Silica nanoparticle design for colorectal cancer treatment: Recent progress and clinical potential.

Colorectal cancer (CRC) is the third most common cancer worldwide and the second most common cause of cancer death. Nanotherapies are able to selectively target the delivery of cancer therapeutics, thus improving overall antitumor efficiency and reducing conventional chemotherapy side effects. Mesoporous silica nanoparticles (MSNs) have attracted the attention of many researchers due to their remarkable advantages and biosafety. We offer insights into the recent advances of MSNs in CRC treatment and their potential clinical application value.

Comprehensive analysis and treatment of intraoral thyroglossal duct cysts with intraoperative techniques: a 7-case series review in a tertiary care center.

OBJECTIVE: Intraoral thyroglossal duct cyst is a relatively rare clinical disease. This article reviews the diagnosis and treatment process of 7 patients and explores the clinical characteristics of diagnosis and treatment of intraoral thyroglossal duct cyst in combination with past literature reports. METHOD: A retrospective analysis was conducted on 7 cases of intraoral thyroglossal duct cyst admitted to the Otolaryngology ward of Dalian Municipal Central Hospital from January 2017 to January 2024. The cases were recorded in terms of gender, age, symptoms, physical signs, radiological examinations, surgical methods, and postoperative complications. All cases were followed up, and the latest follow-up results were recorded. RESULTS: Among the 7 cases, 6 patients underwent laryngoscopic and radiological examinations before surgery, and 1 child was found to have a cyst during surgery. All cases were diagnosed with intraoral thyroglossal duct cyst and treated with plasma radiofrequency surgery. None of the patients had postoperative complications, and no recurrence was found in the six-month follow-up after discharge. CONCLUSION: Intraoral thyroglossal duct cyst is rare in clinical practice. It is important to pay attention to its differential diagnosis clinically, and careful review of images is required before surgery. Cryoablation with low-temperature plasma radiofrequency is not only minimally invasive and has a quick recovery but also has few complications and a low recurrence rate. It is a safe and effective treatment method that is worthy of clinical promotion. LEVEL OF EVIDENCE: Level 3.

Nickel-catalyzed asymmetric hydrogenation for the preparation of α-substituted propionic acids.

Transition metal-catalyzed asymmetric hydrogenation is one of the most efficient methods for the preparation of chiral α-substituted propionic acids. However, research on this method, employing cleaner earth-abundant metal catalysts, is still insufficient in both academic and industrial contexts. Herein, we report an efficient nickel-catalyzed asymmetric hydrogenation of α-substituted acrylic acids affording the corresponding chiral α-substituted propionic acids with up to 99.4% ee (enantiomeric excess) and 10,000 S/C (substrate/catalyst). In particular, this method can be used to obtain (R)-dihydroartemisinic acid with 99.8:0.2 dr (diastereomeric ratio) and 5000 S/C, which is an essential intermediate for the preparation of the antimalarial drug Artemisinin. The reaction mechanism has been investigated via experiments and DFT (Density Functional Theory) calculations, which indicate that the protonolysis of the C-Ni bond of the key intermediate via an intramolecular proton transfer from the carboxylic acid group of the substrate, is the rate-determining step.

RuPHOX-Ru Catalyzed Asymmetric Cascade Hydrogenation of 3-Substituted Chromones for the Synthesis of Corresponding Chiral Chromanols.

An efficient RuPHOX-Ru catalyzed asymmetric cascade hydrogenation of 3-substituted chromones has been achieved under mild reaction conditions, affording the corresponding chiral 3-substituted chromanols in high yields with excellent enantio- and diastereoselectivities (up to 99 % yield, >99 % ee and >20 : 1 dr). Control reactions and deuterium labelling experiments revealed that a dynamic kinetic resolution process occurs during the subsequent hydrogenation of the C=O double bond, which is responsible for the high performance of the asymmetric cascade hydrogenation. The resulting products allow for several transformations and it was shown that the protocol provides a practical and alternative strategy for the synthesis of chiral 3-substituted chromanols and their derivatives.

[Intraoperative slide rail CT assistance in percutaneous sacroiliac joint screws for the treatment of pelvic posterior ring injury].

OBJECTIVE: To compare the clinical efficacy of intraoperative slide rail CT combined with C-arm X-ray assistance and just C-arm for percutaneous screw in the treatment of pelvic posterior ring injury. METHODS: A retrospective analysis was performed on the patient data of 76 patients with posterior pelvic ring injury admitted to the Department of Orthopedic Trauma from December 2018 to February 2022. Among them, 39 patients in the CT group were treated with C-arm combined with slide rail CT-assisted inline fixation including 23 males and 16 females with an average age of (44.98±7.33) years old;and the other 37 patients in the C-arm group were treated with intraline fixation treatment under only C-arm fluoroscopy including 24 males and 13 females with an average age of (44.37±10.82) years old. Among them, 42 patients with anterior ring fractures were treated with percutaneous inferior iliac spines with internal fixation (INFIX) or suprapubic support screws to fix the anterior pelvic ring. Postoperative follow-up time, operation time, complications of the two groups were compared. Results of Matta reduction criteria, Majed efficacy evaluation, the CT grading and the rate of secondary surgical revision were compared. RESULTS: The nailing time of (32.63±7.33) min in CT group was shorter than that of (52.95±10.64) min in C-arm group (t=-9.739, P<0.05). The follow-up time between CT group (11.97±1.86) months and C-arm group (12.03±1.71) months were not statistically significant(P>0.05). The postoperative complication rates between two groups were not statistically significant (χ2=0.159, P>0.05). Results of Matta reduction criteria (Z=2.79, P<0.05), Majeed efficacy evaluation(Z=2.79, P<0.05), CT grading (Z=2.83, P<0.05) in CT group were better than those in C-arm group(P<0.05); the secondary surgical revision rate in the CT group was significantly lower than that in the C-arm group (χ2=5.641, P<0.05). CONCLUSION: Compared with traditional C-arm fluoroscopy, intraoperative slide rail CT combined with C-arm assisted percutaneous sacroiliac joint screw placement surgery has the characteristics of short operation time, high accuracy and safety, and significant decrease in postoperative secondary revision rate, and is one of the effective methods for re-establishing the stability of the posterior ring of pelvic fracture.

Bimetallic Ru/Ru-Catalyzed Asymmetric One-Pot Sequential Hydrogenations for the Stereodivergent Synthesis of Chiral Lactones.

Asymmetric sequential hydrogenations of α-methylene γ- or δ-keto carboxylic acids are established in one-pot using a bimetallic Ru/Ru catalyst system, achieving the stereodivergent synthesis of all four stereoisomers of both chiral γ- and δ-lactones with two non-vicinal carbon stereocenters in high yields (up to 99%) and with excellent stereoselectivities (up to >99% ee and >20:1 dr). The compatibility of the two chiral Ru catalyst systems is investigated in detail, and it is found that the basicity of the reaction system plays a key role in the sequential hydrogenation processes. The protocol can be performed on a gram-scale with a low catalyst loading (up to 11000 S/C) and the resulting products allow for many transformations, particularly for the synthesis of several key intermediates useful for the preparation of chiral drugs and natural products.

Matrisome and Immune Pathways Contribute to Extreme Vascular Outcomes in Williams-Beuren Syndrome.

BACKGROUND: Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability. METHODS AND RESULTS: We performed genome sequencing on 473 individuals with Williams-Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway-level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes/pathways identified here and those ascertained through larger aortic disease/trait genome-wide association studies. We show that SVAS severity in Williams-Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes (ACAN and LTBP4) were uniquely expressed in the aorta. Many genes in the identified pathways were previously reported in genome-wide association studies for aneurysm, bicuspid aortic valve, or aortic size. CONCLUSIONS: Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta-focused genome-wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.

Significance of Nasopharyngeal Cavity Area in Individuals with Adenoid Hypertrophy Assessed by Cone Beam Computed Tomography.

Objective: To determine the significance of the nasopharyngeal cavity area (S) in diagnosing and treating adenoid hypertrophy (AH) in children by measuring it with cone beam computed tomography (CBCT). Methods: A retrospective analysis was conducted on the clinical data of eighty-five 5- to 6-year-old children with AH admitted to the Department of Otorhinolaryngology at Dalian Central Hospital between January 2022 and April 2023. Of the 85 patients, 48 were male and 37 were female; all had been diagnosed with AH and underwent surgery. Sleeping with open-mouth breathing was frequently accompanied by clinical manifestations such as chronic sinusitis in most patients. Every patient was subjected to a CBCT examination of the nasopharynx and 3D airway reconstruction. The adenoid thickness (A) and nasopharyngeal cavity width (N) were measured in the sagittal plane, while the S was measured in the coronal plane. The factors that had a significant impact on S's size was analyzed using linear regression. Results: S and age, A, N, height, weight, BMI, allergic rhinitis, deviated nasal septum, and enlarged turbinate hypertrophy did not differ significantly (P > .05). However, there was a significant linear relationship between A/N and chronic sinusitis (R2 = 0.948, P < .01). Regression equation: S = -4.115 × A/N × 100-5.037 × 1/0 (with chronic sinusitis/without chronic sinusitis) +418. 097. The calculated S in individuals with A/N = 70% and no chronic sinusitis was 130 mm2. Conclusion: The S can be used as an important imaging index for diagnosing and evaluating the severity of AH in minors. When a child exhibits clinical signs of AH but A/N ≤ 70%, it is difficult to determine whether surgical intervention is necessary. At this time, CBCT is required to measure the nasopharyngeal cavity's size. When S ≤ 130 mm2, the patient should actively undertake surgical treatment.

Effects of oral cysteine leukotriene receptor antagonist-montelukast on adenoid lymphoid tissue: a histopathological study under light microscope.

Background: Adenoidal hypertrophy (AH) is one of the most common causes of upper airway obstruction in children. Drug and surgical treatment are the typical treatment of AH. The study on the inflammatory mechanism of AH in children provides a new idea for preoperative intervention and non-surgical treatment with anti-inflammatory drugs such as montelukast sodium (a cysteine leukotriene receptor antagonist). The aim of this study is to evaluate the effect of montelukast sodium on adenoidal lymphoid tissue pathology in children with AH under light microscope. Objective: To study whether there is any change in pathology of the adenoidal lymphoid tissue under the light microscope compared with the control group in children with moderate to severe simple AH treated with montelukast sodium for 1 month before operation. Materials and methods: Twenty patients (8 males, 12 females, 3-8 years old) with moderate to severe AH who were prepared for surgical treatment were selected. All the patients were examined by Nasopharyngeal CT and hemocyte analysis before operation. 20 subjects were randomly divided into two groups: One group was given montelukast chewable tablets 5 mg/d, qn, for 4 weeks; The control group was given placebo 5 mg/d, qn, for 4 weeks. After 4 weeks, the adenoids were removed and examined histopathology. Results: Compared with the control group, the number of lymphocytes in the blood cell analysis of the study group was significantly reduced, with a statistically significant difference (p < 0.05). And the number of germinal centers in adenoid tissue of the study group was relatively reduced, no small cyst was found in the epithelium, and the degree of inflammatory cell infiltration was reduced, with a statistically significant difference (p < 0.05). Conclusion: Montelukast can reduce the number of reactive cells, the number of lymphocytes in blood cells and blood vessels in adenoid lymphoid tissue, which can provide a new idea for preoperative intervention and non-surgical treatment of adenoid hypertrophy in children. However, this is only a pilot study and a longer treatment period is needed to assess the long-term effects of montelukast sodium on adenoid lymphoid tissue. Clinical Trial Registration: www.Chictr.org.cn, identifier ChiCTR2300075040.

Clinical utility of the pan-immune-inflammation value in breast cancer patients.

Background: The newly discovered pan-immune-inflammation value (PIV) has been illustrated to have good prognostic value for cancer patient prognosis. However, the prognostic usefulness of PIV in breast cancer patients is unknown. As a result, to aid the clinic in providing a distinctive and trustworthy biomarker to better assess breast cancer patient's prognosis, we conducted this meta-analysis to investigate the relationship between PIV and the survival of breast cancer patients. Methods: We conducted a systematic search of Pubmed, Embase, the Cochrane Library, and the CNKI databases to screen for eligible studies published up to April 2023. Outcomes included overall survival (OS), progression-free survival (PFS), and pathological complete response (pCR). The hazard ratio (HR) and the corresponding 95% confidence interval (CI) were used as the indicators. STATA 15.0 software was used to perform meta-analysis, sensitivity analysis, and publication bias analysis. Results: A total of eight articles, involving 2953 patients, met the inclusion criteria and were included in this meta-analysis. The results showed that patients with higher PIV levels had a significantly shorter OS (HR: 2.045, 95% CI: 1.355-3.086, P = 0.001) and PFS (HR: 1.466, 95% CI: 1.163-1.848, P = 0.001). Besides, the PIV value was negatively correlated with the efficacy of neoadjuvant chemotherapy. Sensitivity analysis showed that the results of this study were reliable and stable. Conclusions: PIV has a good prognostic value in breast cancer patients and is expected to be a prognostic biomarker for breast cancer.

Rh-Catalyzed Enantioselective Desymmetric Hydrogenation of α-Acetamido-1,3-indanediones Using Ether-Bridged Biphenyl Diphosphine Ligands.

Novel axially chiral biphenyl diphosphine ligands Enm-BridgePhos, bearing an ether chain bridge at the 5,5'-position of the biphenyl backbone, have been developed and successfully applied in the Rh-catalyzed enantioselective desymmetric hydrogenation of α-acetamido-1,3-indanediones, providing chiral α-acetamido-ß-hydroxybenzocyclic pentones in high yields (up to 97%) and with excellent enantioselectivities (up to 99% ee). The reaction could be carried out on a gram scale, and the corresponding products were used as vital intermediates for the synthesis of analogues of chiral spirobenzylisoquinoline alkaloids. Both the crystal structure analysis and the DFT calculations revealed that the large dihedral angle of the Enm-BridgePhos-Rh complexes is highly related to the excellent enantioselectivities.

Diagnosis and Treatment of Double Thyroglossal Duct Cyst.

This retrospective study aimed to investigate clinical diagnostic and management characteristics of double thyroglossal duct cyst (TDC) cases. Seventy-eight patients diagnosed with TDCs who were admitted to the inpatient ward of the Department of Otolaryngology, Dalian Central Municipal Hospital from June 2008 to October 2021 were included in the study. Ultimately, 67 of these patients were diagnosed with single TDCs and 11 patients with double TDCs. Each patient underwent computed tomography and color doppler ultrasound imaging of their neck masses, thyroid color doppler ultrasound imaging, and surgical cyst removal through the classic Sistrunk procedure. All surgically excised specimens were sent to the pathology lab for examination and were confirmed to contain TDCs. Two of the 67 patients with single TDCs experienced postoperative complications related to infections within the operative area, whereas no patients with double TDCs experienced postoperative infection, excessive bleeding, or other surgical complications. All cases were followed up for 1 to 3 years after surgery with no cyst recurrence observed. Double TDCs may present on physical examination as unilateral neck masses that interfere with tongue extension and movement and swallowing that can be identified using imaging methods. Correct clinical diagnosis and complete surgical removal of cysts are key measures for ensuring successful treatment outcomes for patients with TDCs.

A Systematic Review and Meta-analysis of SNOT-22 Outcomes After Sinus Surgery.

Background: All stakeholders in the healthcare system have prioritized and will continue to prioritize enhancing care quality. The measurement of sinus-specific quality of life (QOL) is potentially the most commonly used QOL parameter for chronic rhinosinusitis (CRS). Objective: A systematic review and meta-analysis were used in this study to determine the mean change in patients' scores on the 22-item Sino-Nasal Outcome Test (SNOT-22) before and after endoscopic sinus surgery (ESS) for CRS. Methods: PubMed, Google Scholar, and ScienceDirect were searched for articles that compared SNOT-22 scores before and after ESS in adult patients with CRS and were published between January 2000 and March 2023. The mean post-op change, 95% confidence interval (CI), forest plot, and inverse variance weighting were all generated using a random effects model. A mixed-effects meta-regression was used to analyze the effect of patient-specific characteristics across studies. Results: Fifteen prospective patient cohorts published from 2009 to 2023 were included in this meta-analysis. At an average follow-up of 25.5 months, all studies demonstrated a statistically significant difference in mean SNOT-22 scores between baseline and post-op time periods (P < .05), ranging from 5.1 to 55.4. Across all studies, the mean SNOT-22 changed significantly by 26.02 (95% CI: 12.83-38.60). According to a stepwise multivariate analysis, studies with higher mean age and mean pre-op SNOT-22 scores had greater changes in SNOT-22 scores following ESS, whereas trials with longer mean follow-up duration had smaller changes in SNOT-22 scores. Conclusion: Research utilizing the SNOT-22 instrument has demonstrated that endoscopic sinus surgery (ESS) leads to enhanced quality of life (QOL) outcomes. The literature reports that improvement is influenced by the initial SNOT-22 score, the mean age of the patients, and the duration of the follow-up period.

The Sino-Nasal Outcome Test-22 (SNOT-22) has shown that the quality-of-life results of sinus surgery after endoscopic sinus surgery (ESS) improve significantly. The amount of change seems to vary a lot from one study to the next, and this difference seems to be caused by things like the pre-op SNOT-22 score, the average age of the subjects, and the length of the tracking period. The results of this study give both a single number value and a range of changes that are likely to happen after surgery. These results can be used to guide projects that aim to improve the quality of care. Also, giving the Sino-Nasal Outcome Test-22 (SNOT-22) to people with chronic rhinosinusitis (CRS) before they have surgery may help them understand what effects they can expect, although this is up to each person to decide. Recent preliminary research shows that using SNOT-22 scores and tissue histopathology together could be a new way to predict how well treatment will work for people with CRS. The accuracy and precision of future analyses are likely to get better as efforts are made to get unbiased data and patient-level metrics from a wide range of patients and doctors.

Unraveling the Asymmetric O─O Radical Coupling Mechanism on Ru─O─Co for Enhanced Acidic Water Oxidation.

Heterogeneous oxides with multiple interfaces provide significant advantages in electrocatalytic activity and stability. However, controlling the local structure of these oxides is challenging. In this work, unique heterojunctions are demonstrated based on two oxide types, which are formed via pyrolysis of a ruthenocene metal-organic framework (Ru-MOF) at specific temperatures. The resulted Ru-MOF-400 exhibits excellent electrocatalytic activity, with an overpotential of 190 mV at a current density of 10 mA cm-2 in 0.1 m HClO4 , and a mass activity of 2557 A gRu -1 , three orders of magnitude higher than commercial RuO2 . The Ru─O─Co bond formed by the incorporation of Co into the rutile lattice of RuO2 inhibits the disolution of Ru. Operando electrochemical investigations and density functional theory results reveal that the Ru-MOF-400 undergo asymmetric dual-active site oxide path mechanism during the acidic oxygen evolution reaction process, which is predominantly mediated by the asymmetric Ru─Co dual active site present at the interfaces between Co3 O4 and CoRuOx .

Detection approach for GEO space objects with a wide-field optical telescope array.

In 2020, Changchun Observatory developed a 280 mm wide-field optical telescope array to improve surveillance of space debris in the geosynchronous belt. There are many advantages including a wide field of view, the ability to observe a large area of sky and high reliability. However, the wide field of view causes a significant number of background stars to appear in the image when photographing space objects, making it difficult to detect them. This research focuses on the precise detection of GEO space objects from images taken by this telescope array in order to position them in large quantities. Our work further investigates the motion feature of an object, namely that the object can be seen as being in a uniform linear motion for a brief length of time. Based on this feature, the belt can be divided into a number of smaller areas and the telescope array scans each smaller area one at a time from east to west. To detect objects in the subarea, a combination of image differencing with trajectory association is used. The image differencing algorithm is used to remove most stars and screen out suspected objects in the image. Next, the trajectory association algorithm is employed to further filter out the real objects among the suspected ones, and the trajectories attributed to the same object are linked. The feasibility and accuracy of the approach were verified by the experiment results. The accuracy rate of trajectory association exceeds 90% and on average, more than 580 space objects can be detected per observation night. Since the J2000.0 equatorial system can accurately describe the apparent position of an object, the object can be detected by using this coordinate system as opposed to the pixel coordinate system.

CAR T cell therapy for T cell leukemia and lymphoma: latest updates from 2022 ASH Annual Meeting.

Due to the concern of fratricide, clinical development of CAR T cells for the therapy of T cell malignancies lags behind that for B cell malignancies. Attempts are being made to revise T cell biomarkers so that the re-engineered CAR T cells can target T cell malignancies. CD3 and CD7 are the two pan-T cell surface biomarkers that have been either knocked out or knocked down through genome base- editing technology or by protein expression blockers so that the re-engineered T cells can target T cells without fratricide. We summarized several latest reports on the CAR T cells for the therapy of T cell leukemia /lymphoma from the 2022 ASH Annual Meeting, with latest updates on clinical trials of TvT CAR7, RD-13-01, and CD7 CART.

Clinical Diagnosis and Treatment of Primary Laryngeal Neuroendocrine Carcinoma.

OBJECTIVE: This study aims to investigate the clinical diagnosis and treatment characteristics of primary laryngeal neuroendocrine carcinoma. PATIENTS AND METHODS: A retrospective analysis was performed for the data of 6 patients with primary laryngeal neuroendocrine carcinoma admitted to the Department of Otorhinolaryngology of Dalian Central Hospital from September 2015 to January 2022, all of whom were male patients. And laryngoscopy showed that 4 had a similar appearance to hemangioma, 1 had nodular hyperplasia, and 1 was papilloma-like. The site of onset was located on the laryngeal surface of the epiglottis in 3 cases, situated in the aryepiglottic fold in 2 cases, and the posterior ventricular zone in 1 case. Five patients underwent surgery, including 4 by transoral endoscopic cryogenic plasma radiofrequency mass resection; one underwent a cervical lymph node dissection and supraglottic horizontal hemilaryngectomy. The remaining 1 case was treated in another hospital after the pathological diagnosis was confirmed by biopsy. All patients had no cervical lymph node metastases and were not supplemented with chemoradiotherapy. RESULTS: The postoperative pathological diagnosis of all 5 patients was neuroendocrine carcinoma. No cancer cells were seen at the margins and base. One patient was lost to follow-up after treatment in another hospitals and the rest were followed up for 6 months to 6 years. One patient had removed laryngeal tumor and epiglottis by a low-temperature plasma radiofrequency ablation, recurrence 1 year after surgery, and no recurrence for 5 years after supraglottic horizontal hemilaryngectomy combined with prophylactic cervical lymph node dissection, no recurrence for the other 4 patients after 6 months to 4 years of follow-up. CONCLUSION: The common sites of laryngeal neuroendocrine carcinoma are the laryngeal surface of the epiglottis and the aryepiglottic fold. The appearance of the tumor is mainly similar to that of hemangioma. Moreover, a common pathological classification is atypical carcinoid tumors, where early detection and surgical treatment can achieve a good therapeutic effect.

Middle-age high normal serum sodium as a risk factor for accelerated biological aging, chronic diseases, and premature mortality.

BACKGROUND: It is known that some people age faster than others, some people live into old age disease-free, while others develop age-related chronic diseases. With a rapidly aging population and an emerging chronic diseases epidemic, finding mechanisms and implementing preventive measures that could slow down the aging process has become a new challenge for biomedical research and public health. In mice, lifelong water restriction shortens the lifespan and promotes degenerative changes. Here, we test the hypothesis that optimal hydration may slow down the aging process in humans. METHODS: We performed a cohort analysis of data from the Atherosclerosis Risk in Communities study with middle-age enrollment (45-66 years, n = 15,752) and 25 years follow-up. We used serum sodium, as a proxy for hydration habits. To estimate the relative speed of aging, we calculated the biological age (BA) from age-dependent biomarkers and assessed risks of chronic diseases and premature mortality. FINDINGS: The analysis showed that middle age serum sodium >142 mmol/l is associated with a 39% increased risk to develop chronic diseases (hazard ratio [HR] = 1.39, 95% confidence interval [CI]:1.18-1.63) and >144 mmol/l with 21% elevated risk of premature mortality (HR = 1.21, 95% CI:1.02-1.45). People with serum sodium >142 mmol/l had up to 50% higher odds to be older than their chronological age (OR = 1.50, 95% CI:1.14-1.96). A higher BA was associated with an increased risk of chronic diseases (HR = 1.70, 95% CI:1.50-1.93) and premature mortality (HR = 1.59, 95% CI 1.39-1.83). INTERPRETATION: People whose middle-age serum sodium exceeds 142 mmol/l have increased risk to be biologically older, develop chronic diseases and die at younger age. Intervention studies are needed to confirm the link between hydration and aging. FUNDING: This work was funded by Intramural Research program of the National Heart, Lung, and Blood Institute (NHLBI). The ARIC study has been funded in whole or in part with federal funds from the NHLBI; the National Institutes of Health (NIH); and the Department of Health and Human Services.

The immune microenvironment shapes transcriptional and genetic heterogeneity in chronic lymphocytic leukemia.

In chronic lymphocytic leukemia (CLL), B-cell receptor signaling, tumor-microenvironment interactions, and somatic mutations drive disease progression. To better understand the intersection between the microenvironment and molecular events in CLL pathogenesis, we integrated bulk transcriptome profiling of paired peripheral blood (PB) and lymph node (LN) samples from 34 patients. Oncogenic processes were upregulated in LN compared with PB and in immunoglobulin heavy-chain variable (IGHV) region unmutated compared with mutated cases. Single-cell RNA sequencing (scRNA-seq) distinguished 3 major cell states: quiescent, activated, and proliferating. The activated subpopulation comprised only 2.2% to 4.3% of the total tumor bulk in LN samples. RNA velocity analysis found that CLL cell fate in LN is unidirectional, starts in the proliferating state, transitions to the activated state, and ends in the quiescent state. A 10-gene signature derived from activated tumor cells was associated with inferior treatment-free survival (TFS) and positively correlated with the proportion of activated CD4+ memory T cells and M2 macrophages in LN. Whole exome sequencing (WES) of paired PB and LN samples showed subclonal expansion in LN in approximately half of the patients. Since mouse models have implicated activation-induced cytidine deaminase in mutagenesis, we compared AICDA expression between cases with and without clonal evolution but did not find a difference. In contrast, the presence of a T-cell inflamed microenvironment in LN was associated with clonal stability. In summary, a distinct minor tumor subpopulation underlies CLL pathogenesis and drives the clinical outcome. Clonal trajectories are shaped by the LN milieu, where T-cell immunity may contribute to suppressing clonal outgrowth. The clinical study is registered at clinicaltrials.gov as NCT00923507.