Novel miR-490-3p/hnRNPA1-b/PKM2 axis mediates the Warburg effect and proliferation of colon cancer cells via the PI3K/AKT pathway.

BACKGROUND: Heterogeneous ribonucleoprotein A1 (hnRNPA1) has been reported to enhance the Warburg effect and promote colon cancer (CC) cell proliferation, but the role and mechanism of the miR-490-3p/hnRNPA1-b/PKM2 axis in CC have not yet been elucidated. AIM: To investigate the role and mechanism of a novel miR-490-3p/hnRNPA1-b/PKM2 axis in enhancing the Warburg effect and promoting CC cell proliferation through the PI3K/AKT pathway. METHODS: Paraffin-embedded pathological sections from 220 CC patients were collected and subjected to immunohistochemical analysis to determine the expression of hnRNPA1-b. The relationship between the expression values and the clinicopathological features of the patients was investigated. Differences in mRNA expression were analyzed using quantitative real-time polymerase chain reaction, while differences in protein expression were analyzed using western blot. Cell proliferation was evaluated using the cell counting kit-8 and 5-ethynyl-2'-deoxyuridine assays, and cell cycle and apoptosis were detected using flow cytometric assays. The targeted binding of miR-490-3p to hnRNPA1-b was validated using a dual luciferase reporter assay. The Warburg effect was evaluated by glucose uptake and lactic acid production assays. RESULTS: The expression of hnRNPA1-b was significantly increased in CC tissues and cells compared to normal controls (P < 0.05). Immunohistochemical results demonstrated significant variations in the expression of the hnRNPA1-b antigen in different stages of CC, including stage I, II-III, and IV. Furthermore, the clinicopathologic characterization revealed a significant correlation between hnRNPA1-b expression and clinical stage as well as T classification. HnRNPA1-b was found to enhance the Warburg effect through the PI3K/AKT pathway, thereby promoting proliferation of HCT116 and SW620 cells. However, the proliferation of HCT116 and SW620 cells was inhibited when miR-490-3p targeted and bound to hnRNPA1-b, effectively blocking the Warburg effect. CONCLUSION: These findings suggest that the novel miR-490-3p/hnRNPA1-b/PKM2 axis could provide a new strategy for the diagnosis and treatment of CC.

Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

BACKGROUND: The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. METHODS: Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m 2 docetaxel, 80 mg/m 2 oxaliplatin, 200 mg/m 2 calcium levofolinate, 2600 mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 21 (72.4%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2-89.2%), 78.8% (95% CI, 65.1-95.5%), and 70.9% (95% CI, 54.8-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3-93.1%) and 96.9% (95% CI, 84.3-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. CONCLUSIONS: The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.

Upfront Umbilical Cord Blood Transplantation Versus Immunosuppressive Therapy for Pediatric Patients With Idiopathic Severe Aplastic Anemia.

Umbilical cord blood transplantation (UCBT) has been rarely reported as a first-line treatment for idiopathic severe aplastic anemia (SAA) patients lacking HLA-matched sibling donors (MSD). Our study aimed to compare the clinical outcomes of pediatric SAA patients who received UCBT and immunosuppressive therapy (IST) upfront. A retrospective analysis was performed on 43 consecutive patients who received frontline IST (n = 17) or UCBT (n = 26) between July 2017 and April 2022. The 3-year overall survival (OS) was comparable between the UCBT and IST groups (96.2% versus 100%, P = .419), while the 3-year event-free survival (EFS) was significantly better in the former than in the latter (88.5% versus 58.8%, P = .048). In the UCBT group, 24 patients achieved successful engraftment, 2 patients developed severe acute graft-versus-host disease (aGVHD), no extensive chronic GVHD (cGVHD), and a high GVHD-free, failure-free survival (GFFS) of 84.6% at 3 years. After 1 year of treatment, 12 patients in the IST group responded, while 5 patients did not achieve remission and 2 patients had disease relapse. At both 3 and 6 months after treatment, the proportion of transfusion-independent patients was higher in the UCBT group than in the IST group. Faster immune recovery and earlier transfusion independence further reduced the risk of infection and bleeding, thereby improving health-related quality of life in the UCBT-treated group. Our results suggested that UCBT as upfront therapy may be an effective and safe option for pediatric SAA patients, with favorable outcomes in experienced centers.

Epitope delimitation: A new method for defining epitopes of human IgG-reactive antigenic peptides based on rabbit-recognized epitope motifs.

The use of precise epitope peptides as antigens is essential for accurate serological diagnosis of viral-infected individuals, but now it remains an unsolvable problem for mapping precise B cell epitopes (BCEs) recognized by human serum. To address this challenge, we propose a novel epitope delimitation (ED) method to uncover BCEs in the delineated human IgG-reactive (HR) antigenic peptides (APs). Specifically, the method based on the rationale of similarities in humoral immune responses between mammalian species consists of a pair of elements: experimentally delineated HR-AP and rabbit-recognized (RR) BCE motif and corresponding pair of sequence alignment analysis. As a result of using the ED approach, after decoding four RR-epitomes of human papillomavirus types 16/18-E6 and E7 proteins utilizing rabbit serum against each recombinant protein and sequence alignment analysis of HR-APs and RR-BCEs, 19 fine BCEs in 17 of 22 known HR-APs were defined based on each corresponding RR-BCE motifs, including the type-specificity of each delimited BCE in homologous proteins. The test with 22 known 16/20mer HR-APs demonstrated that the ED method is effective and efficient, indicating that it can be used as an alternative method to the conventional identification of fine BCEs using overlapping 8mer peptides.

A novel capsid-XL32-derived adeno-associated virus serotype prompts retinal tropism and ameliorates choroidal neovascularization.

Gene therapy has been adapted, from the laboratory to the clinic, to treat retinopathies. In contrast to subretinal route, intravitreal delivery of AAV vectors displays the advantage of bypassing surgical injuries, but the viral particles are more prone to be nullified by the host neutralizing factors. To minimize such suppression of therapeutic effect, especially in terms of AAV2 and its derivatives, we introduced three serine-to-glycine mutations, based on the phosphorylation sites identified by mass spectrum analysis, to the XL32 capsid to generate a novel serotype named AAVYC5. Via intravitreal administration, AAVYC5 was transduced more effectively into multiple retinal layers compared with AAV2 and XL32. AAVYC5 also enabled successful delivery of anti-angiogenic molecules to rescue laser-induced choroidal neovascularization and astrogliosis in mice and non-human primates. Furthermore, we detected fewer neutralizing antibodies and binding IgG in human sera against AAVYC5 than those specific for AAV2 and XL32. Our results thus implicate this capsid-optimized AAVYC5 as a promising vector suitable for a wide population, particularly those with undesirable AAV2 seroreactivity.

Phase separation in DNA double-strand break response.

DNA double-strand break (DSB) is the most dangerous type of DNA damage, which may lead to cell death or oncogenic mutations. Homologous recombination (HR) and nonhomologous end-joining (NHEJ) are two typical DSB repair mechanisms. Recently, many studies have revealed that liquid-liquid phase separation (LLPS) plays a pivotal role in DSB repair and response. Through LLPS, the crucial biomolecules are quickly recruited to damaged sites with a high concentration to ensure DNA repair is conducted quickly and efficiently, which facilitates DSB repair factors activating downstream proteins or transmitting signals. In addition, the dysregulation of the DSB repair factor's phase separation has been reported to promote the development of a variety of diseases. This review not only provides a comprehensive overview of the emerging roles of LLPS in the repair of DSB but also sheds light on the regulatory patterns of phase separation in relation to the DNA damage response (DDR).

ECC-PolypDet: Enhanced CenterNet With Contrastive Learning for Automatic Polyp Detection.

Accurate polyp detection is critical for early colorectal cancer diagnosis. Although remarkable progress has been achieved in recent years, the complex colon environment and concealed polyps with unclear boundaries still pose severe challenges in this area. Existing methods either involve computationally expensive context aggregation or lack prior modeling of polyps, resulting in poor performance in challenging cases. In this paper, we propose the Enhanced CenterNet with Contrastive Learning (ECC-PolypDet), a two-stage training & end-to-end inference framework that leverages images and bounding box annotations to train a general model and fine-tune it based on the inference score to obtain a final robust model. Specifically, we conduct Box-assisted Contrastive Learning (BCL) during training to minimize the intra-class difference and maximize the inter-class difference between foreground polyps and backgrounds, enabling our model to capture concealed polyps. Moreover, to enhance the recognition of small polyps, we design the Semantic Flow-guided Feature Pyramid Network (SFFPN) to aggregate multi-scale features and the Heatmap Propagation (HP) module to boost the model's attention on polyp targets. In the fine-tuning stage, we introduce the IoU-guided Sample Re-weighting (ISR) mechanism to prioritize hard samples by adaptively adjusting the loss weight for each sample during fine-tuning. Extensive experiments on six large-scale colonoscopy datasets demonstrate the superiority of our model compared with previous state-of-the-art detectors.

A predictive model combining clinical characteristics and nutritional risk factors for overall survival after umbilical cord blood transplantation.

BACKGROUND: Umbilical cord blood transplantation (UCBT) is a curable therapy for hematological disease; however, the impact of nutritional status on UCBT outcomes remains controversial. To evaluate the joint effect of clinical characteristics and nutritional status on the prognosis of patients who underwent UCBT, we screened various factors to establish a predictive model of overall survival (OS) after UCBT. METHODS: We performed an integrated clinical characteristic and nutritional risk factor analysis and established a predictive model that could be used to identify UCBT recipients with poor OS. Internal validation was performed by using the bootstrap method with 500 repetitions. RESULTS: Four factors, including disease status, conditioning regimen, calf skinfold thickness and albumin level, were identified and used to develop a risk score for OS, which showed a positive predictive value of 84.0%. A high-risk score (≥ 2.225) was associated with inferior 3-year OS post-UCBT [67.5% (95% CI 51.1-79.4%), P = 0.001]. Then, we built a nomogram based on the four factors that showed good discrimination with a C-index of 0.833 (95% CI 0.743-0.922). The optimism-corrected C-index value of the bootstrapping was 0.804. Multivariate analysis suggested that a high calf skinfold thickness (≥ 20.5 mm) and a low albumin level (< 33.6 g/L) conferred poor disease-free survival (DFS). CONCLUSION: The predictive model combining clinical and nutritional factors could be used to predict OS in UCBT recipients, thereby promoting preemptive treatment.

PD98059 protects SH-SY5Y cells against oxidative stress in oxygen-glucose deprivation/reperfusion.

Mitochondria play a key role in the cerebral ischemia-reperfusion injury. Although the extracellular signal-regulated kinase 1/2 inhibitor PD98059 (PD) is a selective and reversible flavonoid that can protect the mitochondria in a rat model of cardiac arrest/cardiopulmonary resuscitation, its role requires further confirmation. In this study, we investigated whether PD could maintain mitochondrial homeostasis and decrease reactive oxygen species (ROS) production in neuroblastoma (SH-SY5Y) cells exposed to oxygen-glucose deprivation/reperfusion (OGD/R). PD improved the mitochondrial morphology and function, reversed the increase in ROS production and cell apoptosis, and reduced total-superoxide dismutase and Mn-superoxide dismutase activities induced by OGD/R. PD decreases ROS production and improves mitochondrial morphology and function, protecting SH-SY5Y cells against OGD/R-induced injury.

RAP80 phase separation at DNA double-strand break promotes BRCA1 recruitment.

RAP80 has been characterized as a component of the BRCA1-A complex and is responsible for the recruitment of BRCA1 to DNA double-strand breaks (DSBs). However, we and others found that the recruitment of RAP80 and BRCA1 were not absolutely temporally synchronized, indicating that other mechanisms, apart from physical interaction, might be implicated. Recently, liquid-liquid phase separation (LLPS) has been characterized as a novel mechanism for the organization of key signaling molecules to drive their particular cellular functions. Here, we characterized that RAP80 LLPS at DSB was required for RAP80-mediated BRCA1 recruitment. Both cellular and in vitro experiments showed that RAP80 phase separated at DSB, which was ascribed to a highly disordered region (IDR) at its N-terminal. Meanwhile, the Lys63-linked poly-ubiquitin chains that quickly formed after DSBs occur, strongly enhanced RAP80 phase separation and were responsible for the induction of RAP80 condensation at the DSB site. Most importantly, abolishing the condensation of RAP80 significantly suppressed the formation of BRCA1 foci, encovering a pivotal role of RAP80 condensates in BRCA1 recruitment and radiosensitivity. Together, our study disclosed a new mechanism underlying RAP80-mediated BRCA1 recruitment, which provided new insight into the role of phase separation in DSB repair.

Multi-Task Learning With Hierarchical Guidance for Locating and Stratifying Submucosal Tumors.

Locating and stratifying the submucosal tumor of the digestive tract from endoscopy ultrasound (EUS) images are of vital significance to the preliminary diagnosis of tumors. However, the above problems are challenging, due to the poor appearance contrast between different layers of the digestive tract wall (DTW) and the narrowness of each layer. Few of existing deep-learning based diagnosis algorithms are devised to tackle this issue. In this article, we build a multi-task framework for simultaneously locating and stratifying the submucosal tumor. And considering the awareness of the DTW is critical to the localization and stratification of the tumor, we integrate the DTW segmentation task into the proposed multi-task framework. Except for sharing a common backbone model, the three tasks are explicitly directed with a hierarchical guidance module, in which the probability map of DTW itself is used to locally enhance the feature representation for tumor localization, and the probability maps of DTW and tumor are jointly employed to locally enhance the feature representation for tumor stratification. Moreover, by means of the dynamic class activation map, probability maps of DTW and tumor are reused to enforce the stratification inference process to pay more attention to DTW and tumor regions, contributing to a reliable and interpretable submucosal tumor stratification model. Additionally, considering the relation with respect to other structures is beneficial for stratifying tumors, we devise a graph reasoning module to replenish non-local relation knowledge for the stratification branch. Experiments on a Stomach-Esophagus and an Intestinal EUS dataset prove that our method achieves very appealing performance on both tumor localization and stratification, significantly outperforming state-of-the-art object detection approaches.

Refining eligibility criteria of unit selection for myeloablative cord blood transplantation in acute leukemia: Real-world experience of a referral center.

The algorithm for cord blood (CB) unit selection is still somewhat ambiguous. We retrospectively analyzed 620 cases of acute leukemia between 2015 and 2020, who were treated with myeloablative single-unit umbilical CB transplantation (UCBT). We found that, when human leukocyte antigen (HLA) mismatch was ≤3/10, CD34+ cell dosage <0.83 × 105/kg-considerably lower than prevalent guidelines-was permissible without affecting survival. Moreover, synergy between donor killer-cell immunoglobulin-like receptors (KIR) haplotypes-B and donor-recipient HLA-C mismatch protected against relapse-related mortality. We submit that minimum required CD34+ cell dosage can possibly be relaxed to broaden access to UCBT, and donor KIR genotyping should be considered during unit selection.

Catalytic Ozonation of Polluter Benzene from -20 to >50 °C with High Conversion Efficiency and Selectivity on Mullite YMn2O5.

Catalytic decomposition of aromatic polluters at room temperature represents a green route for air purification but is currently challenged by the difficulty of generating reactive oxygen species (ROS) on catalysts. Herein, we develop a mullite catalyst YMn2O5 (YMO) with dual active sites of Mn3+ and Mn4+ and use ozone to produce a highly reactive O* upon YMO. Such a strong oxidant species on YMO shows complete removal of benzene from -20 to >50 °C with a high COx selectivity (>90%) through the generated reactive species O* on the catalyst surface (60 000 mL g-1 h-1). Although the accumulation of water and intermediates gradually lowers the reaction rate after 8 h at 25 °C, a simple treatment by ozone purging or drying in the ambient environment regenerates the catalyst. Importantly, when the temperature increases to 50 °C, the catalytic performance remains 100% conversion without any degradation for 30 h. Experiments and theoretical calculations show that such a superior performance stems from the unique coordination environment, which ensures high generation of ROS and adsorption of aromatics. Mullite's catalytic ozonation degradation of total volatile organic compounds (TVOC) is applied in a home-developed air cleaner, resulting in high efficiency of benzene removal. This work provides insights into the design of catalysts to decompose highly stable organic polluters.

Effects of neoadjuvant radiochemotherapy for anorectal function in locally advanced rectal cancer patients: a study protocol for a prospective, observational, controlled, multicentre study.

BACKGROUND: Neoadjuvant chemoradiotherapy (NCRT) and total mesorectal excision are standard treatment regimen for patients with locally advanced rectal cancer (LARC). This sphincter-saving treatment strategy may be accompanied by a series of anorectal functional disorders. Yet, prospective studies that dynamically evaluating the respective roles of radiotherapy, chemotherapy and surgery on anorectal function are lacking. PATIENTS/DESIGN: The study is a prospective, observational, controlled, multicentre study. After screening for eligibility and obtaining informed consent, a total of 402 LARC patients undergoing NCRT followed by surgery, or neoadjuvant chemotherapy followed by surgery, or surgery only would be included in the trial. The primary outcome measure is the average resting pressure of anal sphincter. The secondary outcome measures are maximum anal sphincter contraction pressure, Wexner continence score and low anterior resection syndrome (LARS) score. Evaluations will be carried out at the following stages: baseline (T1), after radiotherapy or chemotherapy (before surgery, T2), after surgery (before closing the temporary stoma, T3), and at follow-up visits (every 3 to 6 months, T4, T5……). Follow-up for each patient will be at least 2 years. DISCUSSION: We expect the program to provide more information of neoadjuvant radiotherapy and/or chemotherapy on anorectal function, and to optimize the treatment strategy to reduce anorectal dysfunction for LARC patients. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05671809). Registered on 26 December 2022.

Impact of Iron Overload and Iron Chelation with Deferasirox on Outcomes of Patients with Severe Aplastic Anemia after Allogeneic Hematopoietic Stem Cell Transplantation.

Patients suffering from severe aplastic anemia (SAA) need frequent blood transfusions during allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, these transfusions can result in an excess of iron in the body tissues, which can negatively impact the success of transplantation. This study aimed to examine the impact of pretransplantation iron overload (IO) on the outcomes of allo-HSCT in patients with SAA. It also investigated whether iron chelation (IC) therapy is necessary to enhance transplantation outcomes in SAA patients by providing guidelines for determining when excess iron should be chelated. The study consisted of 2 parts. In cohort 1, which was retrospective and conducted from April 2012 to December 2018, SAA patients receiving their first allo-HSCT were divided into 2 groups based on their pretransplantation serum ferritin (SF) level: the IO group (SF >1000 ng/mL; n = 17) and the non-IO group (SF ≤1000 ng/mL; n = 48). Cohort 2, a prospective clinical trial conducted from January 2019 to July 2020, included SAA patients diagnosed with IO who were treated with IC therapy using deferasirox at a dose of 10 to 30 mg/kg. Patients were separated into 2 groups based on their pretransplantation SF level: the IC success (ICsuccess) group (SF ≤1000 ng/mL; n = 18) and the IC failure (ICfailure) group (SF >1000 ng/mL; n = 28). All participants were evaluated for the correlation between pretransplantation SF level and transplantation outcomes. A P value <.05 was considered statistically significant. There was no significant difference in the speed of engraftment among the 3 cell lineages or in the incidence of 100-day grade II-IV acute graft-versus-host disease (aGVHD), grade III-IV aGVHD, or 3-year chronic GVHD between the 2 groups in both cohorts. Of note, however, in cohort 1, both 1-year overall survival (OS) (41.2% versus 83.3%; P < .001) and 3-year OS (35.3% versus 83.3%; P < .001) were significantly worse in the IO group. Furthermore, 180-day transplantation related mortality (TRM) (47.1% versus 14.6%; P = .005) and 1-year TRM (52.9% versus 16.7%; P = .002) were significantly higher in the IO group. The IO group was significantly associated with inferior 3-year OS in both univariate and multivariate analyses. In cohort 2, 1-year OS (88.9% versus 42.9%; P = .003) and 3-year OS (83.3% versus 42.9%; P = .007) were significantly better in the ICsuccess group, whereas 180-day TRM (11.1% versus 39.3%; P = .040) and 1-year TRM (11.1% versus 57.1%; P = .003) were significantly lower in the ICsuccess group. These differences were confirmed in both univariate and multivariate analyses. This study involving 2 cohorts shows that pre-HSCT IO has a negative impact on transplantation outcomes in SAA patients. Chelating excess iron with an SF level <1000 ng/mL was found to be necessary and could potentially improve the outcomes.

A comparative study of two single-stage oral mucosal substitution urethroplasty (Kulkarni and Asopa) in the surgical treatments of lichen sclerosus urethral strictures.

Long-segment lichen sclerosus (LS) urethral stricture is a challenge for urologists. Limited data are available for surgeons to make a surgical decision between Kulkarni and Asopa urethroplasty. In this retrospective study, we investigated the outcomes of these two procedures in patients with LS urethral stricture. Between January 2015 and December 2020, 77 patients with LS urethral stricture underwent Kulkarni and Asopa procedures for urethroplasty in the Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (Shanghai, China). Of the 77 patients, 42 (54.5%) underwent the Asopa procedure and 35 (45.5%) underwent the Kulkarni procedure. The overall complication rate was 34.2% in the Kulkarni group and 19.0% in the Asopa group, and no difference was observed ( P = 0.105). Among the complications, no statistical difference was observed in the incidence of urethral stricture recurrence ( P = 0.724) or glans dehiscence ( P = 0.246) except for postoperative meatus stenosis ( P = 0.020). However, the recurrence-free survival rate between the two procedures was significantly different ( P = 0.016). Cox survival analysis showed that antiplatelet/anticoagulant therapy use ( P = 0.020), diabetes ( P = 0.003), current/former smoking ( P = 0.019), coronary heart disease ( P < 0.001), and stricture length ( P = 0.028) may lead to a higher hazard ratio of complications. Even so, these two techniques can still provide acceptable results with their own advantages in the surgical treatment of LS urethral strictures. The surgical alternative should be considered comprehensively according to the patient characteristics and surgeon preferences. Moreover, our results showed that antiplatelet/anticoagulant therapy use, diabetes, coronary heart disease, current/former smoking, and stricture length may be contributing factors of complications. Therefore, patients with LS are advised to undergo early interventions for better therapeutic effects.

The Composite Immune Risk Score predicts overall survival after allogeneic hematopoietic stem cell transplantation: A retrospective analysis of 1838 cases.

There has been little consensus on how to quantitatively assess immune reconstitution after hematopoietic stem cell transplantation (HSCT) as part of the standard of care. We retrospectively analyzed 11 150 post-transplant immune profiles of 1945 patients who underwent HSCT between 2012 and 2020. 1838 (94.5%) of the cases were allogeneic HSCT. Using the training set of patients (n = 729), we identified a composite immune signature (integrating neutrophil, total lymphocyte, natural killer, total T, CD4+ T, and B cell counts in the peripheral blood) during days 91-180 after allogeneic HSCT that was predictive of early mortality and moreover simplified it into a formula for a Composite Immune Risk Score. When we verified the Composite Immune Risk Score in the validation (n = 284) and test (n = 391) sets of patients, a high score value was found to be associated with hazard ratios (HR) of 3.64 (95% C.I. 1.55-8.51; p = .0014) and 2.44 (95% C.I., 1.22-4.87; p = .0087), respectively, for early mortality. In multivariate analysis, a high Composite Immune Risk Score during days 91-180 remained an independent risk factor for early mortality after allogeneic HSCT (HR, 1.80; 95% C.I., 1.28-2.55; p = .00085). In conclusion, the Composite Immune Risk Score is easy to compute and could identify the high-risk patients of allogeneic HSCT who require targeted effort for prevention and control of infection.

Enhanced metagenomic deep learning for disease prediction and consistent signature recognition by restructured microbiome 2D representations.

Metagenomic analysis has been explored for disease diagnosis and biomarker discovery. Low sample sizes, high dimensionality, and sparsity of metagenomic data challenge metagenomic investigations. Here, an unsupervised microbial embedding, grouping, and mapping algorithm (MEGMA) was developed to transform metagenomic data into individualized multichannel microbiome 2D representation by manifold learning and clustering of microbial profiles (e.g., composition, abundance, hierarchy, and taxonomy). These 2D representations enable enhanced disease prediction by established ConvNet-based AggMapNet models, outperforming the commonly used machine learning and deep learning models in metagenomic benchmark datasets. These 2D representations combined with AggMapNet explainable module robustly identified more reliable and replicable disease-prediction microbes (biomarkers). Employing the MEGMA-AggMapNet pipeline for biomarker identification from 5 disease datasets, 84% of the identified biomarkers have been described in over 74 distinct works as important for these diseases. Moreover, the method also discovered highly consistent sets of biomarkers in cross-cohort colorectal cancer (CRC) patients and microbial shifts in different CRC stages.

Microcystin bound on microplastics in eutrophic waters: A potential threat to zooplankton revealed by adsorption-desorption processes.

The presence of microplastics (MPs) in eutrophic waters (both freshwaters and coastal waters) is increasingly reported globally, as has the occurrence of cyanotoxins, including microcystins (MCs). MPs have the potential to act as vectors for MCs in freshwater environments, but the transportation mechanisms and associated risks remain poorly understood. In this study, we investigated how aging process and water conditions influenced the adsorption behavior of the microcystin-leucine-arginine (MC-LR) onto polyethylene (PE) and polypropylene (PP). Adsorption kinetics and isotherms showed that the MC-LR sorption capacity in descending order was aged PP > pristine PP > aged PE > pristine PE. The aging process increased the MC-LR sorption amount by 25.1% and 6.5% for PP and PE, respectively. The increase in sorption affinity of aged MPs may be attributed to the significant surface oxidation and the formation of the hydrogen bonding between MPs and MC-LR. Furthermore, MC-LR sorption can be largely influenced by the aqueous conditions. MC-LR preferred to be much adsorbed onto different MPs in brackish water than in freshwater owing to the cation bridging effect and complexation of high levels of cations. The usual alkalescent pH in eutrophic waters did not favor MC-LR sorption to MPs. Finally, based on the desorption results, assuming a worst-case scenario, MC-LR bound on MPs may have a high risk to daphnids. The findings obtained in this study have improved our knowledge in the interaction of MPs with hydrophilic cyanotoxins in aqueous ecosystems, as well as the risks associated with their coexistence.

Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial.

OBJECTIVE: To compare neoadjuvant chemotherapy (nCT) with CAPOX alone versus neoadjuvant chemoradiotherapy (nCRT) with capecitabine in locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). BACKGROUND DATA: nCRT is associated with higher surgical complications, worse long-term functional outcomes, and questionable survival benefits. Comparatively, nCT alone seems a promising alternative treatment in lower-risk LARC patients with uninvolved MRF. METHODS: Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to nCT group with 4 cycles of CAPOX (Oxaliplatin 130 mg/m2 IV day 1 and Capecitabine 1000 mg/m2 twice daily for 14 d. Repeat every 3 wk) or nCRT group with Capecitabine 825 mg/m² twice daily administered orally and concurrently with radiation therapy (50 Gy/25 fractions) for 5 days per week. The primary end point is local-regional recurrence-free survival. Here we reported the results of secondary end points: histopathologic response, surgical events, and toxicity. RESULTS: Of the 663 initially enrolled patients, 589 received the allocated treatment (nCT, n=300; nCRT, n=289). Pathologic complete response rate was 11.0% (95% CI, 7.8-15.3%) in the nCT arm and 13.8% (95% CI, 10.1-18.5%) in the nCRT arm ( P =0.33). The downstaging (ypStage 0 to 1) rate was 40.8% (95% CI, 35.1-46.7%) in the nCT arm and 45.6% (95% CI, 39.7-51.7%) in the nCRT arm ( P =0.27). nCT was associated with lower perioperative distant metastases rate (0.7% vs. 3.1%, P =0.03) and preventive ileostomy rate (52.2% vs. 63.6%, P =0.008) compared with nCRT. Four patients in the nCT arm received salvage nCRT because of local disease progression after nCT. Two patients in the nCT arm and 5 in the nCRT arm achieved complete clinical response and were treated with a nonsurgical approach. Similar results were observed in subgroup analysis. CONCLUSIONS: nCT achieved similar pCR and downstaging rates with lower incidence of perioperative distant metastasis and preventive ileostomy compared with nCRT. CAPOX could be an effective alternative to neoadjuvant therapy in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results.