Significant Regressions Research Articles

Contribution of neoadjuvant chemotherapy and radiation therapy (intensity-modulated radiation therapy with concurrent chemotherapy versus stereotactic body radiation therapy alone) on tumor volume regression in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma: A single institution experience.

707 Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with a minority of patients (pts) eligible for curative resection. Pts with borderline resectable or locally advanced (BR/LA) PDAC frequently receive neoadjuvant chemotherapy (NAC) +/- radiation therapy (RT) to improve resectability. Here, we report the individual contribution of NAC and RT (either intensity modulated RT + concurrent chemotherapy (IMRT+CC) or stereotactic body RT (SBRT) alone) on tumor regression by measuring tumor volumes. Methods: We performed a single institution retrospective review of PDAC pts who underwent resection between 2011-2021 and were part of a tumor biobank registry. Tumor measurements were performed at baseline, post-NAC, and post-RT by five independent, blinded abdominal radiologists. Analyses were performed using paired t-tests, two-proportion z-tests, log-rank tests, and Mann-Whitney U test. Results: We identified 49 BR/LA pts who received NAC followed by RT who had complete pre- and post-treatment imaging. Fifteen pts received IMRT+CC and 28 received SBRT. The effect of NAC on tumor volumes (-29.2% vs -26.3%, p=0.66; mean percent change) and maximum diameter (-9.2% vs -12.0%, p=0.58) was similar within the IMRT+CC and SBRT groups. Both IMRT+CC (-7.12 cm3, p=0.003) and SBRT (-2.70 cm3, p=0.001) resulted in significant tumor regressions. IMRT+CC achieved a significantly greater overall mean percent change in tumor volume (-53.4% vs -28.8%, p=0.024) and maximum diameter (-30.4% vs -16.2%, p=0.020) compared to SBRT. Pts receiving IMRT+CC or SBRT had similar tumor volumes (10.88 vs 11.74 cm3, p=0.87, respectively) and maximum diameter (3.45 vs 3.17 cm, p=0.48) prior to RT. IMRT+CC resulted in improved tumor volume response (>30% regression; 80.0% vs 46.4%; p=0.033) but not an improved response rate by RECIST criteria (46.7% vs 21.4%; p=0.085). Mean resected tumor volumes (by pathological review) for those receiving IMRT+CC (n=9) and SBRT (n=23) were 4.34 vs 13.1 cm3 (p=0.049). The R0 (86.7% vs 85.7%, p=0.93) and N0 (73.3% vs 53.6%, p=0.21) resection rates between the two groups were similar. Compared to SBRT, IMRT+CC resulted in an improved recurrence free survival (RFS; 2.36 vs 1.31 years; p=0.026), but did not meet statistical significance for an overall survival benefit (mOS; 2.85 vs 2.03 years, p=0.19). Conclusions: We found that IMRT+CC yielded superior radiographic volumetric regression and improved RFS but did not significantly impact mOS. Correspondingly, resected tumors from patients treated with IMRT+CC were smaller than those obtained from patients treated with SBRT. The role of IMRT+CC and SBRT in PDAC remains to be clearly defined.

Interactions between mangrove soil, water, and microbes in degraded, natural, and restored tropical coastline ecosystems

ABSTRACT The interactions among soil, water, and microbes are unique and fundamental in mangrove forests. We examined and compared the physicochemical parameters of soil (pH, Organic Carbon (OC), Electrical Conductivity (EC), N, P, K, Mg, Ca, S, Fe, Zn, Cu, and Mn) and water (pH, temperature, Total Dissolved Solids (TDS), EC) as well as microbial diversity and abundance in nine natural, degraded, and restored mangrove ecosystems along Guyana’s coastline. Sampling was done using a randomized block design for one year in two seasons. Significant differences, correlations (p < 0.05, R > 0.75) and regressions in water and soil parameters were documented for the natural ecosystems and restored ecosystems in both seasons. Additionally, microbial abundance was greater in the restored ecosystems, while seasonal variations in diversity were seen in the degraded and restored ecosystems. Our study lends some credence to the idea that ecosystem type and seasonality can influence soil, water, and microbial interactions, which can ultimately affect mangrove biodiversity.

Abstract PR010: Preliminary safety and pharmacokinetic profiles of RMC-6236, a first-in-class, RAS-selective, tri-complex RASMULTI(ON) inhibitor in patients with KRAS mutant solid tumors on the Phase 1 trial RMC-6236-001

Abstract Background: RMC-6236 is an oral RASMULTI(ON) tri-complex inhibitor that is selective for the active, GTP-bound state of both mutant and wild-type variants of the canonical RAS isoforms. RMC-6236 binds to cyclophilin A, which is abundantly expressed in normal tissues and tumors, resulting in a binary complex that potently binds to RAS(ON) to form a tri-complex, blocking downstream signaling. Preclinical studies with RMC-6236 demonstrated deep and sustained regressions across multiple RASMUT tumor types at well tolerated doses, particularly tumors harboring KRAS glycine-12 substitutions (KRASG12X). Methods: Patients with previously treated, advanced KRASG12X mutant solid tumors were enrolled at escalating doses of single agent RMC-6236 administered once daily (QD). Results: As of May 11, 2023, 54 patients received RMC-6236 at dose levels from 10 to 220 mg QD. The majority of patients had pancreatic cancer (26 [48%]), non-small cell lung cancer (13 [24%]), or colorectal cancer (10 [19%]). The most common (≥10% of patients) treatment-related adverse events (TRAEs) were rash and gastrointestinal (GI)-related toxicities that were all Grade 1 or 2 in severity. Most rashes were acneiform (35%) or maculopapular (13%), consistent with known on-target rash presentation from other RAS pathway inhibitors. Rash frequency, but not severity, was dose-dependent. One patient required a dose reduction due to Grade 2 acneiform rash. The most common GI-related toxicities were nausea (32%), diarrhea (19%), and vomiting (15%) that were manageable with standard supportive care. There were two Grade ≥3 TRAEs in patients with pancreatic cancer: Grade 4 large intestine perforation at the site of an invasive tumor that reduced in size on treatment, and Grade 3 pancreatitis reported at the time of disease progression. Thirty-one patients (57%) remain on treatment, and 23 (43%) discontinued, including 17 (31%) due to progressive disease (PD) per RECIST v1.1, 2 (4%) due to clinical progression, and other reasons due to adverse event (Grade 4 large intestine perforation), death (due to PD), investigator’s decision, or patient withdrawal (1 patient each). RMC-6236 exhibited dose-dependent increases in exposure in patients with no apparent accumulation in the blood following repeated daily dosing. At 220 mg QD, exposure to RMC-6236 was within range of the preclinical exposures in mice that demonstrated significant tumor regressions. Preliminary evidence of anti-tumor activity, including partial responses per RECIST v1.1, was observed in patients across several tumor types and dose levels. Molecular responses were observed with reduction in circulating tumor DNA of the KRAS-mutated allele and other somatic mutations consistent with inhibition of mutant RAS by RMC-6236. Conclusions: RMC-6236 is safe and well tolerated at doses that induce anti-tumor activity in patients with tumors harboring KRASG12X mutations and has favorable pharmacokinetics with oral dosing. A recommended phase 2 dose has not yet been determined and dose escalation is ongoing. Citation Format: Alexander I Spira, Alexander N Starodub, Kathryn C Arbour, David Sommerhalder, Brian M Wolpin, Minal Barve, Ignacio Garrido-Laguna, Salman Punekar, Meredith Pelster, Sumit Kar, Jamie Wong, Tong Lin, Rakesh Raman, Lin Tao, Zeena Salman, Xiaolin Wang, W. Clay Gustafson, David S Hong. Preliminary safety and pharmacokinetic profiles of RMC-6236, a first-in-class, RAS-selective, tri-complex RASMULTI(ON) inhibitor in patients with KRAS mutant solid tumors on the Phase 1 trial RMC-6236-001 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR010.

Performance of leaf extract media in culturing mycorrhizal mushroom mycelium

In-vitro culture of mycorrhizal mushroom (MM) species in southern Africa remains largely unexplored, particularly using tree-derived media. In this study, a Julbernardia globiflora [(Benth.) Troupin] leaf infusion was tested for its ability to promote MM mycelial growth. Amanita loosii, Cantharellus miomboensis and Cantharellus heinemannianus isolates were incubated at a pH of 2, 3, 4, 5, 6 or 7 and at 25 °C in six leaf extract agar (LEA) infusion concentrations of 150, 175, 200, 225 or 250 grams of leaves/L distilled water, with potato dextrose agar (PDA) as a standard. We determined mycelium growth rates for all treatment combinations. Mycelium growth rate was found to be optimal at a pH between 4 and 6 in all leaf infusion concentrations tested. Significant (p&lt;0.001) linear regressions of A. loosii and C. miomboensis were found for pH only (R2=0.837 and 0.8582, respectively) and a significant (p&lt;0.001) regression was found for C. heinemannianus (R2=0.293). Amanita loosii and C. heinemannianus had faster (p&lt;0.001) growth in PDA than in LEA, while C. miomboensis had similar growth rates in the two media. Growth characteristics observed were attributed to acid phosphatase mediated physiological processes in mycelium for the different MM species with an optimum pH of 4–6. MM mycelia were white, mycelia for A. loosii and C. miomboensis were loose and for C. heinemannianus were thin filaments. LEA proved to be a potential alternative medium for culturing MM species. Significance: A novel miombo tree extract medium was tested with three miombo mycorrhizal mushrooms. Our findings show the new medium to be a possible alternative to, but not as viable as, potato dextrose agar. The findings of this study widen the scope of use for the forest tree derived media and demonstrate the cultivability of miombo mycorrhizal mushroom species. Our findings improve the possibility of enhancing food security through culturing and possibly cultivating the less explored African mycorrhizal mushrooms.

Elucidating the Heterogeneity of Immunotherapy Response and Immune-Related Toxicities by Longitudinal ctDNA and Immune Cell Compartment Tracking in Lung Cancer.

Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect-especially in the setting of stable disease-calls for the development of molecularly informed real-time minimally invasive approaches. In addition to capturing tumor regression, liquid biopsies may be informative in capturing immune-related adverse events (irAE). We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles. Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank P = 0.0003) and overall survival (log-rank P = 0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, on-treatment peripheral blood T-cell repertoire reshaping, assessed by significant T-cell receptor (TCR) clonotypic expansions and regressions, was identified on average 5 months prior to clinical diagnosis of an irAE. Molecular responses assist with the interpretation of heterogeneous clinical responses, especially for patients with stable disease. Our complementary assessment of the peripheral tumor and immune compartments provides an approach for monitoring of clinical benefits and irAEs during immunotherapy.

ENSO may have contributed to sea level changes in the Gulf of Thailand during the Late-Holocene

The Gulf of Thailand is ideal for studying eustatic sea level fluctuations in Southeast Asia due to its shallow basin and tectonic stability. However, our understanding of how this region’s relative sea level (RSL) has fluctuated over the Holocene epoch is far from complete. In this study, we used lithostratigraphy, loss on ignition, grain size, and pollen analyses to reconstruct the environmental changes in the Sam Roi Yot wetland, which was significantly influenced by seawater intrusion, driven by fluctuations in RSL in the Gulf of Thailand. Therefore, the analyzed pollen records of the sediment core from the wetland reflected variabilities in the RSL in the Gulf of Thailand. Subsequently, we found that after a sea level highstand prior to 4000 cal y BP, the RSL gradually fell with two significant regressions at c. 2950 and 1850–1450 cal y BP before rising at 1450–1050 cal y BP and declining after that. The inconsistency between RSL reconstruction based on our results and the global sea level changes simulated by the Glacial Isostatic Adjustment (GIA) model further suggests that long–term El Niño Southern Oscillations (ENSO) variabilities may have played a significant role in sea level changes in the Gulf of Thailand over the Late-Holocene period. Thus, during extended El Niño or La Niña conditions, the sea level would have been consistently lower or higher than expected from eustatic and isostatic processes alone. Overall, this study emphasizes the importance of considering regional factors such as ENSO to understand sea level changes in Southeast Asia.

Enabling a process-oriented hydro-biogeochemical model to simulate soil erosion and nutrient losses

Abstract. Water-induced erosion and associated particulate carbon (PC), particulate nitrogen (PN) and particulate phosphorus (PP) nutrient losses are vital parts of biogeochemical cycling. Identifying their intensity and distribution characteristics is of great significance for the control of soil and water loss and nitrogen/phosphorus nonpoint source pollution. This study incorporated modules of physical soil erosion and associated PC, PN and PP losses into a process-oriented hydro-biogeochemical model (Catchment Nutrients Management Model coupled with DeNitrification–DeComposition, CNMM-DNDC) to enable it to predict soil and water loss. The results indicated that the upgraded CNMM-DNDC (i) performed well in simulating the observed temporal dynamics and magnitudes of surface runoff, sediment and PN/PP yields in the lysimetric plot of the Jieliu catchment in Sichuan Province and (ii) successfully predicted the observed monthly dynamics and magnitudes of stream flow, sediment yield and PN yields at the catchment outlet, with significant univariate linear regressions and acceptable Nash–Sutcliffe indices higher than 0.74. The upgraded CNMM-DNDC demonstrated that a greater proportion of PN to total nitrogen (TN) during the period with large precipitation events and amounts than that during the drought period (16.2 %–26.6 % versus 2.3 %–12.4 %). The intensities of soil erosion and particulate nutrient yields in the Jieliu catchment were closely related to land use type in the following order: sloping cultivated upland (SU) &gt; residential areas (RA) &gt; forest land (FL). The scenario analysis demonstrated that high greenhouse gas (GHG) emissions scenarios provided a greater risk of soil erosion than did low GHG emissions scenarios and that land use change (i.e., from SU to FL) could help to mitigate soil and water loss accelerated by climate change in the future. The upgraded model was demonstrated to have the ability of predicting ecosystem productivity, hydrologic nitrogen loads, emissions of GHGs and pollutant gases, soil erosion and particulate nutrient yields, which renders it a potential decision support tool for soil erosion and nonpoint source pollution control coordinated with increasing production and reducing GHG and pollutant gases emissions in a catchment.

Structure-based drug design, synthesis, and biological evaluation of novel 1,3,5-triazine or pyrimidine derivatives containing benzoyl hydrazine moiety as PI3Kα selective inhibitors

Phosphoinositide 3-kinase (PI3K) was an important cellular signal transducer, while PI3Kα was the most mutated family member in cancer. Selective PI3Kα inhibitors have become the frequent research in recent years because of their excellent curative effect and reduced side effects. Here, we described a series of PI3Kα inhibitors with 1,3,5-triazine or pyrimidine skeleton containing benzoyl hydrazine based on the pan-PI3K inhibitor ZSTK474 relying on the strategies of structure-based drug discovery (SBDD) and computer-aided drug design (CADD). Among them, compound F8 exhibited improved selective PI3Kα inhibition with an IC50 value of 0.14 nM and more significant anti-proliferative activities against three tumor-derived cell lines (PC-3 IC50 = 0.28 μM, HCT-116 IC50 = 0.57 μM, and U87-MG IC50 = 1.37 μM) than ZSTK-474. Compound F-8 induced a great decrease in mitochondrial membrane which caused cell cycle arrest at G1 phase and apoptosis in U87-MG cells in a dose-dependent manner. Furthermore, compound F8 induced significant tumor regressions in a xenograft mouse model of U87-MG cell line with no clear evidence of toxicity following intraperitoneal injection of 40 mg/kg. Compound F8 may serve as a PI3Kα-selective inhibitor and provided the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family.

Maize and Wheat Responses to the Legacies of Different Cover Crops under Warm Conditions

Cover crops (CC) have great potential to enhance the sustainability of agroecosystems. However, the wide range of possible rotations of CC and cash crops (CaC) means that important knowledge gaps persist on how CC affects CaC. We investigated the legacy effects of five common CC (three monocultures: vetch, melilotus, and barley, and two mixtures: barley-vetch and barley-melilotus) on two of the most important CaC, maize and wheat. A microcosm, semi-controlled experiment was established simulating warm, low-income Mediterranean conditions. After two cycles, soil physicochemical and microbial properties, as well as plant growth and nutrition variables, were measured at the CC early growth CaC stage. In maize, barley CC had the best soil microbial and nutritional legacy effects, which resulted in the highest biomass and nutrient status. In contrast, barley produced the worst results on wheat, showing the disadvantages of growing two crops from the same tribe consecutively. CC mixtures also did not offer a productive advantage over pure CC. Additionally, our findings suggest that archaea seem to play a role in increasing N and Zn content in maize shoots. Furthermore, shoot B contents showed highly significant regressions with the CaC biomass. These results can help select the appropriate CC in each case.

Vertical, spatial, size, and taxonomic variations in stable isotopes (δ13C and δ15N) of zooplankton and other pelagic organisms in the western North Pacific

Stable isotopes (δ13C and δ15N) of zooplankton and other marine organisms are useful for evaluating trophic levels and the food web structure of marine ecosystems. Further, taxonomic variations and regressions between δ15N and δ13C can provide details of regional differences in the food web structure. Despite their ecological importance, information on the taxonomic differences in the stable isotopes of various pelagic biota and vertical, latitudinal, and size variations in the stable isotopes of the mesozooplankton are scarce in the western North Pacific. In this study, we compared regional differences in the taxonomic variations of the stable isotopes of the all pelagic organisms collected by gillnets and various plankton nets in the subarctic and transitional domains (37–44°N) of the western North Pacific during spring. Additionally, we evaluated the vertical, size, and latitudinal variations in the stable isotopes of mesozooplankton in the western North Pacific. Regressions between δ15N and δ13C were highly significant for the subarctic and transitional domains, while they varied significantly between the two regions (P < 0.0001, ANCOVA). These regional differences in the stable isotopes were characterised by the high δ15N and low δ13C values in the subarctic region, whereas the opposites trend was observed in the transitional domains. Vertical observations from the sea surface to a depth of 3000 m at five stations (29°, 31°, 33°, 37°, and 41°N) showed that there were no significant changes in the δ13C stable isotope of mesozooplankton with depth across the stations. However, for δ15N, the significance of regressions increased with increasing depths at the subtropical stations (29°, 31°, and 33°N), while no significant trends with depth were observed for the subarctic and transitional domain stations (37°, 41°N). The dominance of interzonal copepods (e.g., Neocalanus spp.) in the mesozooplankton biomass in the subarctic and transitional region may mask the vertical changes in δ15N values in that region. Further, δ13C varied neither with size nor latitude. In contrast, δ15N showed clear size and latitudinal patterns. Thus, δ15N values increased with increasing zooplankton size (112 μm < 407 μm < 925 μm), and significant regressions increased with increasing latitude for all three size classes (P < 0.001). Subsequent ANCOVA revealed that the regression did not vary with organism size. Thus, the changing latitudinal patterns in δ15N values (higher for high latitude) had much greater effects than the size differences for mesozooplankton.

Are Age, Self-Selected Walking Speed, or Propulsion Force Predictors of Gait-Related Changes in Older Adults?

There is limited research that directly compares the effect of reduced speed with reduced propulsive force production (PFP) on age-related gait changes. We aimed to determine how changes in the gait of older adults correlate with age, speed, or peak PFP over a 6-year span. We collected kinematics and kinetics of 17 older subjects at 2 time points. We determined which biomechanical variables changed significantly between visits and used linear regressions to determine whether combinations of self-selected walking speed, peak PFP, and age correlated to changes in these variables. We found a suite of gait-related changes that occurred in the 6-year period, in line with previous aging studies. Of the 10 significant changes, we found 2 with significant regressions. Self-selected walking speed was a significant indicator of step length, not peak PFP or age. Peak PFP was a significant indicator for knee flexion. None of the biomechanical changes were correlated to the chronological age of the subjects. Few gait parameters had a correlation to the independent variables, suggesting that changes in gait mechanics were not solely correlated to peak PFP, speed, and/or age. This study improves understanding of changes in ambulation that lead to age-related gait modifications.

Assessing the environmental efficiency of OECD countries through the lens of ecological footprint indices

Environmental efficiency plays a crucial role in achieving sustainable economic development. This study aims to enhance the current understanding of dynamic environmental efficiency by using Data Envelopment Analysis (DEA) in conjunction with the ecological footprint index. This study evaluates 27 OECD countries' environmental performance from 2000 to 2017, employing net capital stock, labor force, and energy consumption as inputs, ecological footprint as undesirable output, and GDP as desirable output. We utilize 16 window Slack-Based Measurement DEA (SBM-DEA) models, each representing consecutive years within the observation period. Additionally, we adopt the Global Malmquist-Luenberger Index (GMLI) techniques to facilitate a simultaneous evaluation of the efficiency levels for each country. Our findings reveal that the United Kingdom and Lithuania were the most and least ecologically efficient countries among the 27 OECD countries, respectively. Over the 18-year observation period, all countries showed both progress and setbacks in environmental efficiency, with a modest overall improvement. Poland, Denmark, Slovakia, and Lithuania were the most improved countries in environmental performance, while Canada and Japan showed the most significant regressions in environmental efficiency. We highlight the need for policymakers to prioritize sustainable economic growth and consider ecological footprints when making economic decisions to enhance environmental efficiency in OECD countries. Our findings have can guide policymakers in designing effective policies and strategies to enhance environmental efficiency and promote sustainable economic development.

A field investigation of short-range dispersal by female Simulium damnosum s.l.

Female Simulium damnosum s.l. were caught at a site in a savannah zone beside the Mono River in Togo and at varying distances westwards perpendicular to it in an experiment to investigate short-range dispersal by the flies. The numbers of flies caught and the percentages that were parous decreased with increasing distance from the river, the latter suggesting that nulliparous flies disperse on average further than parous flies. The decreases were quantified using statistically significant multiple regressions involving distances from the river and the days since the start of the experiment because there was much day-to-day variation, probably attributable to the flies’ gonotrophic cycles. For future modelling purposes a relationship between numbers caught and distance alone was also estimated for both numbers caught and parous rates. Of the different members of the S. damnosum species complex identified in larval samples, S. damnosum s.str. predominated (66.7%), with S. squamosum accounting for 25.5% and the Beffa form of S. soubrense for 7.8%, proportions that were not significantly different from those of adults identified at the river and 10 km away. A small sub-sample of dissected parous flies showed that transmission was occurring at the riverside and at 10 km away from the river.

Phase I Study of Single-Agent Anti-Programmed Death-1 (MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity, Pharmacodynamics, and Immunologic Correlates.

Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, may suppress antitumor immunity. This phase I study sought to determine the safety and tolerability of anti-PD-1 blockade in patients with treatment-refractory solid tumors and to preliminarily assess antitumor activity, pharmacodynamics, and immunologic correlates. Thirty-nine patients with advanced metastatic melanoma, colorectal cancer (CRC), castrate-resistant prostate cancer, non-small-cell lung cancer (NSCLC), or renal cell carcinoma (RCC) received a single intravenous infusion of anti-PD-1 (MDX-1106) in dose-escalating six-patient cohorts at 0.3, 1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort at 10 mg/kg. Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy. Anti-PD-1 was well tolerated: one serious adverse event, inflammatory colitis, was observed in a patient with melanoma who received five doses at 1 mg/kg. One durable complete response (CRC) and two partial responses (PRs; melanoma, RCC) were seen. Two additional patients (melanoma, NSCLC) had significant lesional tumor regressions not meeting PR criteria. The serum half-life of anti-PD-1 was 12 to 20 days. However, pharmacodynamics indicated a sustained mean occupancy of > 70% of PD-1 molecules on circulating T cells ≥ 2 months following infusion, regardless of dose. In nine patients examined, tumor cell surface B7-H1 expression appeared to correlate with the likelihood of response to treatment. Blocking the PD-1 immune checkpoint with intermittent antibody dosing is well tolerated and associated with evidence of antitumor activity. Exploration of alternative dosing regimens and combinatorial therapies with vaccines, targeted therapies, and/or other checkpoint inhibitors is warranted.

Trophic sources and pathways of mesozooplankton and fish larvae in the Kuroshio and its neighboring waters based on stable isotope ratios of carbon and nitrogen

Major forage fishes spend their vulnerable early life stages in the Kuroshio and its neighboring waters where phytoplankton standing stocks are much lower than in coastal areas. Nevertheless, little is known of how mesozooplankton and fish larvae with their high biodiversity are supported in the Kuroshio ecosystem. Here we report stable isotope ratios of carbon (δ13C) and nitrogen (δ15N) for mesozooplankton and fish larvae from coastal to pelagic sites in the East China Sea to evaluate trophic sources and pathways at lower trophic levels in planktonic food webs under different environmental regimes. Although δ13C and δ15N in mesozooplankton and fish larvae varied among taxonomic groups and sites, mesozooplankton δ13C and δ15N tended to be lower for particle-feeders than carnivores and fish larvae and at more pelagic sites than in coastal waters. There were significant linear regressions between δ15N and δ13C of mesozooplankton communities, with the similar slopes among sites and lower intercepts at more pelagic sites. The δ15N and δ13C of small copepods, euphausiids, ostracods, appendicularians and fish larvae were aligned close to the regression line covering all regions, indicating that these were trophic sources and pathways to mesozooplankton and fish larvae. Our results suggest that trophic sources of mesozooplankton and fish larvae are supported through copepods and appendicularian-integrated microbial production and are more dependent on diazotrophic production in more pelagic waters.

DDDR-01. AZD9574 IS A NOVEL, BRAIN PENETRANT PARP-1 SELECTIVE INHIBITOR WITH ACTIVITY IN AN INTRACRANIAL XENOGRAFT MODEL OF TRIPLE NEGATIVE BREAST CARCINOMA WITH HOMOLOGOUS RECOMBINATION REPAIR DEFICIENCY

Abstract The Poly (ADP-ribose) polymerase (PARP) family has numerous essential functions in cellular processes such as transcription, chromatin remodelling, DNA damage response and repair as well as apoptosis. PARP inhibition blocks base excision repair and results in conversion of SSBs to DNA double-strand break (DSBs), the most deleterious form of DNA damage. DSBs can be repaired by homologous recombination repair (HRR) or non-homologous end joining (NHEJ). The physiological importance of HRR is underscored by the observation of genomic instability in HRR-deficient (HRD+) cells and, importantly, the association of cancer predisposition and developmental defects with mutations in HRR genes. PARP1 and PARP2 are required for SSB repair, while PARP1 is also involved in the repair of DNA double-strand breaks (DSBs) and replication fork damage. AZD9574 is a novel brain penetrant PARP1 inhibitor that acts by selectively inhibiting and trapping PARP1 at the sites of SSBs. While AZD9574 inhibited PARP1 enzymatic activity in all tested cell lines irrespective of the HRR status (IC50 range between 0.3 – 2 nM), colony formation assay in isogenic cell lines pairs confirmed higher potency and selectivity towards HRD+ models. In vivo, AZD9574 demonstrated dose-dependent efficacy in a BRCA1 mutant MDA-MB-436 subcutaneous xenograft model. Anti-tumour effects of AZD9574 were manifested by significant growth regressions that were durable after treatment withdrawal. An intracranial xenograft model of breast cancer brain metastases was developed to assess the efficacy of AZD9574 in the context of blood-brain barrier penetrance. Treatment of animals with established intracranial lesions showed sustained tumour growth suppression resulting in a significantly extended survival of tumour-bearing mice. Collectively, we believe that our data support the development of AZD9574 as a potential therapy for patients with HRD+ breast cancer whose disease has spread to the brain.This abstract was previously presented at AACR 2022 (Hamerlik et al, AACR 2022, Abs #3880)

Analysis of Quadratic Correlation between Dryness Indices and Wine Grape Yield to Estimate Future Climate Impacts in Hungary

In many regions, water availability influences grape yield fluctuations more than thermal conditions. This study analyzes dryness indices calculated from observed and simulated RCM data to establish statistical relationships with observed yield data, considered an indicator of food safety. Five dryness indices were analyzed: the number of days without rain, the maximum number of consecutive dry days, climatic water balance, dryness index, and vineyard water indicator. These indices were analyzed for three periods: 1986–2005 (recent past), 2016–2035 (near future) and 2081–2100 (distant future). After this analysis, quadratic regression connections were established between the indices and available wine grape yields in the 22 wine regions of Hungary for 2005–2021 without information on grape varieties and for 2017–2021 with data on grape varieties. Linear agro-technological trends were extracted from these wine grape yield series, whereas the residuals exhibited significant quadratic regression in slightly over 50% of the indices and regions, according to the F-test for the 17 year series. For the short series, these proportions are 29 and 27% for the selected seven white and seven red wine grapes. According to the most significant quadratic regressions, combined with the projected dryness indices, we can expect less average yields with higher interannual variability in the future.

Based on 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474), design, synthesis and biological evaluation of novel PI3Kα selective inhibitors

Based on 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474), three series of novel 1,3,5-triazine or pyrimidine derivatives containing semicarbazones have been designed and synthesized to obtain new potent and selective PI3Kα inhibitors. Their inhibitory activities in vitro were evaluated against PI3Kα and three tumor-derived cell lines (U87-MG, MCF-7, and PC-3). We also tested promising compounds (A4, A6, A10, and B1) for other PI3K class I subtype (PI3Kβ, PI3Kδ, and PI3Kγ) activity. The representative compound A10 exhibited an IC50 value of 0.32 nM against PI3Kα, and demonstrated extraordinary subtype selectivity. Furthermore, compound A10 obviously inhibited proliferation of MCF-7 cell lines, induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells, and arrested G2 phase in a dose-dependent manner. Additionally, compound A10 induced significant tumor regressions in a xenograft mouse model of U87-MG cell line without an obvious sign of toxicity upon 20 mg/kg oral administration. Compound A10 may serve as a PI3Kα-selective inhibitor and provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family.

Patient reported outcome measures in anterior cruciate ligament rupture and reconstruction: The significance of outcome score prediction.

Numerous anterior cruciate ligament (ACL) clinical outcome measures exist. However, the result of one score does not equate to the findings of another even when evaluating the same patient group. To investigate if statistically derived formulae can be used to predict the outcome of one knee scoring system when the result of another is known in patients with ACL rupture before and after reconstruction. Fifty patients with ACL rupture were evaluated using nine clinical outcome measures. These included Tegner Activity Score, Lysholm Knee Score, Cincinnati Knee Score, International Knee Documentation Committee (IKDC) Objective Knee Score, Tapper and Hoover Meniscal Grading Score, IKDC Subjective Knee Score, Knee Outcome Survey - Activities of Daily Living Scale (KOS-ADLS), Short Form-12 Item Health Survey and Knee Injury and Osteoarthritis Outcome Score. Thirty-four patients underwent an ACL reconstruction and were reassessed post-operatively. The mean total of each of the nine outcome scores appreciably differed from each other. Significant correlations and regressions were found between most of the outcome scores and were stronger post-operatively. The strongest correlation was found between Cincinnati and KOS-ADLS (r = 0.91, P < 0.001). The strongest regression formula was also found between Cincinnati and KOS-ADLS (R 2 = 0.84, P < 0.001). The formulae produced from this study can be used to predict the outcome of one knee score when the results of the other are known. These formulae could facilitate the conduct of systematic reviews and meta-analysis in studies relating to ACL injuries by allowing the pooling of substantially more data.

Statewide survey of medically important ticks on white-tailed deer, Odocoileus virginianus Zimmerman, in Alabama, U.S.A.

A statewide survey of the tick fauna found on deer, using harvested deer heads as the sample unit, was conducted during the Alabama hunting seasons of 2019-2020 and 2020-2021. Four species of ticks: Ixodes scapularis (n= 936, % of catch 69.1%), Amblyomma americanum (315, 23.2%), Dermacentor albipictus (97, 7.1%), and Amblyomma maculatum (6, 0.4%) were taken from 151 deer heads harvested from 21 deer processing centers (n = 4-17 heads/processor). A total of 87.7% (prevalence) of deer heads had one or more ticks. We used two standard numerical descriptors of tick numbers, abundance, and relative abundance. No significant stepwise regressions (p > 0.05) were found between tick abundance (all ticks, I. scapularis, A. americanum) and the predictor variables of latitude, deer density, season, and year. In addition, the correlation between the abundance of I. scapularis and A. americanum was not significant (p > 0.5). In contrast, the relative abundance of both I. scapularis and A. americanum showed a significant (P < 0.05) relationship with latitude, with the relative abundance of I. scapularis increasing on deer with increased latitude and A. americanum showing the opposite pattern.