Comparison of Alternative Protein Hydrogels for Delivering Myricetin: Interaction Mechanism and Stability Evaluation.

Food protein carriers from different sources might have distinct stabilizing and enhancing effects on the same small molecule. To elucidate the molecular mechanism, five different sourced proteins including soy protein isolates (SPIs), whey protein isolates (WPIs), edible dock protein (EDP), Tenebrio molitor protein (TMP), and yeast protein (YP) were used to prepare protein hydrogels for delivering myricetin (Myr). The results suggested that the loading capacity order of Myr in different protein hydrogels was EDP (11.5%) > WPI (9.3%) > TMP (8.9%) > YP (8.0%) > SPI (7.6%), which was consistent with the sequence of binding affinity between Myr and different proteins. Among five protein hydrogels, EDP had an optimum loading ability since it possessed the highest hydrophobic amino acid content (45.52%) and thus provided a broad hydrophobic cavity for loading Myr. In addition, these protein-Myr composite hydrogels displayed the core-shell structure, wherein hydrogen bonding and hydrophobic interaction were the primary binding forces between proteins and Myr. Moreover, the thermal stability, storage stability, and sustained-release properties of Myr were significantly enhanced via these protein delivery systems. These findings can provide scientific guidance for deeper utilization of food alternative protein sources.

The Status and Influencing Factors of COVID-19 Vaccination for 3-7-Year-Old Children Born Prematurely.

Objective: To explore the status and influencing factors of COVID-19 vaccination for 3-7-year-old children born prematurely. Methods: A questionnaire was administered to parents of preterm infants born between 1 January 2016 and 31 December 2019 in Gansu Maternal and Child Health Hospital using convenience sampling. Results: It was found that 96.81% of 282 parents had known about COVID-19 vaccines and acquired COVID-19- and vaccine-related knowledge primarily through WeChat (104/282, 36.88%) and TikTok (91/282, 32.27%). Most parents of the group whose children were vaccinated with a COVID-19 vaccine believed that this approach was effective in preventing COVID-19 (49.75%), whereas most parents of the group whose children were not vaccinated were worried about the adverse reaction and safety of the vaccine (45.88%). According to the regression analysis, the risk factors of children born prematurely receiving a COVID-19 vaccine were no vaccination against COVID-19 in the mothers (odds ratio [OR]=48.489, 95% CI: 6.524-360.406) and in younger children (OR=12.157, 95% CI: 6.388-23.139). Previous history of referral (OR=0.229, 95% CI: 0.057-0.920), history of diseases (OR=0.130, 95% CI: 0.034-0.503) and high educational level of guardians (OR=0.142, 95% CI: 0.112-0.557) were protective factors for children born prematurely to receive COVID-19 vaccination. Conclusion: There is a relatively high proportion of children born prematurely receiving COVID-19 vaccination, but some people still have concerns. Publicity in the later stage can be conducted through WeChat, TikTok and other social media platforms, with special attention paid to the populations with lower education levels.

Elevated circulating BMP9 aggravates pulmonary angiogenesis in hepatopulmonary syndrome rats through ALK1-Endoglin-Smad1/5/9 signalling.

BACKGROUND: Bone morphogenetic protein 9 (BMP9) is a hepatokine that plays a pivotal role in the progression of liver diseases. Moreover, an increasing number of studies have shown that BMP9 is associated with hepatopulmonary syndrome (HPS), but its role in HPS is unclear. Here, we evaluated the influence of CBDL on BMP9 expression and investigated potential mechanisms of BMP9 signalling in HPS. METHODS: We profiled the circulating BMP9 levels in common bile duct ligation-induced HPS rat model, and then investigated the effects and mechanisms of HPS rat serum on pulmonary vascular endothelial dysfunction in rat model, as well as in primarily cultured rat pulmonary microvascular endothelial cells. RESULTS: Our data revealed that circulating BMP9 levels were significantly increased in the HPS rats compared to control group. Besides, the elevated BMP9 in HPS rat serum was not only crucial for promoting endothelial cell proliferation and tube formation through the activin receptor-like kinase1 (ALK1)-Endoglin-Smad1/5/9 pathway, but also important for accumulation of monocytes. Treatments with ALK1-Fc or silencing ALK1 expression to inhibit the BMP9 signalling pathway effectively eliminated these effects. In agreement with these observations, increased circulating BMP9 was associated with an increase in lung vessel density and accumulation of pro-angiogenic monocytes in the microvasculature in HPS rats. CONCLUSIONS: This study provided evidence that elevated circulating BMP9, secreted from the liver, promote pulmonary angiogenesis in HPS rats via ALK1-Endoglin-Smad1/5/9 pathway. In addition, BMP9-regulated pathways are also involved in accumulation of pro-angiogenic monocytes in the pulmonary microvasculature in HPS rats.

Amphiregulin, ST2,and REG3α Biomarker Risk Algorithms as Predictors of Non-Relapse Mortality in Patients with Acute GVHD.

Graft-vs-host disease (GVHD) is a major cause of non-relapse mortality (NRM) following allogeneic hematopoietic cell transplant (HCT). Algorithms containing either the GI GVHD biomarker amphiregulin (AREG) or a combination of two GI GVHD biomarkers, (ST2+REG3α) when measured at GVHD diagnosis are validated predictors of NRM risk, but have never been assessed in the same patients using identical statistical methods. We measured serum concentrations of ST2, REG3, and AREG by ELISA at the time of GVHD diagnosis in 715 patients divided by date of transplant into training (2004-2015) and validation (2015-2017) cohorts. The training cohort (n=341) was used to develop algorithms for predicting probability of 12 month NRM that contained all possible combinations of 1-3 biomarkers and a threshold corresponding to the concordance probability was used to stratify patients for risk of NRM. Algorithms were compared to each other based on several metrics including the area under the receiver operating characteristics curve (AUC), proportion of patients correctly classified, sensitivity, and specificity using only the validation cohort (n=374). All algorithms were strong discriminators of 12 month NRM, whether or not patients were systemically treated (n=321). An algorithm containing only ST2+REG3α had the highest AUC (0.757), correctly classified the most patients (75%), and more accurately risk stratified those who developed Minnesota standard risk GVHD and for patients who received post-transplant cyclophosphamide-based prophylaxis. An algorithm containing only AREG more accurately risk stratified patients with Minnesota high risk GVHD. Combining ST2, REG3α, and AREG into a single algorithm did not improve performance.

The MAGIC algorithm probability predicts treatment response and long-term outcomes to second-line therapy for acute GVHD.

The significance of biomarkers at second-line treatment for acute graft-versus-host disease (GVHD) is not well characterized. We analyzed clinical data and serum samples at initiation of second-line systemic treatment of acute GVHD from 167 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC) between 2016 and 2021. Sixty-two patients received ruxolitinib-based therapy while 102 received other systemic agents. In agreement with prospective trials, ruxolitinib resulted in higher day 28 (D28) ORR compared to non-ruxolitinib therapies (55% vs 31%, P=0.003) and patients who received ruxolitinib had significantly lower non-relapse mortality (NRM) than those who received non-ruxolitinib therapies (point estimates at 2-year: 35% vs 61%, p=0.002). Biomarker analyses demonstrated that the benefit from ruxolitinib was observed only in patients with low MAGIC algorithm probabilities (MAPs) at the start of second-line treatment. Among patients with a low MAP, those who received ruxolitinib experienced significantly lower NRM than those who received non-ruxolitinib therapies (point estimates at 2-year: 12% vs 41%, p=0.016). However, patients with a high MAP experienced high NRM regardless of treatment with ruxolitinib or non-ruxolitinib therapies (point estimates at 2-year: 67% vs 80%, p=0.65). A landmark analysis demonstrated that the relationship between D28 response and NRM largely depends on the MAP level at initiation of second-line therapy. In conclusion, the MAP measured at second-line systemic treatment for acute GVHD predicts treatment response and NRM. Outcomes of patients with high MAP are poor, regardless of treatment choice, and ruxolitinib appears to primarily benefit patients with low MAP.

Developmental pleiotropy of SDP1 from seedling to mature stages in B. napus.

Rapeseed, an important oil crop, relies on robust seedling emergence for optimal yields. Seedling emergence in the field is vulnerable to various factors, among which inadequate self-supply of energy is crucial to limiting seedling growth in early stage. SUGAR-DEPENDENT1 (SDP1) initiates triacylglycerol (TAG) degradation, yet its detailed function has not been determined in B. napus. Here, we focused on the effects of plant growth during whole growth stages and energy mobilization during seedling establishment by mutation in BnSDP1. Protein sequence alignment and haplotypic analysis revealed the conservation of SDP1 among species, with a favorable haplotype enhancing oil content. Investigation of agronomic traits indicated bnsdp1 had a minor impact on vegetative growth and no obvious developmental defects when compared with wild type (WT) across growth stages. The seed oil content was improved by 2.0-2.37% in bnsdp1 lines, with slight reductions in silique length and seed number per silique. Furthermore, bnsdp1 resulted in lower seedling emergence, characterized by a shrunken hypocotyl and poor photosynthetic capacity in the early stages. Additionally, impaired seedling growth, especially in yellow seedlings, was not fully rescued in medium supplemented with exogenous sucrose. The limited lipid turnover in bnsdp1 was accompanied by induced amino acid degradation and PPDK-dependent gluconeogenesis pathway. Analysis of the metabolites in cotyledons revealed active amino acid metabolism and suppressed lipid degradation, consistent with the RNA-seq results. Finally, we proposed strategies for applying BnSDP1 in molecular breeding. Our study provides theoretical guidance for understanding trade-off between oil accumulation and seedling energy mobilization in B. napus.

[Clinical and genetic analysis of two pedigrees affected with Carnitine-acylcarnitine translocase deficiency due to variant of SLC25A20 gene].

OBJECTIVE: To analyze the clinical phenotype and genotypes of two children with Carnitine-acylcarnitine translocase deficiency (CACTD). METHODS: Two children diagnosed with CACTD at the Gansu Provincial Maternal and Child Health Care Hospital respectively on January 3 and November 19, 2018 were selected as the study subjects. Trio-whole exome sequencing (trio-WES) was carried out, and candidate variants were validated through Sanger sequencing and pathogenicity analysis. RESULTS: Both children were males and had manifested mainly with hypoglycemia. Trio-WES and Sanger sequencing showed that child 1 had harbored compound heterozygous variants of the SLC25A20 gene, namely c.49G>C (p.Gly17Arg) and c.106-2A>G, which were inherited from his father and mother, respectively. Child 2 had harbored homozygous c.199-10T>G variants of the SLC25A20 gene, which were inherited from both of his parents. Among these, the c.106-2A>G and c.49G>C variants were unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.49G>C (p.Gly17Arg), c.106-2A>G, and c.199-10T>G variants were classified as likely pathogenic (PM2_supporting+PP3+PM3_strong+PP4), pathogenic (PVS1+PM2_supporting+PM5+PP3), and pathogenic (PVS1+PM2_supporting+PP3+PP5), respectively. CONCLUSION: Combined with their clinical phenotype and genetic analysis, both children were diagnosed with CACTD. Above finding has provided a basis for their treatment as well as genetic counseling and prenatal diagnosis for their families.

An inferior vena cava-priority approach in laparoscopic isolated hepatic caudate lobectomy.

PURPOSE: Laparoscopic isolated caudate lobectomy is still a challenging operation for surgeons. The access route of the operation plays a vital role during laparoscopic caudate lobectomy. There are few references regarding this technique. Here, we introduce a preferred inferior vena cava (IVC) approach in laparoscopic caudate lobectomy. METHODS: Twenty-one consecutive patients with caudate hepatic tumours between June 2016 and December 2021 were included in this study. All of them received laparoscopic caudate lobectomy involving an IVC priority approach. The IVC priority approach refers to prioritizing the dissection of the IVC from the liver parenchyma before proceeding with the conventional left or right approach. It emphasizes the importance of the IVC dissection during process. Clinical data, intraoperative parameters and postoperative results were evaluated. Sixteen patients were performed pure IVC priority approach, while 5 patients underwent a combined approach. We subsequently compared the intraoperative and postoperative between the two groups. RESULTS: All 21 patients were treated with laparoscopic technology. The operative time was 190.95 ± 92.65 min. The average estimated blood loss was 251.43 ± 247.45 ml, and four patients needed blood transfusions during the perioperative period. The average duration of hospital stay was 8.43 ± 2.64 (range from 6.0 to 16.0) days. Patients who underwent the pure inferior vena cava (IVC) approach required a shorter hepatic pedicle clamping time (26 vs. 55 min, respectively; P < 0.001) and operation time (150 vs. 380 min, respectively; P = 0.002) than those who underwent the combined approach. Hospitalization (7.0 vs. 9.0 days, respectively; P = 0.006) was shorter in the pure IVC group than in the combined group. CONCLUSIONS: Laparoscopic caudate lobectomy with an IVC priority approach is safe and feasible for patients with caudate hepatic tumours.

The association between circulating fatty acids and stroke in hypertensive patients.

BACKGROUND: Stroke is prevalent in hypertensive population. It has been suggested that unsaturated fatty acids (USFA) have protective effect on stroke. The effect of saturated fatty acids (SFAs) on stroke is still unclear. Therefore, we studied the relationship between circulating fatty acids and acute ischemic stroke (AIS) in hypertensive patients. METHODS: Eighty-nine pairs including 100 men and 78 women matched by sex and age were recruited. Each pair included a hypertensive patient within 48h of AIS onset and a hypertensive patient without stroke. Six circulating fatty acids were methylated before concentration determination which was repeated twice with percent recovery estimated. RESULTS: There were differences in educational level (P = 0.002) and occupation (P < 0.001) between stroke and non-stroke participants. All the 6 fatty acid levels were higher in non-stroke participants (P = 0.017 for palmitoleic acid, 0.001 for palmitic acid, <0.001 for linoleic acid, <0.001 for behenic acid, <0.001 for nervonic acid and 0.002 for lignoceric acid). In logistic regression analysis, AIS was inversely associated with fatty acid levels except for lignoceric acid. After adjustment for education and occupation, the palmitoleic acid and palmitic acid levels were no longer inversely associated with AIS. After further adjustment for systolic blood pressure, smoking, drinking, total cholesterol and triglyceride, the inverse associations of linoleic acid (OR = 0.965, 95%CI = 0.942-0.990, P = 0.005), behenic acid (OR = 0.778, 95%CI = 0.664-0.939, P = 0.009), nervonic acid (OR = 0.323, 95%CI = 0.121-0.860, P = 0.024) with AIS remained significant. CONCLUSIONS: Circulating fatty acids except lignoceric acid were inversely associated with AIS. Both USFAs and SFAs may have beneficial effect on stroke prevention in hypertensive population.

Endophilin A2 controls touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking.

BACKGROUND: Tactile and mechanical pain are crucial to our interaction with the environment, yet the underpinning molecular mechanism is still elusive. Endophilin A2 (EndoA2) is an evolutionarily conserved protein that is documented in the endocytosis pathway. However, the role of EndoA2 in the regulation of mechanical sensitivity and its underlying mechanisms are currently unclear. METHODS: Male and female C57BL/6 mice (8-12 weeks) and male cynomolgus monkeys (7-10 years old) were used in our experiments. Nerve injury-, inflammatory-, and chemotherapy-induced pathological pain models were established for this study. Behavioral tests of touch, mechanical pain, heat pain, and cold pain were performed in mice and nonhuman primates. Western blotting, immunostaining, co-immunoprecipitation, proximity ligation and patch-clamp recordings were performed to gain insight into the mechanisms. RESULTS: The results showed that EndoA2 was primarily distributed in neurofilament-200-positive (NF200+) medium-to-large diameter dorsal root ganglion (DRG) neurons of mice and humans. Loss of EndoA2 in mouse NF200+ DRG neurons selectively impaired the tactile and mechanical allodynia. Furthermore, EndoA2 interacted with the mechanically sensitive ion channel Piezo2 and promoted the membrane trafficking of Piezo2 in DRG neurons. Moreover, as an adaptor protein, EndoA2 also bound to kinesin family member 5B (KIF5B), which was involved in the EndoA2-mediated membrane trafficking process of Piezo2. Loss of EndoA2 in mouse DRG neurons damaged Piezo2-mediated rapidly adapting mechanically activated currents, and re-expression of EndoA2 rescued the MA currents. In addition, interference with EndoA2 also suppressed touch sensitivity and mechanical hypersensitivity in nonhuman primates. CONCLUSIONS: Our data reveal that the KIF5B/EndoA2/Piezo2 complex is essential for Piezo2 trafficking and for sustaining transmission of touch and mechanical hypersensitivity signals. EndoA2 regulates touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking in sensory neurons. Our findings identify a potential new target for the treatment of mechanical pain.

Gilteritinib as Post-Transplant Maintenance for Acute Myeloid Leukemia With Internal Tandem Duplication Mutation of FLT3.

PURPOSE: Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with acute myeloid leukemia (AML) harboring an internal tandem duplication mutation of FLT3 (FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. METHODS: Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. RESULTS: Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). CONCLUSION: Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

Third-party fecal microbiota transplantation for high-risk treatment-naïve acute GVHD of the lower GI tract.

Disruption of the intestinal microbiome is observed with acute graft-versus-host disease (GVHD) of the lower gastrointestinal (LGI) tract and fecal microbiota transplantation (FMT) has successfully cured steroid-refractory cases. In this open-label, single-arm, pilot study (NCT04139577), third-party, single donor FMT was administered in combination with systemic corticosteroids to participants with high-risk acute LGI GVHD, with a focus on treatment-naïve cases. Participants were scheduled to receive one induction dose (15 capsules/day for 2 consecutive days), followed by 3 weekly maintenance doses, consisting of 15 capsules/dose. The primary endpoint of the study was feasibility, which would be achieved if ≥80% of participants able to swallow ≥40 of the 75 scheduled capsules. Ten participants (9 treatment-naïve; 1 steroid-refractory) were enrolled and treated. The study met the primary endpoint, with 9 of 10 participants completing all eligible doses. Organ-specific LGI complete response rate at Day 28 was 70%. Initial clinical response was observed within 1 week for all responders and clinical responses were durable, without recurrent LGI GVHD in complete responders. Exploratory analyses suggest that alpha diversity increased following FMT. While recipient microbiome composition never achieved a high degree of donor similarity, expansion of donor-derived species and increases in tryptophan metabolites and short-chain fatty acids were observed within the first 7 days after FMT. Investigation into the use of microbiome-targeted interventions earlier in the treatment paradigm for acute LGI GVHD is warranted.

Prognostic and clinical significance of tumor-associated macrophages in esophageal squamous cell carcinoma after surgery: do biomarkers and distributions matter?

BACKGROUND: The role of tumor-associated macrophages (TAMs) in patients with esophageal squamous cell carcinoma (ESCC) following surgery remains controversial. Hence, we performed the present study to systematically analyze the prognostic and clinical significance of distinct TAMs biomarkers and distributions in ESCC patients underwent surgery. METHODS: PubMed, Web of Science, and EMBASE databases were searched up to March 31, 2023. The pooled analysis was conducted to evaluate the effects of TAMs on overall survival (OS), disease-free survival (DFS), and clinicopathological characteristics using fixed-effects or random-effect model. RESULTS: Involving a total of 2,502 ESCC patients underwent surgery from 15 studies, the results suggested that the total count of CD68+ TAMs was inversely associated with OS and DFS in ESCC patients, which was also noticed in the relationship of CD68+ TAMs in tumor islet (TI) with OS (all P<0.05), although no association between CD68+ TAMs in tumor stroma (TS) and OS (P>0.05). Moreover, either islet or stromal CD163+ TAMs density was a prognostic factor ESCC (all P<0.05). Similarly, an elevated CD204+ TAMs density in TI predicted a poor DFS (P<0.05), although CD204+ TAMs in TI had no relationship with OS (P>0.05). Besides, a high CD68+ TAMs density was significantly associated with lymphatic vessel invasion, vascular invasion, and lymph node metastasis (all P<0.05). CONCLUSION: Our results demonstrated the prognostic and clinical significance of TAMs in ESCC patients underwent surgery. TAMs should be considered a target that could improve prognostic stratification and clinical outcomes in ESCC after surgery.

tRNA-Derived Small RNAs: A Novel Regulatory Small Noncoding RNA in Renal Diseases.

Background: tRNA-derived small RNAs (tsRNAs) are an emerging class of small noncoding RNAs derived from tRNA cleavage. Summary: With the development of high-throughput sequencing, various biological roles of tsRNAs have been gradually revealed, including regulation of mRNA stability, transcription, translation, direct interaction with proteins and as epigenetic factors, etc. Recent studies have shown that tsRNAs are also closely related to renal disease. In clinical acute kidney injury (AKI) patients and preclinical AKI models, the production and differential expression of tsRNAs in renal tissue and plasma were observed. Decreased expression of tsRNAs was also found in urine exosomes from chronic kidney disease patients. Dysregulation of tsRNAs also appears in models of nephrotic syndrome and patients with lupus nephritis. And specific tsRNAs were found in high glucose model in vitro and in serum of diabetic nephropathy patients. In addition, tsRNAs were also differentially expressed in patients with kidney cancer and transplantation. Key Messages: In the present review, we have summarized up-to-date works and reviewed the relationship and possible mechanisms between tsRNAs and kidney diseases.

A Day 14 Endpoint for Acute GVHD Clinical Trials.

The overall response rate (ORR) 28 days after treatment has been adopted as the primary endpoint for clinical trials of acute graft versus host disease (GVHD). However, physicians often need to modify immunosuppression earlier than day (D) 28, and non-relapse mortality (NRM) does not always correlate with ORR at D28. We studied 1144 patients that received systemic treatment for GVHD in the Mount Sinai Acute GVHD International Consortium (MAGIC) and divided them into a training set (n=764) and a validation set (n=380). We used a recursive partitioning algorithm to create a Mount Sinai model that classifies patients into favorable or unfavorable groups that predicted 12 month NRM according to overall GVHD grade at both onset and D14. In the Mount Sinai model grade II GVHD at D14 was unfavorable for grade III/IV GVHD at onset and predicted NRM as well as the D28 standard response model. The MAGIC algorithm probability (MAP) is a validated score that combines the serum concentrations of suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3-alpha (REG3α) to predict NRM. Inclusion of the D14 MAP biomarker score with the D14 Mount Sinai model created three distinct groups (good, intermediate, poor) with strikingly different NRM (8%, 35%, 76% respectively). This D14 MAGIC model displayed better AUC, sensitivity, positive and negative predictive value, and net benefit in decision curve analysis compared to the D28 standard response model. We conclude that this D14 MAGIC model could be useful in therapeutic decisions and may offer an improved endpoint for clinical trials of acute GVHD treatment.

Group Coping Intervention in Patients With Chronic Graft-Versus-Host Disease: A Pilot Randomized Clinical Trial.

BACKGROUND: More than half the long-term survivors of allogeneic hematopoietic cell transplantation develop chronic graft-versus-host disease (GVHD), a debilitating inflammatory syndrome. Supportive interventions to assist survivors in coping with chronic GVHD are critically needed. PATIENTS AND METHODS: We conducted a pilot randomized clinical trial of a multidisciplinary group intervention (Horizons Program; n=39) versus minimally enhanced usual care (n=41) for patients with moderate or severe chronic GVHD. Horizons participants received 8 weekly sessions about GVHD and coping co-led by a transplant clinician and a behavioral health expert via a secure videoconferencing platform. Participants completed the following surveys before randomization, at 10 weeks, and at 18 weeks: Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT) for quality of life (QoL), Lee Symptom Scale for symptom burden, and Hospital Anxiety and Depression Scale-Depression Symptoms (HADS) for mood. The primary endpoint was feasibility (≥50% enrollment, ≥80% attendance in half the sessions for the Horizons arm only, and ≥80% retention). We also explored preliminary efficacy of the Horizons intervention on changes in patient-reported outcomes with linear mixed effects models and estimates of effect size at 10 weeks. RESULTS: We enrolled and registered 80 (67.2%) of 119 eligible patients (mean age, 62 years; 48.8% female). Of the participants in the Horizons Program, 84.6% attended at least half the sessions. Of registered participants, 91.3% completed assessment follow-ups (Horizons, 35/39 [89.7%]; minimally enhanced usual care, 38/41 [92.7%]). Horizons participants reported improvements in QoL (b = 2.24; d=0.53), anxiety symptoms (b = -0.10; d=0.34), and depression symptoms (b = -0.71; d=0.44) compared with participants who received minimally enhanced usual care. CONCLUSIONS: Participation in a multidisciplinary group intervention study was feasible for patients with chronic GVHD, with promising signals for improving QoL and mood. A full-scale efficacy trial is needed to confirm effects on patient-reported outcomes.

Homoeologous exchanges contribute to branch angle variations in rapeseed: Insights from transcriptome, QTL-seq and gene functional analysis.

Branch angle (BA) is a critical morphological trait that significantly influences planting density, light interception and ultimately yield in plants. Despite its importance, the regulatory mechanism governing BA in rapeseed remains poorly understood. In this study, we generated 109 transcriptome data sets for 37 rapeseed accessions with divergent BA phenotypes. Relative to adaxial branch segments, abaxial segments accumulated higher levels of auxin and exhibited lower expression of six TCP1 homologues and one GA20ox3. A co-expression network analysis identified two modules highly correlated with BA. The modules contained homologues to known BA control genes, such as FUL, YUCCA6, TCP1 and SGR3. Notably, a homoeologous exchange (HE), occurring at the telomeres of A09, was prevalent in large BA accessions, while an A02-C02 HE was common in small BA accessions. In their corresponding regions, these HEs explained the formation of hub gene hotspots in the two modules. QTL-seq analysis confirmed that the presence of a large A07-C06 HE (~8.1 Mb) was also associated with a small BA phenotype, and BnaA07.WRKY40.b within it was predicted as candidate gene. Overexpressing BnaA07.WRKY40.b in rapeseed increased BA by up to 20°, while RNAi- and CRISPR-mediated mutants (BnaA07.WRKY40.b and BnaC06.WRKY40.b) exhibited decreased BA by up to 11.4°. BnaA07.WRKY40.b was exclusively localized to the nucleus and exhibited strong expression correlations with many genes related to gravitropism and plant architecture. Taken together, our study highlights the influence of HEs on rapeseed plant architecture and confirms the role of WRKY40 homologues as novel regulators of BA.

Tumor Homing Chimeric Peptide Rhomboids to Improve Photodynamic Performance by Inhibiting Therapy-Upregulated Cyclooxygenase-2.

Negative therapeutic feedback of inflammation would extensively attenuate the antitumor effect of photodynamic therapy (PDT). In this work, tumor homing chimeric peptide rhomboids (designated as NP-Mel) are fabricated to improve photodynamic performance by inhibiting PDT-upregulated cyclooxygenase-2 (COX-2). The hydrophobic photosensitizer of protoporphyrin IX (PpIX) and palmitic acid are conjugated onto the neuropilin receptors (NRPs) targeting peptide motif (CGNKRTR) to obtain tumor homing chimeric peptide (Palmitic-K(PpIX)CGNKRTR), which can encapsulate the COX-2 inhibitor of meloxicam. The well dispersed NP-Mel not only improves the drug stability and reactive oxygen species (ROS) production ability, but also increase the breast cancer targeted drug delivery to intensify the PDT effect. In vitro and in vivo studies verify that NP-Mel will decrease the secretion of prostaglandin E2 (PGE2) after PDT treatment, inducing the downregulation of IL-6 and TNF-α expressions to suppress PDT induced inflammation. Ultimately, an improved PDT performance of NP-Mel is achieved without inducing obvious systemic toxicity, which might inspire the development of sophisticated nanomedicine in consideration of the feedback induced therapeutic resistance.

Value function assessment to different RL algorithms for heparin treatment policy of patients with sepsis in ICU.

Heparin is a critical aspect of managing sepsis after abdominal surgery, which can improve microcirculation, protect organ function, and reduce mortality. However, there is no clinical evidence to support decision-making for heparin dosage. This paper proposes a model called SOFA-MDP, which utilizes SOFA scores as states of MDP, to investigate clinic policies. Different algorithms provide different value functions, making it challenging to determine which value function is more reliable. Due to ethical restrictions, we cannot test all policies on patients. To address this issue, we proposed two value function assessment methods: action similarity rate and relative gain. We experimented with heparin treatment policies for sepsis patients after abdominal surgery using MIMIC-IV. In the experiments, TD(0) shows the most reliable performance. Using the action similarity rate and relative gain to assess AI policy from TD(0), the agreement rates between AI policy and "good" physician's actual treatment are 64.6% and 73.2%, while the agreement rates between AI policy and "bad" physician's actual treatment are 44.1% and 35.8%, the gaps are 20.5% and 37.4%, respectively. External validation using action similarity rate and relative gain based on eICU resulted in agreement rates of 61.5% and 69.1% with the "good" physician's treatment, and 45.2% and 38.3% with the "bad" physician's treatment, with gaps of 16.3% and 30.8%, respectively. In conclusion, the model provides instructive support for clinical decisions, and the evaluation methods accurately distinguish reliable and unreasonable outcomes.