bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathology of Surgically Resected Lung Cancers Following Neoadjuvant Therapy
Authors: Berezowska Sabina , Keyter Mark , Bouchaab Hasna , Weissferdt Annikka
Published: April 2024

In around 30% of patients, non-small cell lung cancer is diagnosed at an advanced but resectable stage. Adding systemic therapy has shown clear benefit over surgery alone in locally advanced disease, and currently, chemo-immunotherapy in the adjuvant or neoadjuvant setting is the new standard for patients without targetable mutations. One major advantage of the neoadjuvant approach is the possibility of an immediate evaluation of the treatment effect, highlighting the role of pathology as an important contributor at the forefront of clinical decision-making and research. This review provides a summary and an update on current guidelines for histological evaluation of treatment effect after neoadjuvant therapy, also known as regression grading, and discusses newer data focusing on areas of evolving questions and controversies, such as the gross examination of the tumor and tumor bed, weighted versus unweighted evaluation approaches, discussion of histologic tumor type-specific cut-offs for major pathologic response, assessment of lymph nodes and regression grading after immunotherapy and targeted therapy. As no data or recommendations exist on regression grading of multiple tumor nodules, a practical approach is recommended. Lastly, we will touch on additional tissue biomarkers and summarize recent advances in the ardently discussed field of using circulating tumor DNA for the evaluation of treatment response.
The effect of weight gain and metabolic dysfunction-associated steatotic liver disease on liver fibrosis progression and regression in people with HIV
Authors: Guaraldi Giovanni , Milic Jovana , Renzetti Stefano , Motta Federico , Cinque Felice , Bischoff Jenny , Desilani Andrea , Conti Jacopo , Medioli Filippo , del Monte Martina , Kablawi Dana , Elgretli Wesal , Calza Stefano , Mussini Cristina , Rockstroh Juergen K. , Sebastiani Giada
Published: April 2024

Objective:

People with HIV (PWH) have high risk of liver fibrosis. We investigated the effect of weight gain and metabolic dysfunction-associated steatotic liver disease (MASLD) on liver fibrosis dynamics.

Design:

Multicenter cohort study.

Methods:

Fibrosis progression was defined as development of significant fibrosis [liver stiffness measurement (LSM) ≥8 kPa], or transition to cirrhosis (LSM ≥13 kPa), for those with significant fibrosis at baseline. Fibrosis regression was defined as transition to LSM less than 8 kPa, or to LSM less than 13 kPa for those with cirrhosis at baseline. MASLD was defined as hepatic steatosis (controlled attenuation parameter >248 dB/m) with at least one metabolic abnormality. A continuous-time multistate Markov model was used to describe transitions across fibrosis states.

Results:

Among 1183 PWH included from three centers (25.2% with viral hepatitis coinfection), baseline prevalence of significant fibrosis and MASLD was 14.4 and 46.8%, respectively. During a median follow-up of 2.5 years (interquartile range 1.9–3.5), the incidence rate of fibrosis progression and regression was 2.8 [95% confidence interval (CI) 2.3–3.4] and 2.2 (95% CI 1.9–2.6) per 100 person-years, respectively. In Markov model, weight gain increased the odds of fibrosis progression [odds ratio (OR) 3.11, 95% CI 1.59–6.08], whereas weight gain (OR 0.30, 95% CI 0.10–0.84) and male sex (OR 0.32, 95% CI 0.14–0.75) decreased the odds of fibrosis regression. On multivariable Cox regression analysis, predictors of fibrosis progression were weight gain [adjusted hazard ratio (aHR) 3.12, 95% CI 1.41–6.90] and MASLD (aHR 2.72, 95% CI 1.05–7.02).

Conclusion:

Fibrosis transitions are driven by metabolic health variables in PWH, independently of viral hepatitis coinfection and antiretroviral class therapy.
Association between obesity and cancer risk in adults with HIV in Korea
Authors: Jang Yoonyoung , Kim Taehwa , Choi Yunsu , Ahn Kyoung Hwan , Kim Jung Ho , Seong Hye , Kim Youn Jeong , Kim Shin-Woo , Choi Jun Yong , Kim Hyo Youl , Song Joon Young , Choi Hee Jung , Kim Sang Il. , Sohn Jang Wook , Chin BumSik , Choi Bo-Youl , Park Boyoung
Published: April 2024

Introduction:

This study aimed to investigate the association between obesity and cancer risk as well as site-specific cancer risks in adults with HIV using a nationwide health screening database in Korea.

Methods:

Of the 16,671 adults with a new diagnosis of HIV from 2004 to 2020, 456 incident cancer cases and 1814 individually matched controls by sex, year of birth, year of HIV diagnosis, and follow-up duration (1 : 4 ratio) were included in this nested case–control study. The association between obesity (BMI ≥25 kg/m2) and cancer risks was estimated and presented as odds ratios (ORs) and 95% confidence intervals (95% CIs).

Results:

Of the 456 cancer incident cases, there were 146 AIDS-defining cancer cases and 310 non-AIDS-defining cancer cases. Compared with nonobese adults with HIV, obese adults with HIV were at higher risk of non-AIDS-defining cancer (OR = 1.478, 95% CI = 1.118–1.955). Otherwise, the overall risk of AIDS-defining cancer (OR = 0.816, 95% CI = 0.520–1.279) and each type of AIDS-defining cancer (Kaposi sarcoma and non-Hodgkin's lymphoma) were not high in obese adults with HIV. Of the specific types of non-AIDS-defining cancers, obesity was associated with an increased risk of colorectal cancer (OR = 3.090, 95% CI = 1.110–8.604) and liver, bile duct, and pancreatic cancers (OR = 2.532, 95% CI = 1.141–5.617).

Conclusion:

Obesity, which is one of the important health concerns in HIV management, was associated with an increased risk of non-AIDS-defining cancer but not AIDS-defining cancer.
Can Automated 3-Dimensional Dixon-Based Methods Be Used in Patients With Liver Iron Overload?
Authors: Venkatakrishna Shyam Sunder B. , Otero Hansel J. , Khrichenko Dmitry , Serai Suraj D.
Published: April 2024

Purpose

Accurate quantification of liver iron concentration (LIC) can be achieved via magnetic resonance imaging (MRI). Maps of liver T2*/R2* are provided by commercially available, vendor-provided, 3-dimensional (3D) multiecho Dixon sequences and allow automated, inline postprocessing, which removes the need for manual curve fitting associated with conventional 2-dimensional (2D) gradient echo (GRE)–based postprocessing. The main goal of our study was to investigate the relationship among LIC estimates generated by 3D multiecho Dixon sequence to values generated by 2D GRE–based R2* relaxometry as the reference standard.

Methods

A retrospective review of patients who had undergone MRI scans for estimation of LIC with conventional T2* relaxometry and 3D multiecho Dixon sequences was performed. A 1.5 T scanner was used to acquire the magnetic resonance studies. Acquisition of standard multislice multiecho T2*-based sequences was performed, and R2* values with corresponding LIC were estimated. The comparison between R2* and corresponding LIC estimates obtained by the 2 methods was analyzed via the correlation coefficients and Bland-Altman difference plots.

Results

This study included 104 patients (51 male and 53 female patients) with 158 MRI scans. The mean age of the patients at the time of scan was 15.2 (SD, 8.8) years. There was a very strong correlation between the 2 LIC estimation methods for LIC values up to 3.2 mg/g (LIC quantitative multiecho Dixon [qDixon; from region of interest R2*] vs LIC GRE [in-house]: r = 0.83, P < 0.01; LIC qDixon [from segmentation volume R2*] vs LIC GRE [in-house]: r = 0.92, P < 0.01); and very weak correlation between the 2 methods at liver iron levels >7 mg/g.

Conclusion

Three-dimensional–based multiecho Dixon technique can accurately measure LIC up to 7 mg/g and has the potential to replace 2D GRE–based relaxometry methods.
Utility of Combined Use of Imaging Features From Abdominopelvic CT and CA 125 to Identify Presence of CT Occult Peritoneal Metastases in Advanced Gastric Cancer
Authors: Zhu Zhen-Ning , Feng Qiu-Xia , Li Qiong , Xu Wei-Yue , Liu Xi-Sheng
Published: April 2024

Objective

The purpose of this study is to identify the presence of occult peritoneal metastasis (OPM) in patients with advanced gastric cancer (AGC) by using clinical characteristics and abdominopelvic computed tomography (CT) features.

Methods

This retrospective study included 66 patients with OPM and 111 patients without peritoneal metastasis (non-PM [NPM]) who underwent preoperative contrast-enhanced CT between January 2020 and December 2021. Occult PMs means PMs that are missed by CT but later diagnosed by laparoscopy or laparotomy. Patients with NPM means patients have neither PM nor other distant metastases, indicating there is no evidence of distant metastases in patients with AGC. Patients' clinical characteristics and CT features such as tumor marker, Borrmann IV, enhancement patterns, and pelvic ascites were observed by 2 experienced radiologists. Computed tomography features and clinical characteristics were combined to construct an indicator for identifying the presence of OPM in patients with AGC based on a logistic regression model. Receiver operating characteristic curves and the area under the receiver operating characteristic curve (AUC) were generated to assess the diagnostic performance of the combined indicator.

Results

Four independent predictors (Borrmann IV, pelvic ascites, carbohydrate antigen 125, and normalized arterial CT value) differed significantly between OPM and NPM and performed outstandingly in distinguishing patients with OPM from those without PM (AUC = 0.643–0.696). The combined indicator showed a higher AUC value than the independent risk factors (0.820 vs 0.643–0.696).

Conclusions

The combined indicator based on abdominopelvic CT features and carbohydrate antigen 125 may assist clinicians in identifying the presence of CT OPMs in patients with AGC.
Using Patient-Specific Contrast Enhancement Optimizer Simulation Software During the Transcatheter Aortic Valve Implantation—Computed Tomography Angiography in Patients With Aortic Stenosis
Authors: Masuda Takanori , Nakaura Takeshi , Higaki Toru , Funama Yoshinori , Matsumoto Yoriaki , Sato Tomoyasu , Okimoto Tomokazu , Arao Keiko , Imaizumi Hiromasa , Arao Shinichi , Ono Atsushi , Hiratsuka Junichi , Awai Kazuo
Published: April 2024

Objectives

This study assessed whether patient-specific contrast enhancement optimizer simulation software (p-COP) can reduce the contrast material (CM) dose compared with the conventional body weight (BW)-tailored scan protocol during transcatheter aortic valve implantation-computed tomography angiography (TAVI-CTA) in patients with aortic stenosis.

Methods

We used the CM injection protocol selected by the p-COP in group A (n = 30). p-COP uses an algorithm that concerns data on an individual patient's cardiac output. Group B (n = 30) was assigned to the conventional BW-tailored CM injection protocol group. We compared the CM dose, CM amount, injection rate, and computed tomography (CT) values in the abdominal aorta between the 2 groups and classified them as acceptable (>280 Hounsfield units (HU)) or unacceptable (<279 HU) based on the optimal CT value and visualization scores for TAVI-CTA. We used the Mann–Whitney U test to compare patient characteristics and assess the interpatient variability of subjects in both groups.

Results

Group A received 56.2 mL CM and 2.6 mL/s of injection, whereas group B received 76.9 mL CM and 3.4 mL/s of injection (P < 0.01). The CT value for the abdominal aorta at the celiac level was 287.0 HU in group A and 301.7HU in group B (P = 0.46). The acceptable (>280 HU) and unacceptable (<280 HU) CT value rates were 22 and 8 patients in group A and 24 and 6 patients in group B, respectively (P = 0.76). We observed no significant differences in the visualization scores between groups A and B (visualization score = 3, P = 0.71).

Conclusion

The utilization of p-COP may decrease the CM dosage and injection rate by approximately 30% in individuals with aortic stenosis compared with the body-weight-tailored scan protocol during TAVI-CTA.
Assessing the Feasibility of Simplifying the Scanning Protocol for Spinal Metastases With Vertebral Compression Fractures Using Only the Dixon T2-Weighted Sequence
Authors: Jiang Jiuming , Miao Lei , Zhang Li , Shi Zhuo , Zhang Huanhuan , Wen Xin , Hu Sijie , Xu Libin , Gong Lihua , Li Meng
Published: April 2024

Objective

Conventional imaging protocols, including sagittal T1-weighted imaging (T1WI) and water-only T2-weighted imaging (T2WI), are time consuming when screening for spinal metastases with vertebral compression fractures (VCFs). In this study, we aimed to assess the accuracy of using only the Dixon T2-weighted sequence in the diagnosis of spinal metastases with VCFs to determine its suitability as a simplified protocol for this task.

Methods

This retrospective study included 27 patients diagnosed with spinal metastases and VCFs. Qualitative analysis was performed separately by two musculoskeletal radiologists, who independently performed diagnostic evaluations of each vertebra using both conventional and simplified protocols. McNemar's test was then used to compare the differences in diagnostic results, and Cohen's kappa coefficient was used to assess interobserver and interprotocol agreement. Diagnostic performance values for both protocols, including sensitivity, specificity, and area under the curve, were then determined based on the reference standard. Quantitative image analysis was performed randomly for 30 metastases on T1WI and fat-only T2WI to measure the signal intensity, signal-to-noise ratio, and contrast-to-noise ratio.

Results

The diagnosis of VCFs by both radiologists was in full agreement with the reference standard. The classification of spinal metastases and diagnostic performance values determined by both radiologists were not significantly different between the two protocols (all P > 0.05), and the consistency between observers and protocols was excellent (κ = 0.973–0.991). The contrast-to-noise ratio of fat-only T2WI was significantly higher than that of T1WI (P < 0.001).

Conclusions

The Dixon T2-weighted sequence alone performed well in diagnosing spinal metastases with VCFs, performing no worse than the conventional protocol (T1WI and water-only T2WI). This suggests that the Dixon T2-weighted sequence alone can serve as a simplified protocol for the diagnosis of spinal metastases with VCFs, thereby avoiding the need for more intricate scanning procedures.
Ultralow-Dose Dynamic Expiratory CT and Repeated Imaging Enhance Evaluation for Tracheomalacia
Authors: Lee Seung Yup , Bade Brett C. , Sison Cristina P. , Karp Jason , Inra Matthew , Paul Subroto , Lee Paul , Lazzaro Richard S. , Shah Rakesh , Cohen Stuart L.
Published: April 2024

Objective

This study aims to determine if a novel imaging protocol (ultralow-dose dynamic expiratory computed tomography [CT] with repeated imaging) identifies tracheomalacia (TM) more reliably than traditional dynamic tracheal CT.

Methods

We performed a retrospective evaluation of 184 consecutive ultralow-dose dynamic CTs for TM during 2017. The protocol obtains images during 1 inspiration and 2 forced expirations. Tracheal narrowing during both expirations (airway narrowing [percentage] during first dynamic expiration CT [DE1], airway narrowing [percentage] during second dynamic expiration CT [DE2]) was reported as a percentage of inspiratory area. We identified maximum narrowing of each patient's sequence (maximum narrowing [percentage] on either dynamic expiration CT [DEmax] = greatest narrowing of DE1 or DE2) and compared DE1, DE2, and DEmax in individual studies and between patients. Outcomes included frequency of TM, tracheal narrowing, and severity. Reliability was assessed by comparing tracheal area narrowing and TM grade.

Results

There was significantly more airway narrowing using 2 expiratory image acquisitions. Average DEmax tracheal area was 12% narrower than DE1 alone and 21% worse than DE2 alone (both P < 0.001). Using DEmax, TM was diagnosed 35% more often than DE1 alone and 31% more often than DE2 alone (P < 0.001). DEmax identified more severe distribution of TM compared with DE1 or DE2 alone (P < 0.001). Reliability between DE1 and DE2 was good for tracheal narrowing and moderate for TM grade. The mean effective radiation dose was 2.41 millisievert (mSv) for routine inspiration CT and 0.07 mSv for each dynamic expiration CT (total effective radiation, 2.55 mSv).

Conclusions

Dynamic expiration CT with 2 expiratory image acquisitions enhanced evaluation of TM, minimally increased radiation dose, and should be considered as a noninvasive screening option.
The Utility of Prostate-Specific Membrane Antigen-11 PET in Detection and Management of Central Nervous System Neoplasms
Authors: Dawod Mina , Rush Evan , Nagib Paul B. , Aduwo Jessica , Bodempudi Pranav , Appiah-Kubi Emmanuel
Published: April 2024

We present a case series of 5 patients diagnosed with schwannoma and 1 patient diagnosed with astrocytoma who underwent PSMA PET imaging for tumor detection. We retrospectively analyzed the records of 4 male and 2 female patients (mean age, 53.2 ± 13.2) who underwent PSMA PET imaging between March and September 2023. PET interpretation showed increased Ga-PSMA-11 accumulation in all patients with a mean SUVmaxof 3.11 ± 1.8. This series underscores PSMA PET’s potential for CNS neoplasm detection.
Diagnostic Role of FDG PET/CT in Pediatric Patients With Chronic Recurrent Multifocal Osteomyelitis
Authors: Xu Yanfeng , Wang Guanyun , Wang Yu , Wang Wei , Kan Ying , Yang Jigang
Published: April 2024

Purpose

Chronic recurrent multifocal osteomyelitis (CRMO), or chronic nonbacterial osteomyelitis, is difficult to diagnose. The accurate diagnosis of CRMO relies on comprehensive imaging examinations because of its multifocal nature. In this regard, 18F-FDG PET/CT has demonstrated significant utility in inflammatory diseases. This study tries to determine the value of FDG PET/CT in the evaluation of CRMO.

Patients and Methods

We retrospectively collected imaging data from pediatric CRMO patients who underwent FDG PET/CT scans. Lesions exhibiting abnormal metabolism with/without structural abnormalities on FDG PET/CT were identified as CRMO lesions, and their location and SUVmax were recorded.

Results

A total of 21 pediatric patients with CRMO were included in this study. The median age at diagnosis was 9.4 years. Total 131 foci of abnormal activity were identified using FDG PET/CT imaging. The distribution pattern showed a higher prevalence of lower limbs and pelvis involvement. Among all identified lesions, abnormalities were detected on both PET and CT images of 93 lesions, whereas exclusively positive findings on 18F-FDG PET alone were observed for 38 of them.

Conclusions

Our study findings suggest a higher prevalence of lesions in the bones of the lower limbs and pelvis among children with CRMO. Compared with CT scans, FDG PET exhibits superior sensitivity in detecting these lesions.
Detection of Adenocarcinoma of the Colon on 18F-Fluciclovine PET/CT
Authors: Desai Charisma , Clark Angela , Surasi Devaki Shilpa , Flynt Lesley
Published: April 2024

An 85-year-old man with prostate cancer and de novo bone metastases was treated with hormonal therapy with resolution of bone lesions, improved primary disease, and improved serum tumor markers. Although on hormonal therapy, biochemical recurrence prompted performance of 18F-fluciclovine PET/CT. Fluciclovine PET/CT revealed primary prostate cancer progression with incidental note of avid foci in the colon for which colonoscopy was recommended. Colonoscopy with biopsy was performed with pathology revealing primary colon adenocarcinoma. Before reinitiation of prostate cancer therapy, segmental colon resection was performed with pathology positive for additional sites of colon cancer.
Favorable Response of 225Ac-PSMA in the Treatment of Castration-Resistant Prostate Cancer With High Bone Metastasis Burden
Authors: Wang Yudi , Hua Qingchu , Zhang Yu , Wang Wei , Chen Yue
Published: April 2024

225Ac-PSMA treatment demonstrated low hematologic toxicity for prostate cancer with diffuse red marrow infiltration. A 70-year-old man with diffuse bone metastases of castration-resistant prostate cancer received 225Ac-PSMA radiation therapy. After 1 treatment cycle, the patient’s skeletal lesions demonstrated a significant response and a significant decrease in PSA. 225Ac-PSMA may be a promising therapeutic option for metastatic castration-resistant prostate cancer patients with high bone metastatic burden.
Intense FDG Uptake in Well-Differentiated Inflammatory Liposarcoma of the Retroperitoneum
Authors: Zhao Qian , Dong Aisheng , Zuo Changjing , Fang Yu
Published: April 2024

Inflammatory variant of well-differentiated liposarcoma is a rare subtype of liposarcoma, and its imaging features have been rarely reported. We describe FDG PET/CT findings in a case of well-differentiated inflammatory liposarcoma. The tumor showed no detectable fat and intense FDG uptake and caused diffuse FDG uptake of the bone marrow due to paraneoplastic leukemoid reaction. Microscopically, there were extensive inflammatory infiltrates in the tumor, which may contribute to the intense FDG uptake. This case indicates that although well-differentiated liposarcoma usually shows low-grade FDG uptake, inflammatory variant of well-differentiated liposarcoma can show intense FDG uptake mimicking high-grade liposarcoma.
18F-FDG PET/CT in Solitary Extramedullary Plasmacytoma of the Penis
Authors: Chen Xueqi , Chen Guoqian , Li Qian , Fu Zhanli
Published: April 2024

A 72-year-old man presented with a painless penile mass for 3 months. Contrast-enhanced CT revealed heterogeneous enhancement, whereas 18F-FDG PET/CT displayed inhomogeneous 18F-FDG accumulation in the lesion without other abnormal activity. The histopathological examination from biopsied specimen confirmed the diagnosis of a plasmacytoma. However, the subsequent tests, including serum/urine immunofixation electrophoresis, serum/urine free light chain assay, and bone marrow smear/biopsy, did not show any abnormalities. The conclusive diagnosis was a solitary extramedullary plasmacytoma of the penis.
Multiple Ring-Enhancing Brain Lesions: Fulminant Diffuse Cerebral Toxoplasmosis or Cerebral Metastases?
Authors: De Keersmaecker Sebastiaan , Van Cauter Sofie , Bekelaar Kim
Published: April 2024

In this case report, we describe a 76-year-old woman, presenting with dizziness for the past 2 months, without other focal neurological signs. A magnetic resonance imaging of the brain was ordered by her GP. The MRI demonstrated multiple ring-enhancing lesions, both supratentorial and infratentorial. Lumbar puncture showed normal findings, in particular a normal cell count and culture. Because of the radiologic appearance, initially thought to be suggestive of cerebral abscesses, antibiotics were started. However, further workup revealed a new diagnosis of a stage IV (metastatic) small cell lung carcinoma, making diffuse brain metastases more likely. The patient was transferred to oncology/pneumology, where she was started on whole-brain radiotherapy, after which systemic therapy would start. However, because of further clinical deterioration, she was admitted at the palliative ward, where she died only 3 months after the initial presentation. In this case report, we emphasize the importance of keeping a broad differential diagnosis and briefly review the various possible pathologies causing ring-enhancing lesions.
Exclusive Transcervical Drainage for Posterior Mediastinal Abscess Originating from a Mandibular Molar
Authors: Nagaoka Masato , Motegi Masaomi
Published: April 2024

The progression of a cervical abscess toward the mediastinum is rare but remains one of the most serious diseases, even in the era of antibiotics. A mediastinal abscess can originate from an odontogenic infection and presents a challenge for otolaryngologists and craniofacial surgeons, particularly when it spreads caudally to the tracheal bifurcation. For successful treatment of such an abscess, patients are generally referred to a thoracic surgeon for drainage. We present a distinctive case of an odontogenic infection-induced wide mediastinal abscess that could be drained only through cervical manipulation by using a sump-type tube. The patient was discharged on postoperative day 55 without any complications. This is the first report showing that descending mediastinal abscesses extending below the tracheal bifurcation could be drained by head and neck surgeons alone. The technique is easy and hence reproducible, safe, and convenient to perform.
UNVEILING THE PROTECTIVE MECHANISMS OF PUERARIN AGAINST ACUTE LUNG INJURY: A COMPREHENSIVE EXPLORATION OF THE ROLES AND MECHANISMS OF MST1/ERS SIGNALING
Authors: Chen Wen-xuan , Zhang Wen-long , Zhang Huan-huan , Lai Yuan-zhen , Huang Jun , Lei Yang , Liu Yan-juan , Wang Xiao-li , Deng Hua-fei
Published: April 2024

Objectives: Puerarin, the principal active constituent extracted from Pueraria, is believed to confer protection against sepsis-induced lung injury. The study aimed to elucidate the role and mechanism of Mst1/ERS in puerarin-mediated protection against acute lung injury (ALI). Methods: Monolayer vascular endothelial cell permeability was assessed by gauging the paracellular flow of FITC-dextran 40,000 (FD40). ELISA was employed for the quantification of inflammatory cytokines. Identification of target proteins was conducted through western blotting. Histological alterations and apoptosis were scrutinized using hematoxylin-eosin staining and TUNEL staining, respectively. The ultrastructure of the endoplasmic reticulum was observed via transmission electron microscopy. Results: Puerarin significantly protected mice from LPS-induced ALI, reducing lung interstitial width, neutrophil and lymphocyte infiltration, pulmonary interstitial and alveolar edema, and lung apoptosis. Puerarin treatment also markedly attenuated levels of TNF-α and IL-1β in both alveolar lavage fluid and serum. Furthermore, puerarin significantly attenuated LPS-induced increases in Mst1, GRP78, CHOP, and Caspase12 protein expression and blunted LPS-induced decrease in ZO-1 protein expression in lung tissues. Puerarin obviously reduced endoplasmic reticulum expansion and vesiculation. Similarly, puerarin significantly mitigated the LPS-induced reduction in HUVEC cell viability and ZO-1 expression. Puerarin also attenuated LPS-induced increase in apoptosis, TNF-α and IL-1β, FD40 flux, and Mst1, GRP78, CHOP, and Caspase12 expression in HUVEC cells. Nevertheless, the inhibitory impact of puerarin on vascular endothelial cell injury, lung injury, and endoplasmic reticulum stress (ERS) was diminished by Mst1 overexpression. Conclusion: These findings demonstrated that the Mst1/ERS signaling pathway played a pivotal role in the development of LPS-induced vascular endothelial cell dysfunction and ALI. Puerarin exhibited the ability to attenuate LPS-induced vascular endothelial cell dysfunction and ALI by inhibiting the Mst1/ERS signaling pathway.
Investigating flock-associated mimicry: examining the evidence for, and drivers of, plumage mimicry in the greater and lesser necklaced laughingthrush
Authors: Gosai Kamal Raj , Zhou Liping , Liu Yang , Braun Edward L. , Kimball Rebecca T. , Robinson Scott K. , Jiang Aiwu , Goodale Eben
Published: April 2024

Visual mimicry is less understood in birds than in other taxa. The interspecific social dominance mimicry (ISDM) hypothesis asserts that subordinate species resemble dominant ones to reduce aggression. Plumage mimicry has also been consistently noted in mixed-species flocks (MSFs), suggesting a connection to grouping behaviour, although it is unclear whether this is linked to ISDM. We studied greater necklaced laughingthrush (GNLT,
Pterorhinus pectoralis
) and lesser necklaced laughingthrush (LNLT,
Garrulax monileger
), which were recently placed in different genera. Measurements of 162 museum specimens showed LNLT converging in sympatry with GNLT in necklace colour, but diverging in necklace to body ratio, with proportionally smaller necklaces. The species were closely associated in six of seven MSF systems from Nepal to China. In a study of foraging behaviour in Nepal, aggression was rare between the species, LNLT followed GNLT and had lower foraging rates when further from GNLT. Our data suggest a link between this MSF-associated mimicry and ISDM, and that the subordinate LNLT may be the mimic and gain more from the resemblance. The species spend much time together in dense and poorly lit vegetation, where the LNLTs resemblance to GNLTs potentially allows them to forage closer to GNLTs than would be otherwise possible.
The mating ritual of a rainforest tinamou,Tinamus major
Authors: Guo Yinger , Falk Jay J. , Medina-Madrid Jorge L. , Wang Silu
Published: April 2024

The mating systems of many tropical birds remain poorly understood, especially those that elude observation in dense rainforest understories. Here we dissect mating behaviors between two Great Tinamous,Tinamus major(Tinamidae), a secretive species with a wide range across the lowland Central and South American tropics. Despite anecdotal preconceptions that males court the females, we observed courtship displays solely from the putative female tinamou. In this mating ritual recorded in their natural habitat, we observed clucking and soft-rolling songs along with a suite of courtship displays, such as neck-elongation, tail-raising, crouching, and feather-fluffing performed by the putative female. In contrast, the putative male watched while standing still, approached, walked away, and carried out a few mounting attempts. The clucking and soft-rolling songs sung by the putative female were of lower frequency, energy, and amplitude, but higher entropy than the common morning territorial songs recorded in the vicinity. The clucking song by the putative female was not previously described but we repeatedly observed this song type immediately before the soft-rolling songs during the behavioral displays. Clucking was of lower frequency and energy, and around ten times shorter than the soft-rolling songs. This behavioral auditory analysis enriches understanding of rainforest tinamou mating rituals and motivates scrutiny of the partition of courtship roles between sexes in a male parental-care mating system with little sexual dichromatism and reversed sexual size dimorphism.
Multimodal assessment of acute stress dynamics using an Aversive Video Paradigm (AVP)
Authors: Roy Sumit , Fan Yan , Mosayebi-Samani Mohsen , Claus Maren , Mutlu Nilay , Kleinsorge Thomas , Nitsche Michael A.
Published: April 2024

This study explored the efficacy of inducing stress through aversive video clips and investigated its impact on psychological processes, brain, and vegetative physiology. It had a randomized, single-blinded, crossover design, where participants were exposed in separate sessions to aversive or neutral video clips. Subjective feelings of stress were assessed via questionnaires. Electroencephalography (EEG) with 62 electrodes was recorded continuously. EEG power and connectivity changes based on coherence were analyzed. Heart rate (HR) and heart rate variability (HRV) data were obtained during the whole experiment, and saliva was collected for cortisol and cytokine analysis at different time intervals. Subjective data showed increased anxiety and negative affect induced by the aversive video clips, accompanied by elevated salivary cortisol levels after exposure to the stressful clips, and decreased heart rate variability. Cytokine levels however increased over time in both control and stress conditions, which argues against a stress-specific alteration of cytokines in this specific stress protocol. EEG alterations during stress induction suggest a disruption of top-down control and increased bottom-up processing. These results show that aversive video clips are suited to induce psychological stress in an experimental setting reliably, and are associated with stress-specific emotional, and physiological changes.
H-current modulation of cortical Up and Down states
Authors: Dalla Porta Leonardo , Barbero-Castillo Almudena , Sanchez-Sanchez José Manuel , Cancino Nathalia , Sanchez-Vives Maria V.
Published: April 2024

Understanding the link between cellular processes and brain function remains a key challenge in neuroscience. One crucial aspect is the interplay between specific ion channels and network dynamics. This work reveals a role for h-current, a hyperpolarization-activated cationic current, in shaping cortical slow oscillations. Cortical slow oscillations exhibit rhythmic periods of activity (Up states) alternating with silent periods (Down states). By progressively reducing h-current in both cortical slices and in a computational model, we observed Up states transformed into prolonged plateaus of sustained firing, while Down states were also significantly extended. This transformation led to a five-fold reduction in oscillation frequency. In a biophysical recurrent network model, we identified the cellular mechanisms: an increased input resistance and membrane time constant, increasing neuronal responsiveness to even weak inputs. HCN channels, the molecular basis of h-current, are known neuromodulatory targets, suggesting potential pathways for dynamic control of brain rhythms.
Cardiaca adipokinetic hormone and hedgehog signaling combine to generate intracellular waves of Ca++in starvedDrosophila melanogasterfat body
Authors: Kang Min , Luo Anthea , Becam Isabelle , Plessis Anne , Holmgren Robert A.
Published: April 2024

TheDrosophila melanogasterfat body combines the functions of the vertebrate liver and fat. It plays a central role in metabolism where it integrates information about nutritional status to regulate fat utilization. During feeding, signaling through the Insulin Receptor causes lipogenesis, while fasting leads to signaling through the cardiaca Adipokinetic Hormone Receptor (AKHR) and mobilization of lipid stores. Here we examine intracellular calcium levels in the fat body during fasting. In fasting early third instar larvae, spikes of intracellular calcium are generated in the fat body lobes on either side of the brain. These spikes propagate through a narrow connection into the main lobes of the fat body that lie along the length of the larva. The spikes of intracellular Ca++are dependent on the corpora cardiaca AKH expressing neurons and AKHR. Unexpectedly, the spikes also require Hedgehog (Hh) signaling from the midgut enterocytes and within the fat body. When Hh signaling is blocked, the Ca++levels in the fat body are elevated and the spiking behavior lost. Hh signaling appears to regulate fat body intracellular Ca++using both the transcription factor Cubitus interruptus and the trimeric G protein Gαi. AKH/Hh signaling in the fat body lobes on either side of the brain appears to function as a pulse generator to initiate Ca++spikes that then propagate through the main lobes of the fat body. These studies show how signaling from the brain and the midgut and within the fat body are integrated to regulate a key intracellular second messenger.
Increased EZH2 function in regulatory T cells promotes their capacity to suppress autoimmunity by driving effector differentiation prior to activation
Authors: Peeters Janneke G.C. , Silveria Stephanie , Ozdemir Merve , Ramachandran Srinivas , DuPage Michel
Published: April 2024

The immunosuppressive function of regulatory T (Treg) cells is essential for maintaining immune homeostasis. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27) methyltransferase, plays a key role in maintaining Treg cell function upon CD28 co-stimulation, andEzh2deletion in Treg cells causes autoimmunity. Here we assessed whether increased EZH2 activity in Treg cells would improve Treg cell function. Using an Ezh2 gain-of-function mutation,Ezh2Y641F, we found that Treg cells expressingEzh2Y641Fdisplayed an increased effector Treg phenotype and were poised for improved homing to organ tissues. Expression ofEzh2Y641Fin Treg cells led to more rapid remission from autoimmunity. H3K27me3 profiling and transcriptomic analysis revealed a redistribution of H3K27me3, which prompted a gene expression profile in naïveEzh2Y641FTreg cells that recapitulated aspects of CD28-activatedEzh2WTTreg cells. Altogether, increased EZH2 activity promotes the differentiation of effector Treg cells that can better suppress autoimmunity.

Highlights

EZH2 function promotes effector differentiation of Treg cells.

EZH2 function promotes Treg cell migration to organ tissues.

EZH2 function in Treg cells improves remission from autoimmunity.

EZH2 function poises naïve Treg cells to adopt a CD28-activated phenotype.
Repeat-based holocentromeres of the woodrushLuzula sylvaticareveal new insights into the evolutionary transition from mono- to holocentricity
Authors: Mata-Sucre Yennifer , Krátká Marie , Oliveira Ludmila , Neumann Pavel , Macas Jiří , Schubert Veit , Huettel Bruno , Kejnovský Eduard , Houben Andreas , Pedrosa-Harand Andrea , Souza Gustavo , Marques André
Published: April 2024

Although the centromere is restricted to a single region of the chromosome in most studied eukaryotes, members of the rush family (Juncaceae) harbor either monocentric (Juncus)or holocentric (Luzula) chromosomes. This provides an opportunity to study the evolutionary mechanisms involved in the transition to holocentricity. Here by combining chromosome-scale genome assembly, epigenetic analyses, immuno-FISH, and super-resolution microscopy, we report the occurrence of repeat-based holocentromeres inL. sylvatica. We found an irregular distribution of genes, centromeric units, and most repeats along the chromosomes. We determined the centromere function predominantly associated with two satellite DNA repeats,Lusy1andLusy2of 124– and 174-bp monomer length, respectively, while CENH3 also binds satellite-free gene-poor regions. Comparative repeat analysis revealed thatLusy1is present in mostLuzulaspecies, suggesting a conserved centromere role of this repeat. Synteny betweenL. sylvatica(n= 6) andJ. effusus(n= 21) genomes further evidenced a chromosome number reduction inLuzuladerived from multiple chromosome fusions of ancestralJ. effusus-like chromosomes. We propose that the transition to holocentricity inLuzulainvolves: (i) fusion of small chromosomes resemblingJuncus-like centromeres; (ii) expansion of atypical centromeric units; and (iii) colonization of satellite DNA for centromere stabilization.
MicroRNAs and PFAS: A Pilot Study in Blood Collected from Firefighters
Authors: Zhang Xing , Sands Mia , La Frano Michael , Spinella Michael J. , Masoud Farzaneh , Fields Christopher , Madak-Erdogan Zeynep , Jensen Tor , Irudayaraj Joseph
Published: April 2024

Per- and polyfluoroalkyl substances (PFAS) are chemicals with widespread industrial and consumer applications, and firefighters are known to be at risk of elevated PFAS exposure due to their occupational activities. This study aims to assess PFAS exposure and explore potential mechanistic insights through miRNA sequencing of plasma exosomes, in relation to PFAS levels in the general population. The study included 34 firefighter participants. PFAS levels in plasma were analyzed, and miRNA sequencing of plasma exosomes was conducted. The findings were compared with the general population data from the National Health and Nutrition Examination Survey (NHANES). While total PFAS levels did not significantly differ between firefighters and the general population in the cohort considered, variations in individual PFAS compounds were observed. MiRNA sequencing revealed substantial heterogeneity in miRNA expression patterns. Associations between serum PFAS levels and biochemical indicators suggested potential health implications, although further mechanistic insights need to be explored.
Interpreting single-cell and spatial omics data using deep networks training dynamics
Authors: Karin Jonathan , Mintz Reshef , Raveh Barak , Nitzan Mor
Published: April 2024

Single-cell and spatial genomics datasets can be organized and interpreted by annotating single cells to distinct types, states, locations, or phenotypes. However, cell annotations are inherently ambiguous, as discrete labels with subjective interpretations are assigned to heterogeneous cell populations based on noisy, sparse, and high-dimensional data. Here, we show that incongruencies between cells and their input annotations can be identified by analyzing a rich but overlooked source of information: the difficulty of training a deep neural network to assign each cell to its input annotation, or annotation trainability. Furthermore, we demonstrate that annotation trainability encodes meaningful biological signals. Based on this observation, we introduce the concept of signal-aware graph embedding, which facilitates downstream analysis of diverse biological signals in single-cell and spatial omics data, such as the identification of cellular communities corresponding to a target signal. We developed Annotatability, a publicly-available implementation of annotation-trainability analysis. We address key challenges in the interpretation of genomic data, demonstrated over seven single-cell RNA-sequencing and spatial omics datasets, including auditing and rectifying erroneous cell annotations, identifying intermediate cell states, delineating complex temporal trajectories along development, characterizing cell diversity in diseased tissue, identifying disease-related genes, assessing treatment effectiveness, and identifying rare healthy-like cell populations. These results underscore the broad applicability of annotation-trainability analysis via Annotatability for unraveling cellular diversity and interpreting collective cell behaviors in health and disease.
Nucleosome wrapping energy in CpG islands and the role of epigenetic base modifications
Authors: Giniūnaitė Rasa , Sharma Rahul , Maddocks John H. , Kriaučionis Skirmantas , Petkevičiūtė-Gerlach Daiva
Published: April 2024

The majority of vertebrate promoters have a distinct DNA composition, known as a CpG island. Cytosine methylation in promoter CpG islands is associated with a substantial reduction of transcription initiation. We hypothesise that both atypical sequence composition, and epigenetic base modifications may affect the mechanical properties of DNA in CpG islands, influencing the ability of proteins to bind and initiate transcription. In this work, we model two scalar measures of the sequence-dependent propensity of DNA to wrap into nucleosomes: the energy of DNA required to assume a particular nucleosomal configuration and a measure related to the probability of linear DNA spontaneously reaching the nucleosomal configuration. We find that CpG density and modification state can alter DNA mechanics by creating states more or less compatible with nucleosome formation.
Neuropeptide Bursicon and its receptor mediated the transition from summer-form to winter-form ofCacopsylla chinensis
Authors: Zhang Zhixian , Li Jianying , Wang Yilin , Li Zhen , Liu Xiaoxia , Zhang Songdou
Published: April 2024

Seasonal polyphenism enables organisms to adapt to environmental challenges by increasing phenotypic diversity.Cacopsylla chinensisexhibits remarkable seasonal polyphenism, specifically in the form of summer-form and winter-form, which have distinct morphological phenotypes. Previous research has shown that low temperature and the temperature receptorCcTRPMregulate the transition from summer-form to winter-form inC. chinensisby impacting cuticle content and thickness. However, the underling neuroendocrine regulatory mechanism remains largely unknown. Bursicon, also known as the tanning hormone, is responsible for the hardening and darkening of the insect cuticle. In this study, we report for the first time on the novel function of Bursicon and its receptor in the transition from summer-form to winter-form inC. chinensis. Firstly, we identifiedCcBurs-α andCcBurs-β as two typical subunits of Bursicon inC. chinensis, which were regulated by low temperature (10°C) andCcTRPM. Subsequently,CcBurs-α andCcBurs-β formed a heterodimer that mediated the transition from summer-form to winter-form by influencing the cuticle chitin contents and cuticle thickness. Furthermore, we demonstrated thatCcBurs-Racts as the Bursicon receptor and plays a critical role in the up-stream signaling of the chitin biosyntheis pathway, regulating the transition from summer-form to winter-form. Finally, we discovered that miR-6012 directly targetsCcBurs-R, contributing to the regulation of Bursicon signaling in the seasonal polyphenism ofC. chinensis. In summary, these findings reveal the novel function of neuroendocrine regulatory mechanism underlying seasonal polyphenism and provide critical insights into insect Bursicon and its receptor.
Tradeoffs in ATP metabolisms via hypoxic gradient migration assays
Authors: Orabi Mohamad , Duan Kai , Zhou Mengyang , Lo Joe F.
Published: April 2024

Migration and scratch assays are helpful tools to investigate wound healing and tissue regeneration processes, especially under disease conditions such as diabetes. However, traditional migration (injury-free) assays and scratch (with injury) assays are limited in their control over cellular environments and provide only simplified read-outs of their results. On the other hand, microfluidic-based cell assays offer a distinct advantage in their integration and scalability for multiple modalities and concentrations in a single device. Additionally,in situstimulation and detection helps to avoid variabilities between individual bioassays. To realize an enhanced, smarter migration assay, we leveraged our multilayered oxygen gradient (1-16%) to study HaCaT migrations in diabetic conditions with spatial and metabolic read-outs. An analysis of the spatial migration over time observed a new dynamic between hypoxia (at 4.16-9.14% O2) and hyperglycemia. Furthermore,in situadenosine triphosphate (ATP) and reactive oxygen species (ROS) responses suggest that this dynamic represents a switch between stationary versus motile modes of metabolism. Thus, elevated glucose and hypoxia are synergistic triggers of this switch under disease conditions. These findings illustrate the benefits of spatial microfluidics for modeling complex diseases such as hypoxia and diabetes, where multimodal measurements provide a more deterministic view of the underlying processes.
CAR Tregs mediate linked suppression and infectious tolerance in islet transplantation
Authors: Wardell Christine M. , Fung Vivian C.W. , Chen Eleanor , Haque Manjurul , Gillies Jana , Spanier Justin A. , Mojibian Majid , Fife Brian T. , Levings Megan K.
Published: April 2024

Regulatory T cells (Tregs) have potential as a cell-based therapy to prevent or treat transplant rejection and autoimmunity. Using an HLA-A2-specific chimeric antigen receptor (A2-CAR), we previously showed that adoptive transfer of A2-CAR Tregs limited anti-HLA-A2 alloimmunity. However, it was unknown if A2-CAR Tregs could also limit immunity to autoantigens. Using a model of HLA-A2+islet transplantation into immunodeficient non-obese diabetic mice, we investigated if A2-CAR Tregs could control diabetes induced by islet-autoreactive (BDC2.5) T cells. In mice transplanted with HLA-A2+islets, A2-CAR Tregs reduced BDC2.5 T cell engraftment, proliferation and cytokine production, and protected mice from diabetes. Tolerance to islets was systemic, including protection of the HLA-A2negativeendogenous pancreas. In tolerant mice, a significant proportion of BDC2.5 T cells gained FOXP3 expression suggesting that long-term tolerance is maintained byde novoTreg generation. Thus, A2-CAR Tregs mediate linked suppression and infectious tolerance and have potential therapeutic use to simultaneously control both allo- and autoimmunity in islet transplantation.

One Sentence Summary

Alloreactive chimeric antigen receptor-engineered regulatory T cells limit diabetogenic T cell engraftment and function to prevent type 1 diabetes.