mutation burden and tumor neoantigen burden. Patients with high tumor mutation burden all benefited from therapy. Conclusions and Relevance: This study found that TNT with induction chemoimmunotherapy followed by long-course chemoradiation was safe and effective for patients with high-risk rectal cancer with pMMR status. Longer follow-up and larger clinical studies are needed to validate this innovative regimen. There is also an urgent need to further validate the predictive value of LRP1B and discover other novel biomarkers with potential predictive value for rectal cancer.

Recent advances in the role of dissolved organic matter during antibiotics photodegradation in the aquatic environment.

The presence of residual antibiotics in the environment is a prominent issue. Photodegradation behavior is an important way of antibiotics reduction, which is closely related to dissolved organic matter (DOM) in water. The review provides an overview of the latest advancements in the field. Classification, characterization of DOM, and the dominant mechanisms for antibiotic photodegradation were discussed. Furthermore, it summarized and compared the effects of DOM on different antibiotics photodegradation. Moreover, the review comprehensively considered the factors influencing the photodegradation of antibiotics in the aquatic environment, including the characteristics of light, temperature, dosage of DOM, concentration of antibiotics, solution pH, and the presence of coexisting ions. Finally, potential directions were proposed for the development of predictive models for the photodegradation of antibiotics. Based on the review of existing literature, this paper also considered several pathways for the future study of antibiotic photodegradation. This study allows for a better understanding of the DOM's environmental role and provides important new insights into the photochemical fate of antibiotics in the aquatic environment.

Combined role of ground cover management in altering orchard surface‒subsurface erosion and associated carbon-nitrogen-phosphorus loss.

The combined role of ground cover management in controlling soil erosion and nutrient loss from new orchards is still less understood. In this study, four ground cover management practices, orchard with grass cover (OG), orchard with interplant cover (OI), orchard with straw cover (OS), and orchard with bare ground (OB), were designed to identify their impacts on soil erosion and associated carbon-nitrogen-phosphorus loss in new orchards by rainfall simulation tests with rainfall intensities of 60, 90, and 120 mm h-1 and 90 min rainfall duration. The results showed that OS had the lowest surface flow coefficient (6.6%) and highest subsurface flow coefficient (32.5%). The highest soil loss rate occurred in the OB plot (65.4 g m-2 min-1), and the lowest soil loss rate occurred in the OS plot (0.5 g m-2 min-1). OS plot showed better effectiveness in improving soil erosion. However, the increased infiltration capacity was facilitated in terms of causing non-point source pollution. The C-N-P ratios of surface flow in different cover measures (OB, OI, OG, and OS) were 1.4:1.2:0.9:1, 1.8:1.7:1.2:1, and 2.3:1.9:1.2:1, respectively. The ratios of sediment in different cover measures were 7.3:9:2.3:1, 2:1.5:1.2:1, and 1.2:1:0.8:0.7, respectively. Cover management plots play an active role in reducing nutrient loss in surface flow and sediment, but the increased infiltration in covered management plots is associated with the risk of groundwater contamination in subsurface flow. The C-N-P ratios of subsurface flow in OB and covered managed plots (OI, OG, and OS) were 1:3.3:1.6:2.7, 1:1.5:2.2:2.4 and 1:1.2:1.5:1.3, respectively. Therefore, when managing the phenomenon of soil erosion through ground cover measures, attention should also be focused on the function of cover measures in regulating non-point source pollution underground, such as subsurface flow. This research recommends a combination of cover management measures to further mitigate erosion and the risk of groundwater contamination.

Preoperative assessment of retroperitoneal Liposarcoma using volume-based 18F-FDG PET/CT: implications for surgical strategy and prognosis.

PURPOSE: Retroperitoneal liposarcoma (RLPS) poses a challenging scenario for surgeons due to its unpredictable biological behavior. Surgery remains the primary curative option for RLPS; however, the need for additional information to guide surgical strategies persists. Volume-based 18F-FDG PET/CT may solve this issue. METHODS: We analyzed data from 89 RLPS patients, measuring metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum standardized uptake value (SUVmax) and explored their associations with clinical, prognostic, and pathological factors. RESULTS: MTV, TLG of multifocal and recurrent RLPS were significantly higher than unifocal and primary ones (P < 0.001, P < 0.001, P = 0.003 and P = 0.002, respectively). SUVmax correlated with FNCLCC histological grade, mitotic count and Ki-67 index (P for G1/G2 = 0.005, P for G2/G3 = 0.017, and P for G1/G3 = 0.001, P < 0.001 and P = 0.024, respectively). MTG, TLG and SUVmax of WDLPS were significantly lower than DDLPS and PLPS (P for MTV were 0.009 and 0.022, P for TLG were 0.028 and 0.048, and P for SUVmax were 0.027 and < 0.001, respectively). Multivariable Cox analysis showed that MTV > 457.65 (P = 0.025), pathological subtype (P = 0.049) and FNCLCC histological grade (P = 0.033) were related to overall survival (OS). CONCLUSIONS: Our findings indicate that MTV is an independent prognostic factor for RLPS, while MTV, TLG, and SUVmax can preoperatively predict multifocal lesions, histological grade, and pathological subtype. Volume-based 18F-FDG PET/CT offers valuable information to aid in the decision-making process for RLPS surgical strategies.