bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the pro-survival potential of apoptotic bodies derived from 2D- and 3D- cultured adipose stem cells in ischaemic flaps
Authors: Yu Gaoxiang , Ding Jian , Yang Ningning , Ge Lu , Chen Nuo , Zhang Xuzi , Wang Qiuchen , Liu Xian , Zhang Xuanlong , Jiang Xiaoqiong , Geng Yibo , Zhang Chenxi , Pan Jiadong , Wang Xiangyang , Gao Weiyang , Li Zhijie , Zhang Hongyu , Ni Wenfei , Xiao Jian , Zhou Kailiang , Yang Liangliang
Published: June 2024

In the realm of large-area trauma flap transplantation, averting ischaemic necrosis emerges as a pivotal concern. Several key mechanisms, including the promotion of angiogenesis, the inhibition of oxidative stress, the suppression of cell death, and the mitigation of inflammation, are crucial for enhancing skin flap survival. Apoptotic bodies (ABs), arising from cell apoptosis, have recently emerged as significant contributors to these functions. This study engineered three-dimensional (3D)-ABs using tissue-like mouse adipose-derived stem cells (mADSCs) cultured in a 3D environment to compare their superior biological effects against 2D-ABs in bolstering skin flap survival. The findings reveal that 3D-ABs (85.74 ± 4.51) % outperform 2D-ABs (76.48 ± 5.04) % in enhancing the survival rate of ischaemic skin flaps (60.45 ± 8.95) % (all p < 0.05). Mechanistically, they stimulated angiogenesis, mitigated oxidative stress, suppressed apoptosis, and facilitated the transition of macrophages from M1 to M2 polarization (all p < 0.05). A comparative analysis of microRNA (miRNA) profiles in 3D- and 2D-ABs identified several specific miRNAs (miR-423-5p-up, miR30b-5p-down, etc.) with pertinent roles. In summary, ABs derived from mADSCs cultured in a 3D spheroid-like arrangement exhibit heightened biological activity compared to those from 2D-cultured mADSCs and are more effective in promoting ischaemic skin flap survival. These effects are attributed to their influence on specific miRNAs.
The impact of different imputation methods on estimates and model performance: an example using a risk prediction model for premature mortality
Authors: Hurst Mackenzie , O’Neill Meghan , Pagalan Lief , Diemert Lori M. , Rosella Laura C.
Published: June 2024

Objective

To compare how different imputation methods affect the estimates and performance of a prediction model for premature mortality.

Study Design and Setting

Sex-specific Weibull accelerated failure time survival models were run on four separate datasets using complete case, mode, single and multiple imputation to impute missing values. Six performance measures were compared to access predictive accuracy (Nagelkerke R2, integrated brier score), discrimination (Harrell’s c-index, discrimination slope) and calibration (calibration in the large, calibration slope).

Results

The highest proportion of missingness for a single variable was 10.86% for the female model and 8.24% for the male model. Comparing the performance measures for complete case, mode, single and multiple imputation: the Nagelkerke R2 values for the female model was 0.1084, 0.1116, 0.1120 and 0.111–0.1120 with the male model exhibited similar variation of 0.1050, 0.1078, 0.1078 and 0.1078–0.1081. Harrell’s c-index also demonstrated small variation with values of 0.8666, 0.8719, 0.8719 and 0.8711–0.8719 for the female model and 0.8549, 0.8548, 0.8550 and 0.8550–0.8553 for the male model.

Conclusion

In the scenarios examined in this study, mode imputation performed well when using a population health survey compared to single and multiple imputation when predictive performance measures is the main model goal. To generate unbiased hazard ratios, multiple imputation methods were superior. This study shows the need to consider the best imputation approach for a predictive model development given the conditions of missing data and the goals of the analysis.
Self-reported decreases in the purchases of selected unhealthy foods resulting from the implementation of warning labels in Mexican youth and adult population
Authors: Contreras-Manzano Alejandra , White Christine M. , Nieto Claudia , Quevedo Kathia L. , Vargas-Meza Jorge , Hammond David , Thrasher James F. , Barquera Simón , Jáuregui Alejandra
Published: June 2024

Background

Front-of-package nutritional warning labels (WLs) are designed to facilitate identification and selection of healthier food choices. We assessed self-reported changes in purchasing different types of unhealthy foods due to WLs in Mexico and the association between the self-reported reductions in purchases of sugary beverages and intake of water and sugar-sweetened beverages.

Methods

Data came from 14 to 17 year old youth (n = 1,696) and adults ≥ 18 (n = 7,775) who participated in the Mexican arm of the 2020–2021 International Food Policy Study, an annual repeat cross-sectional online survey. Participants self-reported whether the WLs had influenced them to purchase less of each of nine unhealthy food categories due to WLs. Among adults, a 23-item Beverage Frequency Questionnaire was used derive past 7-day intake of water and sugary beverages analyzed to determine the relationship between self-reported reductions in purchasing sugary drinks due to the WLs. Multilevel mixed-effects logistic regression models were fitted to estimate the percentage of participants who self-reported reducing purchases within each food group, and overall. Sociodemographic characteristics associated with this reduction were investigated as well.

Results

Overall, 44.8% of adults and 38.7% of youth reported buying less of unhealthy food categories due to the implementation of WL, with the largest proportion reporting decreased purchases of cola, regular and diet soda. A greater impact of WLs on the reported purchase of unhealthy foods was observed among the following socio-demographic characteristics: females, individuals who self-identified as indigenous, those who were overweight, individuals with lower educational levels, those with higher nutrition knowledge, households with children, and those with a significant role in household food purchases. In addition, adults who reported higher water intake and lower consumption of sugary beverages were more likely to report reduced purchases of sugary drinks due to the WLs. Adults who reported greater water intake and lower sugary beverages intake were significantly more likely to report buying fewer sugary drinks due to the WLs.

Conclusion

Our findings suggest that implementation of WLs has reduced perceived purchases of unhealthy foods in Mexico. These results underscore the potential positive impact of the labeling policy particularly in subpopulations with lower levels of education and among indigenous adults.
New evidence for a role of DANCR in cancers: a comprehensive review
Authors: Yuan Rong , Xu Zhao-jun , Zhang Sheng-kang , Cao Xian-ya , Dai Ai-guo , Song Lan
Published: June 2024

Cancer remains a leading cause of mortality and poses a substantial threat to public health. Studies have revealed that Long noncoding RNA DANCR is a cytoplasmic lncRNA whose aberrant expression plays a pivotal role in various cancer types. Within tumour biology, DANCR exerts regulatory control over crucial processes such as proliferation, invasion, metastasis, angiogenesis, inflammatory responses, cellular energy metabolism reprogramming, and apoptosis. By acting as a competitive endogenous RNA for miRNAs and by interacting with proteins and mRNAs at the molecular level, DANCR contributes significantly to cancer progression. Elevated DANCR levels have also been linked to heightened resistance to anticancer drugs. Moreover, the detection of circulating DANCR holds promise as a valuable biomarker for aiding in the clinical differentiation of different cancer types. This article offers a comprehensive review and elucidation of the primary functions and molecular mechanisms through which DANCR influences tumours.
Potential long-term, global effects of enhancing the domestic terrestrial carbon sink in the United States through no-till and cover cropping
Authors: Weber Maridee , Wise Marshall , Lamers Patrick , Wang Yong , Avery Greg , Morris Kendalynn A. , Edmonds Jae
Published: June 2024

Background

Achieving a net zero greenhouse gas United States (US) economy is likely to require both deep sectoral mitigation and additional carbon dioxide removals to offset hard-to-abate emissions. Enhancing the terrestrial carbon sink, through practices such as the adoption of no-till and cover cropping agricultural management, could provide a portion of these required offsets. Changing domestic agricultural practices to optimize carbon content, however, might reduce or shift US agricultural commodity outputs and exports, with potential implications on respective global markets and land use patterns. Here, we use an integrated energy-economy-land-climate model to comprehensively assess the global land, trade, and emissions impacts of an adoption of domestic no-till farming and cover cropping practices based on carbon pricing.

Results

We find that the adoption of these practices varies depending on which aspects of terrestrial carbon are valued. Valuation of all terrestrial carbon resulted in afforestation at the expense of domestic agricultural production. In contrast, a policy valuing soil carbon in agricultural systems specifically indicates strong adoption of no-till and cover cropping for key crops.

Conclusions

We conclude that under targeted terrestrial carbon incentives, adoption of no-till and cover cropping practices in the US could increase the terrestrial carbon sink with limited effects on crop availability for food and fodder markets. Future work should consider integrated assessment modeling of non-CO2 greenhouse gas impacts, above ground carbon storage changes, and capital and operating cost considerations.
Association between hyperglycemia and the development of chemotherapy-induced peripheral neuropathy among patients with breast cancer.
Authors: Klahr Miriam Pearl , Faheem Khadija , Raghunathan Rohit R. , Hershman Dawn L. , Accordino Melissa Kate
Published: June 2024

12125

Background: Poorly controlled diabetes is a predictor of chemotherapy induced peripheral neuropathy (CIPN), and hyperglycemia (HG) may mediate CIPN risk. The association between CIPN and HG is not well studied. Our objective was to evaluate the association between HG and CIPN development. Methods: The CONTRoL trial was a phase IIB randomized adaptive sequential selection trial that evaluated cryotherapy vs. compression vs. placebo to prevent CIPN in patients with Stage I-III breast cancer during taxane therapy. Patients completed the Functional Assessment of Cancer Therapy Neurotoxicity (FACT-NTX) survey at baseline, week-12, and week-24. CIPN development was defined as ≥ 5-point increase in FACT-NTX from baseline. We included patients who completed FACT-NTX at baseline and week-12. HG (any glucose ≥ 140 mmol/L) was assessed via chart review of random glucose laboratory results collected from time of taxane initiation through week-24. Patients were divided into two groups based on CIPN development (yes/no). For each group we calculated the proportion of patients with HG, and mean glucose at baseline, week-12 and week-24 with values obtained +/-7 days of specified timeframe; 95% confidence intervals were constructed. Results: Sixty-three patients participated in the CONTRoL study and 59 patients were included in this analysis. All 59 patients had ≥1 recorded glucose value during the 24-week period (n= 410 total values), with a median of 6 values (range 1-12) per patient. When comparing patients who did and did not develop CIPN, 29.4% vs. 20.0% were Black (p=0.72), 41.2% vs. 52.0% were Hispanic/Latino (p=0.69), 17.6% vs. 8.0% had diabetes (p=0.49) and 64.7% vs. 48.0% received docetaxel (p=0.31). There were higher rates of HG, 47.1% vs. 36.0%, in patients who developed CIPN vs. those who did not (p=0.56). Mean glucose was higher in patients who developed CIPN compared to those who did not at all timepoints (Table). Conclusions: In this secondary analysis, we found that almost half of patients with CIPN had HG compared to about a third of patients without CIPN, and that patients with CIPN had higher mean glucose at all timepoints compared to patients without CIPN. Due to the small sample size, differences were not statistically significant, but notable trends were observed. Further research is needed to confirm this finding and evaluate the impact of glucose lowering interventions on preventing the development of CIPN. Clinical trial information: NCT03873272 . [Table: see text]
Pharmacokinetics and biomarker analysis from a phase 1/2 open-label study of the anti-GPC3 T-cell engager SAR444200, in patients with advanced solid tumors.
Authors: Chenard-Poirier Maxime , Almhanna Khaldoun , Lim Darren Wan-Teck , El-Khoueiry Anthony B. , Samol Jens , Ryoo Baek-Yeol , Yong Hong Jung , MENG ROBIN , Abbadessa Giovanni , Masciari Serena , Kefsi Asma , Zhang Yiding , Guillemin-Paveau Helene , Pasquier Benoit , Lepine Lucie , Dumbrava Ecaterina Elena
Published: June 2024

2579

Background: SAR444200 is a novel NANOBODY T cell engager that simultaneously binds TCRαβ and glypican-3 (GPC3) to co-engage T cells with GPC3-expressing tumor cells, resulting in T cell-dependent cellular cytotoxicity. Here we present updated safety, pharmacokinetics (PK) and biomarker data from 6 and 5 dose levels (DL), respectively in patients with advanced solid tumors in the dose escalation cohort (Part 1A) from the first-in-human Phase 1/2 trial (NCT05450562). Methods: This ongoing Phase 1/2 trial evaluated open label, intravenously administered SAR444200 (every week with lead-in doses) at DL1 (3 mg), DL1A (1 mg), DL2A (2.5 mg), DL3A (4.5 mg), DL4A (18 mg), and DL5A (36 mg) in adult patients with GPC3+ solid tumors. On study imaging was performed every 9 weeks after the date of first infusion of SAR444200. Whole blood samples were collected to assess the plasma concentrations of SAR444200 and for biomarker analysis. PK analysis was performed with electrochemiluminescence-based total PK assay using Meso Scale Discovery platform. Anti-drug antibody (ADA) monitoring was performed using a PandA assay. Results: As of 19 January 2024, a total of 24 patients with GPC3+ solid tumors received SAR444200, 4 patients per DL (DL1, DL1A, DL2A, DL3A, DL4A, DL5A). Most of the patients (17 patients, 71%) had hepatocellular carcinoma. No dose-limiting toxicities were observed. Twenty-two patients (92%) reported treatment-related adverse events (TRAEs) of any grade, including three patients with a serious TRAE (2 events with hospitalization prolongation for a Grade 1 and 2 cytokine release syndrome [CRS] that recovered completely without and with Tocilizumab, respectively, 1 event with pneumonitis Grade 3). All CRS (19 patients, 79%) and infusion-related reaction (7 patients, 29%) were Grade 1 or 2. Cmax was observed at the end or shortly after completion of infusion. The maximum ADA titer, though high, stabilized despite the target dose increased from Cycle 2. Biomarker analysis showed an increase of interleukin-6 and interferon gamma during lead-in doses, supporting CRS. Cytokines declined after Cycle 1. Among 14 HCC patients with baseline alpha-fatal protein (AFP) higher than 20 ng/ml, 4 (29%) had at least a 20% AFP decrease on treatment. Two patients (both with HCC) have been on study drug for more than 6 months. Conclusions: These results suggest that SAR444200 is tolerable at the tested dose levels in patients with GPC3+ advanced solid tumors. Dose escalation continues at this time. Clinical trial information: NCT05450562 .
Development of an mRNA therapeutic vaccine for virally driven Merkel cell carcinoma.
Authors: Frey Alexander , Perry Curtis , Olino Kelly , Ishizuka Jeffrey Joseph
Published: June 2024

2637

Background: Merkel Cell Carcinoma (MCC) is a neuroendocrine skin cancer associated with integration of a truncated form of Merkel Cell Polyomavirus Large T Antigen (LTA) in most U.S. cases. LTA is a robust antigen and its expression is required for proliferation of MCC, rendering it an ideal target for an mRNA therapeutic vaccine approach. Methods: B16-F10 murine melanoma cells that express the truncated LTA oncoprotein were generated for use as an in vivoMCC model. In vitro transcription was used to create an optimized mRNA coding for the LTA and was encapsulated in lipid nanoparticles for intramuscular injection. LTA expressing tumor cells were injected subcutaneously in C57BL/6 mice and treated with LTA mRNA or placebo +/- anti-PD1 antibodies. Tumor growth and survival were tracked, and flow cytometry of ex-vivo tumor samples was used to characterize immune infiltration. Separate mice were treated with a three-dose series of LTA mRNA or placebo 60 days prior to tumor cell injection, and tumor growth and survival were measured. MCC patient PBMCs were collected and used as a model for human in vitro vaccination. Monocyte derived dendritic cells were transfected with LTA mRNA or placebo and used to stimulate the remainder of the PBMC pool every seven days. LTA specific T cell proportion, activation markers, cytokine release, and MCC specific tumor cell killing were measured. Results: Treatment with LTA mRNA suppressed tumor growth compared to placebo (day 21 mean volume 47.28 mm3 vs. 575.12mm3 P<.001) and prolonged median survival (46 vs. 24 days P<.001). Combination treatment with anti-PD1 resulted in 100% tumor regression compared to 50% with anti-PD1 only (median survival 117 days) and 0% with placebo (median survival 28.5 days). Flow cytometry of ex vivotumors from LTA mRNA treated mice revealed increased immune infiltration (mean CD45+ 11.56% vs. 7.81% P=.037) with an increased proportion of CD3+ cells (mean 69.74% vs. 57.36% P=.0013) and CD8+ cells with increased cytotoxic markers (MFI GZMB 26785 vs. 13607 P=.0026). Prophylactic vaccination with LTA mRNA resulted in 80% tumor rejection vs. 0% with placebo (median survival undefined vs. 31.5 days P<.0001). Furthermore, in the prophylactic vaccination group there were no detectable tumors until day 60 following tumor challenge. In vitro vaccination of patient PBMCs resulted in expansion of LTA tetramer specific CD8+ T cells by day 10 (0.3% vs. 0.077%). Exposure of treated cells to antigen loaded DCs resulted in increased IFNg release by day 10 (21.78ng/mL vs. 5.35ng/mL P<.0001) and increased specific MCC tumor cell killing on day 14 (mean tumor death 9.14% vs. 4.18% P=.0001). Conclusions: Therapeutic vaccination with LTA targeting mRNA suppresses tumor growth and prolongs survival in vivo by increasing infiltration of cytotoxic immune populations. In vitrohuman vaccination increases the proportion LTA specific CD8+ T cells, IFNg release, and specific killing of MCC cells.
Phase 1 study of LB1410, a bivalent TIM-3/PD-1 bispecific antibody, in patients with advanced solid tumors.
Authors: Liu Jiajian , Zhou Caicun , Li Wei
Published: June 2024

2639

Background: LB1410 is a recombinant humanized anti-PD-1/TIM-3 bispecific antibody (BsAb) developed by L&L Biopharma Co., Ltd, which blocks the immune checkpoint PD-1 and TIM-3-mediated immunosuppressive signal pathways, and showed better T/DC cell activity and in vivo anti-tumor efficacy compared to TIM-3 and PD-1 antibody combination in preclinical studies. Here we report the results of the first-in-human, multicenter, open-label, phase I trial of LB1410 monotherapy in pts with advanced solid tumors ( Keyplus-001 ). Methods: Eligible pts were ≥ 18 yr old with ECOG PS 0-1 and previous treatment. Dose escalation cohorts ranged from 0.001 mg/kg to 20 mg/kg IV Q2W: 0.001mg/kg-1mg/kg in an accelerated titration design, and 3 mg/kg-20 mg/kg using traditional 3+3 design. The primary objective is safety, including dose-limiting toxicities (DLTs). Secondary/exploratory objectives include efficacy, pharmacokinetics (PK), and immunogenicity. Data cutoffs were January 5, 2024 for safety, and January 25, 2024 for efficacy. Results: In total, 52 pts received LB1410 from 0.001 mg/kg to 20 mg/kg as of Jan 5, 2024, median age 58 yr, 69% male. All of patients enrolled had multiple organ metastases or multiple metastases in a single organ, and were heavily treated with anti-tumor treatment, 36/52 (69.2%) were resistant to or refractory to PD-1/PD-L1 inhibitors, and 16/52 (30.8%) were MSS CRC. Treatment related AEs (TRAEs) occurred in 65.4% of pts. The most common TRAE was anemia (19.2%). 2 patients developed Gr3 hypokalemia. There were no DLTs. Tumor response evaluation were available in 40 pts: 14 had stable disease, 25 had progression, and 1 was not evaluable. Target lesion shrinkage was observed in 9 pts, including one patient's sum of target lesion reduced by 48.7% from baseline. Of 14 pts who had stable disease, there were 2 pts with stable disease lasting for more than 6 months. PK was generally dose proportional within 1 mg/kg~15 mg/kg, with t1/2 ~4.12 days in 10 mg/kg, and t1/2 ~4.77 days in 15 mg/kg. Of the 22 subjects tested for ADA, only one produced ADA for LB1410, the positive rate was 4.5%. Antidrug antibodies had limited impact on PK. As of Jan 5, 2024, 39 pts remained on the study; updated data will be presented. Conclusions: LB1410 has manageable safety and shows preliminary efficacy. Additional dose and efficacy expansion study is ongoing in immunotherapy-naive pts with MSS CRC and pts who are resistant to immunotherapy. Clinical trial information: NCT05357651 .
Primary analysis of a phase 1/2 study of LM-101: An anti-SIRPα antibody as a single agent in patients with advanced malignancies.
Authors: Xia Yi , Zhou Fuling , Kong Liang , Fei Da , Bai Tian , Qin Xia , Fang Xiaojie , Ji Dongmei , Cai Qingqing
Published: June 2024

2640

Background: LM-101 is a humanized monoclonal antibody which binds to both V1 and V2 isoforms of SIRPα that expressed on macrophages and dendritic cells and enables phagocytosis of tumor cells. LM-101 has shown optimal pre-clinical safety profiles and promising anti-tumor activity in animal models. Here we report the primary analysis of the single agent dose escalation results of a phase 1/2 study (NCT05615974). Methods: This is an open-label, phase 1/2, first-in-human, multicenter dose escalation study with dose expansion evaluating safety and clinical activity of LM-101 as a single agent in patients with advanced malignancies. Eligible patients were aged ≥ 18 years with advanced solid tumors or relapsed/refractory lymphoma who had progressed on standard therapy, or intolerable to the available standard therapy, or had no available standard therapy for treatment. In the dose escalation part, enrolled patients were administered with LM-101 intravenously every three weeks at dose levels of 3 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, and 40 mg/kg as per traditional 3+3 design. The objectives for this dose escalation part included safety and clinical activity as per RECIST v1.1 criteria or Lugano 2014 criteria. Results: As of January 24, 2024, 17 patients were enrolled in the single agent dose escalation part. No DLT was observed at all dose levels and MTD for single agent was not reached. The most frequent adverse event (AE) related to the study drug was lymphocyte counts decreased. Two patients experienced grade ≥ 3 AEs which were related to LM-101. Out of 16 patients from single agent dose-escalation groups who had at least one time tumor assessment post treatment, one patient achieved complete response (CR), one patient achieved partial response (PR) and five patients achieved stable disease (SD). Conclusions: LM-101 monotherapy showed excellent safety profile and promising anti-tumor activity in patients with advanced malignancies. Further investigation of LM-101 as a single agent and in combination with other anti-tumor agents are ongoing. Clinical trial information: NCT05615974 .
The tumor immune microenvironment features and their prognostic value in rectal and sigmoid colon signet-ring cell carcinoma.
Authors: An Yang , Su Lan , Lin Guole , Chen Han , Liu Yuxin , Zhou Jiaolin
Published: June 2024

3544

Background: Signet-ring cell carcinoma (SRCC) of the rectum and sigmoid colon is a rare and highly malignant challenge in clinical practice. Although high PD-1+CD8+ tumor-infiltrating lymphocyte (TIL) infiltration has been reported as a positive prognostic factor in gastric cancer, pancreatic cancer, etc., its role in colorectal SRCC remains unclear. This study aims to explore the immune landscape of colorectal SRCC and its prognostic implications. Methods: The study included 34 patients with stage II-IV SRCC of the rectum and sigmoid colon. The immune contextures of tumor tissues were characterized using multiplex immunofluorescence assays and compared with a cohort of 57 cases of stage II-IV AC. The ratio density and spatial distribution of CD3+, CD8+, PD-1+, PD-L1+ cells, M1/M2 macrophages, and NK cells were quantitively analyzed in both parenchymal (p) and interstitial (i) regions. Characteristics of immune cell infiltration and their prognostic value for long-term survival were investigated in SRCC cases. Results: Compared to AC, SRCC exhibited significantly higher infiltration of CD8+ and CD3+ iTILs in the interstitial region (P=0.00024; P=0.00321, respectively) and elevated CD8+ pTILs infiltration in tumor parenchyma (P=0.041). Conversely, parenchymal infiltration of TILs co-expressing PD-1 was significantly lower in SRCC than AC (PD-1+CD8+ pTILs: P=0.00035; PD-1+CD3+ pTILs: P=5.0e-05). SRCC showed significantly lower infiltration of M1 macrophages in both parenchyma and interstitium (P=0.0035; P=5.4e-09, respectively), lower interstitial infiltration of M2 macrophages (P=1.5e-05), and a borderline lower parenchymal infiltration of M2 macrophages (P=0.0522), compared to AC. Additionally, patients with high parenchymal or interstitial infiltration of PD-1+CD8+ TILs exhibited significantly longer DFS (P=0.00024; P=0.0041, respectively) and OS (P=0.011; P=0.0044, respectively) than those with low infiltration. Multivariate analysis indicated that the level of PD-1+CD8+ pTILs infiltration is an independent prognostic factor for DFS, being independent of CEA levels and TNM stage (P = 0.018; P = 0.02, respectively). Among patients with normal CEA level or of stage II-III, high level of PD-1+CD8+ pTILs infiltration was still associated with significantly improved DFS (P<0.0001; P=0.00018, respectively) and OS (P=0.00021; P<0.0001, respectively). Conclusions: SRCC of rectum and sigmoid colon exhibits distinct immune profiles compared to conventional AC, characterized by higher infiltration of CD8+ and CD3+ TILs, but lower infiltration of PD-1+CD8+ TILs. The unique immune landscape in SRCC, particularly the level of PD-1+CD8+ TILs infiltration and its positive predictive value for DFS and OS, provides new perspectives for immune-based stratification and therapeutic strategies for this clinically significant cancer subtype.
A phase 2 study evaluating response and biomarkers in patients with microsatellite stable (MSS) advanced colorectal cancer (CRC) treated with nivolumab/relatlimab.
Authors: Christenson Eric , Durham Jennifer N. , Brancati Madelena , Davis Bruning Heather , Petrie Susan , Wang Hao , Lu Jiayun , Bever Katherine M. , Laheru Dan , De Jesus-Acosta Ana , Donehower Ross C. , Pishvaian Michael J. , Azad Nilofer Saba , Zhu Qingfeng , Llosa Nicolas Jose , Housseau Franck , Anders Robert , Pardoll Drew M. , Le Dung T.
Published: June 2024

3554

Background: Lymphocyte-activation gene 3 (LAG-3) is an immunosuppressive signal, impairing T effector (Teff) activation. Pre-clinical studies suggest LAG-3 inhibition promotes anti-tumor immunity by enhancing Teff function. Correlative studies linked increased LAG-3 levels with reduced overall survival (OS) in CRC. These data prompted optimism that combined LAG-3/PD-1 inhibition might promote anti-tumor responses in MSS CRC. Methods: We conducted a phase 2 study of nivolumab (Nivo) (aPD1)/relatlimab (Rela) (aLAG3) in patients with previously treated advanced MSS CRC. This study enrolled patients onto 1 of 3 arms. Arms A and B used a Composite PD-L1 and acellular Mucin (CPM) score to define patients as CPM(+) in Arm A (CPM≥ 15%) and CPM(-) in Arm B (CPM< 15%). Patients in Arm A and B received Nivo 480mg/Rela 160mg IV q4 weeks. Arm C enrolled patients without biomarker selection who received Nivo 480mg/Rela 960mg or Rela 480mg/Nivo 480mg. The primary endpoint was objective response, and each arm was powered to detect an objective response rate (ORR) of ≥20%. Results: Fifty nine evaluable patients were enrolled (Arm A: 12, Arm B: 15, Arm C: 32). Patient characteristics and responses are outlined. Treatment was well tolerated with no new safety signals over aPD1 alone. Three (5%) patients achieved a partial response (PR), 6 (10%) stable disease (SD), and 50 with progression of disease (PD) as best response. The median progression-free survival was (Arm A: 2.2 mo., Arm B: 2.8 mo., Arm C: 2.6 mo.) while median OS was (Arm A: 4.3 mo., Arm B: 14.2 mo., Arm C: 12.4 mo.). In N=6 patients with lung-only metastases, 2 (33%) experienced a PR, and 1 (17%) a SD, for a clinical benefit rate of 50%. The trial incorporated translational correlates. We will report mass cytometry on PBMCs, RNAseq on baseline biopsies, and imaging mass cytometry on pre- and on-treatment biopsies. Conclusions: This combination did not meet the primary endpoint of 20% ORR for any of the 3 cohorts, but there was intriguing possible activity in patients with lung only metastases, consistent with emerging data. Clinical trial information: NCT03642067 .
Safety in the use of granulocyte-colony stimulating factor during concurrent chemotherapy and thoracic radiotherapy in patients with small-cell lung cancer: A meta-analysis.
Authors: Zarpelão Fabíola Furtuoso , Barbosa Larissa Irigoyen Teixeira , Sousa Jhefferson da Silva , Napoleão Luísa , De Souza Abner Lucas , Vilbert Maysa
Published: June 2024

e20124

Background: There is an ongoing debate about whether patients with small cell lung cancer (SCLC) undergoing concurrent chemoradiotherapy should receive granulocyte-colony stimulating factor (G-CSF). The main concern relies on safety issues. Therefore, we performed a systematic review and meta-analysis to assess the safety and efficacy of prophylactic G-CSF use in patients with SCLC receiving concurrent chemoradiotherapy. Methods: We systematically searched the MEDLINE, Cochrane, and EMBASE databases up to December 2023 for studies assessing prophylactic use of G-CSFs versus non-prophylactic use in SCLC undergoing concurrent chemoradiotherapy. We included randomized and non-randomized clinical trials. The main safety outcomes were thrombocytopenia, febrile neutropenia, anemia, and radiotherapy toxicity. We performed statistical analysis using RevMan 5.4.1 and pooled odds ratio (OR) and 95% confidence interval (95%CI) of binary outcomes. We defined a significant threshold as p-value < 0.05. We used I² statistics for heterogeneity, with I² > 25% being defined as high heterogeneity. Results: We included five studies with a total of 774 patients, of whom 322 (42%) received G-CSF prophylactically, and 452 (58%) were in the control group. The majority of patients (97.5%) presented with Limited Stage disease. The minimum follow-up period had a median duration of 16.9 months, while the maximum follow-up extended to a median of 45 months (Table). Patients in the prophylactic group had a significantly lower incidence of neutropenia (OR: 0.34; 95% CI: 0.14-0.85; p = 0.02) than those who did not use G-CSF prophylactically. Radiotherapy toxicity (OR: 0.98; 95% CI: 0.63-1.53; p = 0.93) and severe hematological toxicity (grade III-IV) were similar in both groups. Hematological toxicity included thrombocytopenia (OR: 1.21; 95% CI: 0.32-4.58; p = 0.78), febrile neutropenia (OR: 1.11; 95% CI: 0.29-4.28; p = 0.88), and anemia (OR: 0.51; 95% CI: 0.13-1.97; p = 0.33). Conclusions: Our systematic review and meta-analysis supports the prophylactic use of G-CSF during concurrent chemoradiotherapy for patients with SCLC. Prophylactic G-CSF promoted a significant reduction in the incidence of neutropenia without any hematologic or radiotherapy-related toxicity increase. Incorporating G-CSF prophylaxis into SCLC chemoradiotherapy regimens can be a beneficial strategy for minimizing neutropenic complications without compromising overall treatment safety. [Table: see text]
Phase II study of anlotinib plus durvalumab and chemotherapy as first-line treatment in extensive-stage small cell lung cancer (ES-SCLC): Efficacy and safety analysis.
Authors: Chen Lijuan , Zhao Yanqiu
Published: June 2024

e20131

Background: The combination of PD-L1 Checkpoint inhibitor and chemotherapy has revolutionized the first-line standard of care of ES-SCLC, yet the prognosis still need to be improved. In this phase 2 study, we aimed to enhance the patients benefit by adding anlotinib to durvalumab and chemotherapy, assessing its efficacy and safety. Methods: Eligible treatment naïve ES-SCLC patients, aged 18-75 years, were enrolled. Anlotinib + durvalumab + etoposide + carboplatin or cisplatin was administered for 4-6 cycles, followed by anlotinib and durvalumab maintenance until disease progression or intolerable toxicity. During the treatment, dose reduction of anlotinib was permitted, which could be reduced to 10mg or 8mg if it was intolerable. The primary endpoint is overall objective response rate (ORR), secondary endpoints are PFS and safety. Results: Between December 2020 and June 2022, 22 patients with extensive-stage SCLC were enrolled, including 8 patients (36.4%) with brain metastases and 11 patients (50%) with liver metastases. The median age was (39-73) years, 15 patients were males (68.2%). ORR was 100%, with 27.3% complete response rate (CR). The median PFS of all patients was 8.51months, and the PFS of patients with liver metastasis and brain metastasis were 9.43 months and 8.51 months respectively. The median OS was not reached. The most common grade ≥3 TEAEs ( > 10% incidence) included neutropenia and leukopenia (each 16.7%, 2/22), no new safety signals were observed. No grade 5 AE occurred. Conclusions: Durvalumab plus anlotinib and chemotherapy demonstrated promising PFS, ORR and manageable safety profile for the first-line treatment of ES-SCLC. Clinical trial information: NCT04660097 .
The Iatriki Biblos (Book of Medicine) by Nikolaos Ieropais. Α 17th-century manuscript examined from a medical viewpoint
Authors: Leibaditou Alexandra
Published: June 2024

The “Iatriki Biblos” (“Book of Medicine”) is part of codex no. 46, hosted at the library of the Olympiotissa Monastery in Elassona, Greece. It is a medical manual that includes many diseases in the form of ailment groups, recording their aetiology, signs and symptoms on which diagnosis and the relevant therapy is based. This treatise constitutes a compendium of many Greek, Arab, Italian or French medical authors’ works. We have examined the “Biblos” from a medical viewpoint to find supporting evidence of: a. The scientific rigor of the text and its correlation with any possible theoretical basis regarding the signs and symptoms described. Although the classification system used today is different, it was possible to identify specific diseases based on the recorded signs and symptoms. Special attention was paid to the Greek terminology, because many terms are used to this day, with the same or different meanings.b. The influence of ancient medical authorities and the prevailing medical knowledge of Ieropais’ time.c. The usefulness or otherwise of the listed iamata (medicaments). We studied the active substances of the proposed plants, animal tissues and minerals, with the aim of ascertaining whether they had any positive or negative effect on the described symptoms.We discuss the problematic nature of such an investigation, as many essential details concerning their action as medicaments are absent.In conclusion, the 17th-century Greek doctor Nikolaos Ieropais adhered to the principles of natural philosophy in medicine of his time. His references to western Renaissance doctors of the 16th century add no new knowledge. The proposed therapies have a slight general and rarely a targeted effect.
Experimental study of stem cells transplantation in a model of myocardial ischemia
Authors: Κουτέλα Αντωνέλλα
Published: June 2024

Οι ισχαιμικές μυοκαρδιοπάθειες παραμένουν ένα μέγιστο ιατρικό πρόβλημα παγκοσμίως με υψηλό ποσοστό θνητότητας. Παρά τις πολυάριθμες προσπάθειες ερευνών και τα πολυάριθμα πειραματικά μοντέλα που έχουν αναπτυχθεί στο πέρασμα των ετών, δεν έχει γίνει ακόμα απολύτως κατανοητό το πώς εγκαθίσταται το έμφραγμα του μυοκαρδίου οδηγώντας σε απώλεια μυοκαρδιακού ιστού. Επιπλέον, η αναγέννηση του μυοκαρδίου και η βελτίωση της μυοκαρδιακής δραστηριότητας μετά την ισχαιμία είναι ένα από τα πιο σημαντικά πεδία έρευνας και ενδιαφέροντος στην παγκόσμια ιατρική (και ειδικά την καρδιαγγειακή) κοινότητα. Διαπιστώθηκε η ευεργετική δράση της έγχυσης μεσεγχυματικών βλαστοκυττάρων σε ένα πρωτότυπο πειραματικό μοντέλο με ζωικό πρότυπο τον αρουραίο με χειρουργικά εγκατεστημένη ισχαιμία του μυοκαρδίου. Από κλινική σκοπιά αυτή η μελέτη υποστηρίζει τη χειρουργική εναπόθεση μεσεγχυματικών βλαστοκυττάρων στην ισχαιμική περιοχή κατά τη διάρκεια αορτοστεφανιαίας παράκαμψης. Η αναγέννηση του μυοκαρδίου και η βελτίωση της μυοκαρδιακής δραστηριότητας μετά την ισχαιμία είναι από τα μέγιστα πεδία ενδιαφέροντος στην καρδιαγγειακή έρευνα. Αναπτύχθηκε ένα νέο πειραματικό μοντέλο με χρήση αρουραίων και χρησιμοποιήθηκε για να αξιολογηθεί η δράση των μεσεγχυματικών βλαστοκυττάρων στη μυοκαρδιακή ισχαιμία με τη χρήση σπινθηρογραφήματος SPECT-CT και ανοσοϊστοχημείας. Σε ανοιχτή θωρακοτομή υποβλήθηκαν 40 θηλυκοί ενήλικες αρουραίοι εκ των οποίων οι 30 υπέστησαν ισχαιμική περίδεση του πρόσθιου κατιόντα κλάδου της στεφανιαίας αρτηρίας ενώ οι 10 όχι. Η βιωσιμότητα του μυοκαρδίου αξιολογήθηκε με σπινθηρογράφημα SPECT-CT επτά ημέρες πριν τη χειρουργική περίδεση καθώς και επτά και δεκατέσσερις ημέρες μετεγχειρητικά. Την ημέρα μηδέν (ημέρα χειρουργείου) τα 15 ζώα έλαβαν μεσεγχυματικά βλαστοκύτταρα με άμεση έγχυση διεγχειρητικά στο ισχαιμικό πεδίο που είχε εγκατασταθεί στην αριστερή κοιλία της καρδιάς. Η ανάλυση του σπινθηρογραφήματος SPECT-CT έδειξε μειωμένη δραστηριότητα των μυοκαρδιακών κυττάρων στην αριστερή κοιλία μια εβδομάδα μετά την πρόκληση ισχαιμίας. Η αναγέννηση του ισχαιμικού μυοκαρδίου δεκαπέντε ημέρες μετά το χειρουργείο διαπιστώθηκε μόνο στα ζώα που έλαβαν τα βλαστοκύτταρα. Αυτά τα αποτελέσματα επιβεβαιώθηκαν με ιστολογική και ανοσοϊστοχημική ανάλυση με σημαντικά μεγαλύτερη έκφραση των GATA4 και Nkx2.5. Συμπερασματικά η θετική επίδραση της μεταμόσχευσης μεσεγχυματικών βλαστοκυττάρων στο ισχαιμικό μυοκάρδιο καταγράφηκε αδιαμφισβήτητα. Η χρήση σπινθηρογραφήματος SPECT-CT επέτρεψε μια ξεκάθαρη αξιολόγηση τόσο ποιοτική όσο και ποσοτική του ζωντανού μυοκαρδιακού ιστού μετά την πρόκληση ισχαιμίας οδηγώντας σε μια νέα προσέγγιση της έρευνας των καρδιαγγειακών παθήσεων. Από κλινικής πλευράς, η χρήση των μεσεγχυματικών βλαστοκυττάρων μπορεί να είναι ευεργετική όταν συνδυάζεται με τεχνικές επαναιμάτωσης του μυοκαρδίου.
Aronia: superowoc i czarny polski skarb
Authors: Wawer Iwona
Published: June 2024

Superowoc to owoc, który zawiera szczególnie dużo korzystnych dla zdrowia składników odżywczych, w tym antyoksydantów. Ciemne jagody aronii, które mają najwyższą aktywność antyoksydacyjną spośród testowanych owoców, nazywane są superjagodami. Unikalną cechą aronii jest wysoka zawartość antocyjanin, procyjanidyn, tanin i kwasów chlorogenowych. Te biologicznie czynne związki wykazują aktywność przeciwzapalną, przeciwbakteryjną i przeciwwirusową, mogą wspierać rekonwalescentów, którzy przeszli COVID-19, są ważne w profilaktyce oraz stanowią dietetyczne wsparcie leczenia chorób układu krążenia, chorób neurodegeneracyjnych czy cukrzycy. Innowacyjne produkty aroniowe, takie jak sok, syrop, wino, a zwłaszcza suche ekstrakty w kapsułkach, powinny być standaryzowane.
Sala de emergencias: decisiones críticas en los límites de la vida
Authors: Pinto Bustamante Boris Julián , Gómez Córdoba Ana Isabel , Cataño Rodríguez María Paula , Rovira Rodríguez Darys Daniela , Pedraza López Natalia Andrea , Monsalve Serrano Edson Andrés
Published: June 2024

El presente capítulo aborda la complejidad de la toma de decisiones en situaciones críticas, en las cuales es necesario contar con destrezas clínicas y de razonamiento ético y jurídico que permitan la rápida identificación de obligaciones morales y la implementación de conductas que respeten los derechos fundamentales de los pacientes. Decisiones como el inicio y la suspensión de los esfuerzos de reanimación cardiopulmonar, el papel que juegan los documentos de voluntades anticipadas en los procesos de toma de decisiones, la obstinación terapéutica, la omisión de socorro y la revelación del error médico, entre otros, constituyen auténticos desafíos para cualquier equipo de salud. Si bien es imposible eliminar la incertidumbre ética y pronóstica en estos escenarios, la consideración de algunos criterios fundamentales desde la bioética puede contribuir en los procesos de razonamiento moral, así como en la identificación de estos conflictos en narrativas audiovisuales de la cultura popular.
Fast Exact Simulation of the First Passage of a Tempered Stable Subordinator Across a Non-Increasing Function
Authors: González Cázares Jorge Ignacio , Lin Feng , Mijatović Aleksandar
Published: June 2024

We construct a fast exact algorithm for the simulation of the first-passage time, jointly with the undershoot and overshoot, of a tempered stable subordinator over an arbitrary, nonincreasing, absolutely continuous function. We prove that the running time of our algorithm has finite exponential moments and provide bounds on its expected running time, with explicit dependence on the characteristics of the process and the initial value of the function. The expected running time grows most cubically in the stability parameter (as it approaches either 0 or 1) and is linear in the tempering parameter and the initial value of the function. Numerical performance, based on the implementation in the dedicated GitHub repository, exhibits a good agreement with our theoretical bounds. We provide numerical examples to illustrate the performance of our algorithm in Monte Carlo estimation.

Funding: J. I. González Cázares and A. Mijatović are supported by the EPSRC Grant EP/V009478/1 and by The Alan Turing Institute under the EPSRC grant EP/X03870X/1. A. Mijatović is also supported by the EPSRC grant EP/W006227/1. F. Lin is funded by The China Scholarship Council and The University of Warwick PhD scholarship.
Rethinking how you safeguard data
Authors: Grindey Mark
Published: June 2024

The breach of 23andMe has highlighted the vulnerability of a cloud-only approach to data storage. One way that organisations can mitigate similar risks is by implementing on-premises and hybrid cloud solutions. These technologies can play a vital role in safeguarding organisational data, so long as you approach them in the right way.
The AI vs AI showdown
Authors: Horswell Simon
Published: June 2024

As we struggle to understand the real impact that AI is going to have on society, business and individual lives, we also need to work to put in place safeguards to shield us from malicious use of the technology. And while policies, laws and regulations all have their part to play, AI itself could be the answer to keeping AI in check.
Going Underground
Authors: Smith David
Published: June 2024

We take an exclusive look at the development of one of Liebherr’s most specialised new vehicles – the R 390 Tunnel. It’s a crawler excavator that’s compact enough to fit into confined spaces, while delivering the necessary power and protection for operators – and offering bespoke setups for each client
Are Steroids Always Necessary in Multisystem Inflammatory Syndrome in Children (MIS-C)?
Authors: Camporesi Anna , Zoia Elena , Raso Irene , Ferrario Stefania , Diotto Veronica , Izzo Francesca , Garbin Massimo , Melloni Giorgio E.M.
Published: June 2024

Multisystem Inflammatory Syndrome in Children (MIS-C) treatment is still under debate and involves Intravenous Immunoglobulins (IVIG) and/or steroids. We retrospectively analysed data from the patients admitted to Our Institution during the year 2020 to investigate whether prompt IVIG treatment conditions cardiac dysfunction and need for support and if addition of steroids in different doses correlates with outcomes.
Days of fever, time between fever appearance and IVIG treatment, left ventricular ejection fraction (LVEF%) at admission and Cardiac Function Recovery Time (time between worst LVEF and resume of LVEF >55%) were used as outcomes.
38 patients were admitted with MIS-C. All except one received IVIG; 24 received also different Methylprednisolone dosages. Time to IVIG treatment, adjusted for age and sex, correlated with global duration of fever (Coefficient: 1.2; 95% CI:0.73-1.68) and with Vasoactive Inotropic Score (VIS) (Coefficient: 0.09; 95% CI 0.02-0.15), with pericardial effusion (Coefficient: 2.37; 95% CI: 0.45-4.2). Global duration of fever was associated with time to IVIG (Coefficient: 0.8; 95% CI :0.49-1.13) and positive Covid-19 swab (Coefficient: 1.71; 95% CI 0.21-3.22). Cardiac Function Recovery Time did not show differences with different steroid dose regimens. High-dose steroids did not show any benefit in our cohort.
UMA ANÁLISE DO PECADO EM SOREN KIERKEGAARD
Authors: Bisneto Pedro João
Published: June 2024

A modernidade, enquanto fomentadora de um viés crítico e coerente aos preceitos religiosos, fundamenta bem o posicionamento de vários autores no que se refere às discussões que retornam às bases teóricas da fé cristã. Assim, conceitos basilares à fé passam a ser negados e entendidos como limitados diante de uma perspectiva filosófica. Contudo, autores como Soren Kierkegaard se colocam como propulsores dessas discussões, sem perder de vista nem a fé cristã nem as bases da filosofia, estabelecendo o diálogo entre essas duas “contradições”, de modo que ele decide por conciliar suas duas posições. Dito isso, tomaremos, como ponto de partida deste trabalho, a formulação de uma análise filosófica do conceito de pecado, circundado na obra de Kierkegaard, especificamente em seu livro O Conceito de Angústia, analisando como, para o autor dinamarquês, o pecado se torna fundamental para dissecar perspectivas como liberdade, hereditariedade, queda e subjetividade, estando, todos esses conceitos, ligados ao caráter paradoxal da fé cristã.
CONDUTAS DO PROFESSOR PRECEPTOR NO PROGRAMA DE INICIAÇÃO À DOCÊNCIA, POSSÍVEIS INFLUÊNCIAS E IMPACTOS NA FUTURA ATUAÇÃO PROFISSIONAL DOS BOLSISTAS
Authors: SANTOS JASSILENE
Published: June 2024

Este relato de experiência foi produzido por uma estudante bolsista, do curso de Licenciatura de Educação Física da Universidade Estadual de Feira de Santana (UEFS). O material foi elaborado durante a participação no Programa Residência Pedagógica, vinculado à Universidade, no edital 001/PRP/UEFS/2022, e deu enfoque às observações da bolsista a respeito do profissional professor preceptor, que acompanha os bolsistas do Programa na escola campo. Neste relato, estão elencadas considerações a respeito das singularidades dos trabalhos pedagógicos, a  importância  do professor  preceptor, as experiências vivenciadas na escola campo sob a orientação desse profissional, e as apreensões e aprendizagens da bolsista residente, através da análise da conduta da professora preceptora que a acompanhou no Programa. Dentre as observações de relações possibilitadas no contexto do Programa, foi evidenciada a imprescindível conduta apropriada do professor preceptor atuante na escola campo, durante a vivência no Programa.