bluuebunny/crossref_metadata_2025 huggingface dataset:
Severe Periodontitis Is a Major Contributory Factor to Unmet Dental Healthcare Needs among Rheumatoid Arthritis Patients in Hong Kong
Authors: Mok Mo Yin , Kong Wing Yin , Leung Katherine Chiu Man , Chow Mei Kuen , Lo Yi , Tsang Claudia Pui Ling , Fung Henry Kwok Kong , Lau Wallace Chak Sing , Leung Wai Keung
Published: December 2022

Objective. This study aimed to examine the frequency and predictive factors of adverse oral and dental outcomes in patients with rheumatoid arthritis (RA) with the goal to address their unmet dental healthcare needs in the metropolitan city of Hong Kong. Methods. 238 RA patients followed up at local public hospitals were recruited in this cross-sectional study. A full dental examination was performed. Data were compared with the retrospective data collected from age-matched control groups in the community conducted in a territory-wide oral health survey in 2011. Predictive factors for severe periodontitis including various demographic and disease-specific factors were examined by multiple logistic regression analysis. Results. Loose teeth and gum bleeding were frequent dental complaints. Only 85.0% of RA patients had >20 natural teeth. Total edentulism was observed in 3.8% of patients, which was higher among adult (22–64 years) and elderly (>65 years old) RA patients than their respective age-matched community control groups. RA patients had a higher decayed, missing, and filled tooth score. Adult RA patients had a 5.3-fold increase in risk of severe periodontitis than their community counterparts. The plaque index was the main predisposing factor for severe periodontitis (odds ratio 17.5,

p
=
0.001

), which was worse among the 22–34 age group of patients. More RA patients required tooth extraction compared to dental filling for their community controls. Conclusion. Severe periodontitis is a major cause of unmet dental healthcare needs among RA patients in Hong Kong. It is recommended that dental care plans for RA patients be commenced early among newly diagnosed patients.
Ipsilateral Limb Extension of Referred Trigeminal Facial Pain due to Greater Occipital Nerve Entrapment: A Case Report
Authors: Son Byung-Chul , Lee Changik
Published: December 2022

We report a very rare case of referred pain associated with entrapment of the greater occipital nerve (GON) occurring not only in the ipsilateral hemiface but also in the ipsilateral limb. There is an extensive convergence of cutaneous, tooth pulp, visceral, neck, and muscle afferents onto nociceptive and nonnociceptive neurons in the trigeminal nucleus caudalis (medullary dorsal horn). In addition, nociceptive input from trigeminal, meningeal afferents projects into trigeminal nucleus caudalis and dorsal horn of C1 and C2. Together, they form a functional unit, the trigeminocervical complex (TCC). The nociceptive inflow from suboccipital and high cervical structures is mediated with small-diameter afferent fibers in the upper cervical roots terminating in the dorsal horn of the cervical cord extending from the C2 segment up to the medullary dorsal horn. The major afferent contribution is mediated by the spinal root C2 that is peripherally represented by the greater occipital nerve (GON). Convergence of afferent signals from the trigeminal nerve and the GON onto the TCC is regarded as an anatomical basis of pain referral in craniofacial pain and primary headache syndrome. Ipsilateral limb pain occurs long before the onset of the referred facial pain. The subsequent severe hemifacial pain suggested GON entrapment. The occipital nerve block provided temporary relief from facial and extremity pain. Imaging studies found a benign osteoma in the ipsilateral suboccipital bone, but no direct contact with GON was identified. During GON decompression, severe entrapment of the GON was observed by the tendinous aponeurotic edge of the trapezius muscle, but the osteoma had no contact with the nerve. Following GON decompression, the referred trigeminal and extremity pain completely disappeared. The pain referral from GON entrapment seems to be attributed to the sensitization and hypersensitivity of the trigeminocervical complex (TCC). The clinical manifestations of TCC hypersensitivity induced by chronic entrapment of GONs are diverse when considering the occurrence of extremity pain as well as facial pain.
Abstract IA003: Catalytic and noncatalytic mechanisms of chromatin modifiers
Authors: Armache Karim-Jean
Published: December 2022

Many mechanisms regulate chromatin structure to ensure that genes are active or silent. Some are considered epigenetic, ensuring the heritable transmission of a specific chromatin state. One of the mechanisms of chromatin regulation is based on posttranslational modifications of histones. Chemical groups are deposited, read, and removed by protein complexes that regulate chromatin structure. Histone modifications correlate with and sometimes directly affect critical processes such as transcription, replication, recombination, and repair. They are the subject of many clinical studies, as aberrant histone modifications and deregulation of enzymes responsible for their deposition occur in many cancers. These modifications rarely function in isolation, and there is often crosstalk between them that results in a coordinated transcriptional output. The central question in the field is to understand the regulation of histone modifications and associated molecular complexes, their role in gene expression, and their pathology in cancer. Another critical question is to discover and characterize the intricate relationships between different histone modifications and histone modifying enzymes at the mechanistic level. I will discuss our progress in understanding the roles of histone methylation and how it interfaces with other chromatin modifications that play critical roles in gene regulation.

Citation Format: Karim-Jean Armache. Catalytic and noncatalytic mechanisms of chromatin modifiers. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA003.
Abstract IA006: Systematic functional screening of chromatin factors identifies strong lineage and disease dependencies in normal and malignant haematopoiesis
Authors: Huntly Brian
Published: December 2022

Interactions between transcription factors (TF) and chromatin factors (CF) regulate gene expression programmes to determine cellular fate. However, unlike for TF, the exact role of CF in this process is poorly understood. Using haematopoiesis as a model system, we address this fundamental question in lineage choice of normal haematopoiesis and the maintenance of acute myeloid leukaemia (AML). To do this, we have functionally characterized the requirement ex vivo of 550 CFs in normal lineage differentiation and further dissected, with single-cell resolution, the roles of 40 CFs during in vivo lineage commitment (using Perturb-seq). Further, utilizing epigenetic profiling (ATAC-seq and ChIP-seq) we have probed TF-CF interactions that have lineage regulatory potential. Finally, we compare the functions of key CFs and their TF-associations between normal and malignant haematopoiesis. These studies demonstrate, both ex vivo and in vivo, that similar complexes, including three MLL-H3K4 COMPASS methyltransferases (KMTs) and non-canonical (nc-BAF) and canonical BAF (c-BAF) complexes, regulate disparate lineage decisions across haematopoiesis. However, somewhat paradoxically, we demonstrate that unrelated Repressive complexes function similarly, but non-redundantly, to restrain excessive myeloid differentiation and protect lineage diversity. We identify interactions between CF and TF that explain the regulatory function of CF and demonstrate that KO of the nc-BAF member Brd9 leads to a premalignant accumulation of myeloid progenitors, related to impaired recruitment of late myeloid TFs. Finally, utilizing similar experiments in a relevant murine AML model, we identify perturbations of MLL-, BAF- and Repressive CF that trigger partial differentiation and loss of leukaemia potential. Our data also highlight opposing functions for the same CF in normal and malignant haematopoiesis. CFs such as COMPASS members and cBAF remodelers are critical for the balanced differentiation of specific normal haematopoietic lineages, however the same CF are critical for the maintenance of leukaemia fitness, where they act predominantly to maintain differentiation blockade. Finally, we demonstrate that this altered effect occurs through the differential utilization of TF by CF complexes between normal and malignant haematopoiesis, such as corrupted Stat5a-CF interactions, potentially identifying specific CF-TF complexes as therapeutic targets in AML. Taken all together, our work greatly elucidates the role of CF and their TF partners across normal and malignant haematopoiesis.

Citation Format: Brian Huntly. Systematic functional screening of chromatin factors identifies strong lineage and disease dependencies in normal and malignant haematopoiesis. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA006.
Abstract A02: MEK-CDK4/6 inhibition induces plasma cell tumor infiltration and sensitizes de novo MPNSTs to immune checkpoint blockade
Authors: Lingo Joshua , Kohlmeyer Jordan , Kaemmer Courtney , Scherer Amanda , Voigt Ellen , Chimenti Michael , Tanas Munir , Monga Varun , Darbro Ben , Meyerholz David , Dodd Rebecca , Quelle Dawn
Published: December 2022

Malignant peripheral nerve sheath tumors (MPNSTs) are deadly, Ras-driven sarcomas that lack effective therapies. Many tumors are unresectable and toxic chemotherapies are ineffectual. The sensitivity of MPNSTs to immune checkpoint blockade (ICB) therapies is not known, although sarcomas are generally unresponsive. Patient tumor analyses comparing MPNSTs to benign precursors identified Ras effectors, MEK and CDK4/6 kinases, as rational targets for therapy. We tested the efficacy of dual MEK-CDK4/6 inhibition versus single drug therapy using preclinical MPNST models. In MPNST cells, low-dose drug combinations synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death and decreased clonogenic survival. In de novo MPNSTs in immune competent mice, combination therapy caused tumors to shrink, substantially delayed resistant tumor outgrowth and improved survival relative to monotherapies. Tumor regression was associated with an immune activation gene expression profile featuring plasma cell infiltration, an event not previously observed with MEK-CDK4/6 inhibitor therapy. In other human tumor types, intratumoral plasma cells prognose better overall survival and improved response to ICB therapies. Excitingly, MEK-CDK4/6 therapy sensitized de novo MPNSTs to anti-programmed death ligand 1 (PD-L1) therapy with the combination achieving complete tumor ablation and apparent cure in 10% of mice. These findings implicate a critical role for plasma cells in mediating MPNST regression in response to kinase inhibitor therapy and sensitizing tumors to PD-L1 targeting. This novel therapeutic combination is a promising option for MPNST therapy that could improve ICB efficacy in other solid tumors.

Citation Format: Joshua Lingo, Jordan Kohlmeyer, Courtney Kaemmer, Amanda Scherer, Ellen Voigt, Michael Chimenti, Munir Tanas, Varun Monga, Ben Darbro, David Meyerholz, Rebecca Dodd, Dawn Quelle. MEK-CDK4/6 inhibition induces plasma cell tumor infiltration and sensitizes de novo MPNSTs to immune checkpoint blockade [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A02.
Abstract A18: In vivo CRISPR screening in syngeneic tumor models to identify novel combinations for cancer immunotherapy
Authors: Sa Qila , Liang Hongyu , Kostadinov Rumen , Yu Jong , Waight Jeremy , Van Horn Stephanie , Xie Qing , Griffin Sue , Hopson Chris , Sun Ning
Published: December 2022

Inducible T cell Co-Stimulator (ICOS, CD278) is a receptor belonging to the CD28/CTLA-4 superfamily that is predominantly expressed on T cells following T cell receptor (TCR) activation and plays an important role in regulating adaptive immune response. ICOS represents possible node of therapeutic intervention for cancer, and as such, is under clinical evaluation. Although ICOS agonists have been shown to promote significant monotherapeutic efficacy in non-clinical studies, most patients do not respond to the single-agent approaches. Therefore, it is crucial to better understand the potential mechanisms of action as well as to develop novel combination strategies and biomarkers to best position therapeutic in the clinic. In an effort to identify novel combination partners and/or biomarkers for ICOS agonist, we utilized pooled in vivo genetic screening via CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 genome editing in the syngeneic CT26 colorectal mouse tumor model alongside agonist treatment for the target. We evaluated 509 druggable genes with four sgRNAs targeting each gene to identify genes where loss in CT26 tumor cells can increase sensitivity or resistance to this treatment. With a false discovery rate (FDR) <0.05, we were able to identify 38 sensitizing hits for ICOS agonist. To our knowledge, this is the first in vivo genetic screening in mouse models aiming to uncover potential combinational targets for anti-ICOS agonist. Importantly, this screening strategy can be adapted to orthogonal tumor types to confirm current hits or identify undescribed combination targets for a range of other immunotherapeutic approaches.

Citation Format: Qila Sa, Hongyu Liang, Rumen Kostadinov, Jong Yu, Jeremy Waight, Stephanie Van Horn, Qing Xie, Sue Griffin, Chris Hopson, Ning Sun. In vivo CRISPR screening in syngeneic tumor models to identify novel combinations for cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A18.
Abstract IA24: The evolution of neoadjuvant immunotherapy in bladder cancer
Authors: Galsky Matthew D.
Published: December 2022

PD-1/PD-L1 blockade has transformed the treatment landscape for advanced bladder cancer. Based on the durable disease control achieved in a subset of patients with such therapy, in the context of a relatively favorable tolerability profile, a logical progression of the clinical development of PD-1/PD-L1 blockade in bladder cancer is to move these treatments to earlier disease states. The neoadjuvant, or pre-surgical, treatment platform affords a number of potential opportunities for clinical drug development which encompass scientific, pragmatic, patient-centered, and regulatory domains. However, this platform may serve to both advance the development of drugs and also advance the development of treatment paradigms and no single trial is likely poised to fully address these related, but distinct, goals. Neoadjuvant trials incorporating immune checkpoint blockade in bladder cancer have already demonstrated sufficient signals of activity to support the initiation of multiple large definitive phase 3 trials, generate novel immunobiologic insights, and even provide a new path for curative-intent bladder-sparing treatment.

Citation Format: Matthew D. Galsky. The evolution of neoadjuvant immunotherapy in bladder cancer [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr IA24.
Osteoradionecrosis versus Cancer Recurrence: An Unresolved Clinical Dilemma
Authors: Tufano-Sugarman Andrea M. , Wang Kevin Y. , Kohn Nina , Ghaly Maged , Parashar Bhupesh , Frank Douglas , Kamdar Dev , Pereira Lucio , Fantasia John , Seetharamu Nagashree
Published: December 2022

Introduction: Osteoradionecrosis is a rare and debilitating risk of definitive chemoradiotherapy for head and neck squamous cell carcinoma. It is difficult to distinguish between osteoradionecrosis and recurrent or progressive disease, as clinical and radiologic features may be similar. Our aim was to compare the clinical presentation and radiologic features of osteonecrosis with those of recurrent or progressive cancer. Methods: We conducted a single-center case series of 19 patients with head and neck squamous cell carcinoma diagnosed between 2011 and 2019 who subsequently developed clinical and/or radiological suspicion of osteoradionecrosis. The population was a referred sample from head and neck cancer physicians at Northwell Health Cancer Institute. Clinician notes and imaging reports were reviewed to assign a final diagnosis of either cancer, osteonecrosis, or indeterminate. Results: No differences were found in the clinical presentation or radiologic features between groups. Median time between treatment and development of symptoms was longer in patients with a final diagnosis of osteoradionecrosis than recurrent or progressive disease (5 vs. 3 months), but this difference was not statistically significant. Radiation dose and type were not associated with diagnosis. Mean standard uptake value maximums on positron emission tomography/computed tomography were significantly higher in the cancer group (median 14.8 vs. 9.1, p < 0.0152). At 1 year after first suspicion of osteoradionecrosis, 100% of osteoradionecrosis patients were alive, versus 28.6% of cancer patients. Discussion/Conclusion: There is significant overlap in clinical and radiologic features of osteoradionecrosis and cancer. Standard uptake maximums may be helpful in predicting diagnosis. Occurrence of symptoms within 6 months of completing chemoradiotherapy should raise the concern for malignancy.
Oxygen Saturation Ranges for Healthy Newborns within 2 h at Altitudes between 847 and 4,360 m: A Prospective Cohort Study
Authors: Li Yangfang , Ze Bi , Zhang Tiesong , Liu Xiaomei , Gao Jin , Mao Hui , Qin Mingcai , Lai Yinzhen , jiu Suo nan ba , Li Guoyun , Du Kun , Yu Zhangbin , Zhou Wenhao ,   for the Chinese High Altitude Neonatal Medicine Alliance CHANMA
Published: December 2022

Introduction: The partial oxygen pressure in the air decreases with increasing altitude. This study was designed to compare the pulse oxygen saturation (SpO2) among well full-term neonates at different altitudes during their first 2 h after birth and to establish cutoff values of SpO2 identifying hypoxemia between 30 and 120 min after birth. Methods: A multisite prospective cohort study was conducted at five participating hospitals from the Chinese High Altitude Neonatal Medicine Alliance. Healthy full-term infants were recruited and divided into four groups based on the altitude. Preductal SpO2 was recorded at 10 min, 10–30 min, and 30–120 min after birth. The 2.5th percentile of the SpO2 distribution range was considered as the cutoff for identifying hypoxemia at each altitude. Results: A total of 727 infants were eligible for analysis. The SpO2 of neonates at different altitudes increased with the time after birth. A higher altitude was associated with lower SpO2, especially Shangri-La (3,509 m) and Yushu (4,360 m). The cutoff SpO2 for identifying hypoxemia during 30–120 min after birth were 94% in Xishuangbanna (847 m), 92% in Kunming (1,983 m), 89% in Shangri-La (3,509 m), and 83% in Yushu (4,360 m). Conclusion: An increase in altitude, especially Shangri-La (3,509 m) and Yushu (4,360 m), had a significant impact on SpO2 among healthy full-term neonates during their first 2 h of life. Establishing the cutoff value of SpO2 for identifying hypoxemia during the early postnatal period serves to optimize the oxygen therapy at different altitudes.
Meta-Analysis of Human Leukocyte Antigen-G 3′UTR Polymorphisms Confer Susceptibility to Recurrent Miscarriage
Authors: Chen Xiaoyan , Zhang Jun , Xu Qiao , Liu Zhaoming , Chen Jun , Yang Yong , Zhou Wei
Published: December 2022

Objectives: The current systematic review and meta-analysis have shown that specific HLA-G 3′ UTR variants are associated with recurrent miscarriage (RM). Our aim was to investigate the relevance of HLA-G 3′ UTR polymorphisms with the risk of RM. Design: A combined meta-analysis was implemented in this study. Participants/Materials, Setting, Methods: Common electronic databases including PubMed, Embase, Web of Science, China National Knowledge Infrastructure, Cochrane Library, and Google Scholar were used to seek eligible articles up to August 2021. Results: Forty-four eligible articles with 4,467 cases and 3,955 controls were finally enrolled. Our meta-results suggested that 14 bp insertion allele was associated with elevated risk of RM (allelic model: OR = 1.18, 95% CI = 1.07–1.31, p = 0.001). Besides, a significant heterogeneity was observed between studies. Further subgroup analyses based on ethnicity revealed similar positive results in both the Caucasian and Asian subgroups but not in the Middle East subgroup. Moreover, rs1063320 G allele conferred elevated susceptibility to RM in Asian group (allelic model: OR = 1.54, 95% CI = 1.17–2.03, p = 0.002). Additionally, pooled results showed a decreased risk of RM in mothers carrying rs1710 G allele (allelic model: OR = 0.68, 95% CI = 0.55–0.85, p < 0.001) and an increased risk with rs9380142 A allele (allelic model: OR = 1.45, 95% CI = 1.15–1.83, p = 0.002). Further stratified analyses by race showed that these positive results were mainly from the associations observed in Asian populations. Limitations: The main limitation is that the enrolled number of individuals was relatively small. Thus, the results should be cautiously considered. Conclusions: Although the current systematic review and meta-analysis have shown that specific HLA-G 3′ UTR variants are associated with RM, a high degree of bias is present and further studies are needed to validate this causative effect.
Onkologie und Palliativmedizin: Mehr Zusammenarbeit für eine bestmögliche Lebensqualität der Patienten
Authors: Brandt Julia
Published: December 2022

Benefits of early palliative care referral in oncology are well-validated. At the Veneto Institute of Oncology-IRCCS, a simultaneous-care outpatient clinic (SCOC) has been active since 2014, where patients with advanced cancer are evaluated by an oncologist together with a palliative care team. We prospectively assessed SCOC patients’ characteristics and SCOC outcomes through internal procedure indicators. Data were retrieved from the SCOC prospectively maintained database. There were 753 eligible patients. The median age was 68 years; primary tumor sites were gastrointestinal (75.2%), genitourinary (15.0%) and other sites (9.8%). Predominant symptoms were psychological issues (69.4%), appetite loss (67.5%) and pain (65.9%). Dyspnea was reported in 53 patients (7%) in the referral form, while it was detected in 226 patients (34.2%) during SCOC visits (p < 0.0001). Median survival of patients after the SCOC visit was 7.3 months. Survival estimates by the referring oncologist were significantly different from the actual survival. Psychological intervention was deemed necessary and undertaken in 34.6% of patients, and nutritional support was undertaken in 37.9% of patients. Activation of palliative care services was prompted for 77.7% of patients. Out of 357 patients whose place of death is known, 69.2% died at home, in hospice or residential care. With regard to indicators’ assessment, the threshold was reached for 9 out of 11 parameters (81.8%) requested by the procedure. This study confirmed the importance of close collaboration between oncologists and palliative care teams in responding properly to cancer patients’ needs. The introduction of a procedure with indicators allowed punctual assessment of a team’s performance.
Febrile Neutropenie: Welche Prophylaxe schneidet besser ab?
Authors: Link Hartmut
Published: December 2022

Untersucht wurde das Auftreten von Neutropenie und febriler Neutropenie (FN) sowie die damit verbundenen Gesundheitsressourcen bei Krebspatienten, die eine myelosuppressive Chemotherapie in Kombination mit Pegfilgrastim im Vergleich zu Lipegfilgrastim erhielten. Es handelt sich um eine retrospektive Analyse anhand einer deutschen Datenbank mit Krankenversicherungsansprüchen. Erwachsene, die eine Chemotherapie mit Pegfilgrastim (n = 734) oder Lipegfilgrastim (n = 346) erhielten, wurden über einen Zeitraum von 1 Jahr beobachtet. Das FN-Risiko basierte auf dem Chemotherapieschema und zusätzlichen Neutropenie-Risikofaktoren. Die meisten Patienten wurden in die Gruppe mit hohem FN-Risiko eingestuft. Das Durchschnittsalter betrug 58,2 Jahre in der Pegfilgrastim-Kohorte und 58,0 Jahre in der Lipegfilgrastim-Kohorte, mit mehr weiblichen als männlichen Patienten. Die Mehrheit hatte Brustkrebs. Insgesamt traten bei 10,0% bzw. 10,4% der Patienten, die Pegfilgrastim oder Lipegfilgrastim erhielten, Neutropenie-Ereignisse auf (p = 0,82), wobei 4,4% bzw. 3,5% der Patienten ein FN-Ereignis erlitten (p = 0,49). Die durchschnittlichen, mit Neutropenie-Ereignissen zusammenhängenden Gesundheitskosten betrugen 604 € und 441 € für die Pegfilgrastim- und die Lipegfilgrastim-Kohorte. Insgesamt waren die mit Pegfilgrastim und Lipegfilgrastim behandelten Patienten in Bezug auf das Auftreten von Neutropenien in der 1-Jahres-Follow-up-Phase vergleichbar. Bei Patienten mit Lymphomen waren die mit Neutropenie-Ereignissen verbundenen Gesundheitskosten und die Krankenhausaufenthalte insgesamt in dieser Studie unter Pegfilgrastim signifikant höher als unter Lipegfilgrastim; dies sollte jedoch angesichts der begrenzten Stichprobengröße und des Fehlens klinischer Informationen mit Vorsicht interpretiert werden.
Kolorektales Karzinom: Ist eine adjuvante Chemotherapie nach Lebermetastasenresektion sinnvoll?
Authors: Homayounfar Kia
Published: December 2022

Purpose: Adjuvant chemotherapy after hepatectomy is controversial in liver-only metastatic colorectal cancer (CRC). We conducted a randomized controlled trial to examine if adjuvant modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) is superior to hepatectomy alone for liver-only metastasis from CRC. Patients and Methods: In this phase II or III trial (JCOG0603), patients age 20-75 years with confirmed CRC and an unlimited number of liver metastatic lesions were randomly assigned to hepatectomy alone or 12 courses of adjuvant mFOLFOX6 after hepatectomy. The primary end point of phase III was disease-free survival (DFS) inintention-to-treat analysis. Results: Between March 2007 and January 2019, 300 patients were randomly assigned to hepatectomy alone (149 patients) or hepatectomy followed by chemotherapy (151 patients). At the third interim analysis of phase III with median follow-up of 53.6 months, the trial was terminated early according to the protocol because DFS was significantly longer in patients treated with hepatectomy followed by chemotherapy. With median follow-up of 59.2 months, the updated 5-year DFS was 38.7% (95% CI, 30.4 to 46.8) for hepatectomy alone compared with 49.8% (95% CI, 41.0 to 58.0) for chemotherapy (hazard ratio, 0.67; 95% CI, 0.50 to 0.92; one-sided P=.006). However, the updated 5-year overall survival (OS) was 83.1% (95% CI, 74.9 to 88.9) with hepatectomy alone and 71.2% (95% CI, 61.7 to 78.8) with hepatectomy followed by chemotherapy. In the chemotherapy arm, the most common grade 3 or higher severe adverse event was neutropenia (50% of patients), followed by sensory neuropathy (10%) and allergic reaction (4%). One patient died of unknown cause after three courses of mFOLFOX6 administration. Conclusion: DFS did not correlate with OS for liver-only metastatic CRC. Adjuvant chemotherapy with mFOLFOX6 improves DFS among patients treated with hepatectomy for CRC liver metastasis. It remains unclear whether chemotherapy improves OS.
NSCLC: irHPC-Scoring-System zur Vorhersage des Ansprechens auf neoadjuvante Immuntherapie
Authors: Möller Miriam , Schütte Wolfgang
Published: December 2022

Background: Although neoadjuvant anti-PD-1 immunotherapies have shown good efficacy in non-small cell lung cancer (NSCLC) patients, there is still a lack of effective predictive markers. We aimed to develop a pretreatment histologic scoring system to predict the efficacy of neoadjuvant immunotherapy. Methods: One hundred forty NSCLC cases were evaluated in this study. Initially, surgical specimens from 31 squamous cell lung cancer patients treated with neoadjuvant anti-PD-1 therapy and their eligible paired pretreatment biopsies were used for pathologic evaluation and developing the pretreatment scoring system, immune-related histologic phenotype assessment criteria (irHPC). Three trained pathologists independently scored the haematoxylineosin (HE) slides of the pretreatment tumour biopsies according to irHPC. The follow-up was from 07 March 2018 to 31 December 2021, mainly focusing on disease-free survival (DFS) and overall survival (OS). Second, 109 biopsies of lung squamous cell carcinoma were evaluated to explore the relationship between eosinophils and PD-L1 expression. Results: Superior 2-year DFS rates and 2-year OS rates were observed in patients who achieved major pathologic response (MPR) (MPR vs. non-MPR: 92.9% vs. 78.6%; 100.0% vs. 93.3%). Whether necrosis was included in the calculation of the per cent of residual viable tumour (%RVT) or not had almost no effect on the consistency of pathologic assessment and the histological response grouping. The interpathologist variability in assessing %RVT with immuneactivated phenotype was not statistically significant (P = 0.480). Four immune-related features of pretreatment biopsies were included for calculating the predictive score. The trained pathologist accurately predicted most cases according to irHPC. For interobserver reproducibility using «2 points» as the cutoff, the overall per cent agreement was 77.8%. The reliability between pathologists for a binary tumour evaluation showed «moderate» agreement (κ = 0.54). Patients with scores ≥ 2 points tended to have better 2-year DFS rates and 2-year OS rates than those with scores < 2 points (85.7% vs. 71.4%; 100.0% vs. 87.5%). Conclusions: The irHPC scoring system reflecting the preexisting immune response could be used to predict pathologic response to neoadjuvant immunotherapy, possibly further predicting the long-term prognosis, but larger trials are needed for verification.
Molecular Basis of Intestinal Fibrosis in Inflammatory Bowel Disease
Authors: Andoh Akira , Nishida Atsushi
Published: December 2022

Background: Intestinal fibrosis in Crohn’s disease (CD) is considered to be irreversible and induces persistent luminal narrowing and strictures. In the past decades, substantial advances have been made in the understanding of the cellular and molecular mechanisms underlying intestinal fibrosis in inflammatory bowel disease (IBD). Summary: Intestinal fibrosis is typically associated with mesenchymal cell hyperplasia, tissue disorganization, and deposition of extracellular matrix (ECM). The transient appearance of mesenchymal cells is a feature of normal wound healing, but the persistence of these cells is associated with ECM deposition and fibrosis, leading to loss of normal architecture and function. When homeostatic control of the repair process becomes dysregulated, perpetual activation of profibrotic responses and sustained accumulation of ECM are induced. In the process of intestinal fibrosis, myofibroblasts are considered to be the key effector cells, being responsible for the synthesis of ECM proteins. Activation and accumulation of myofibroblasts in the stricturing lesions of CD patients are mediated by various factors such as growth factors, cytokines, epithelial-to-mesenchymal or endothelial-to-mesenchymal transitions. Despite the identification of many putative targets and target pathways applicable to antifibrotic therapies, no such treatment has yet been successful. Predictive biomarkers and non-invasive diagnostic tools for intestinal fibrosis are still insufficient in IBD. Key Message: We summarize recent advances in the understanding of the cellular and molecular mechanisms underlying intestinal fibrosis in IBD.
Retinal Neurodegeneration in Euglycemic Hyperinsulinemia, Prediabetes, and Diabetes
Authors: Ebrahimi Moein , Sivaprasad Sobha , Thompson Paul , Perry George
Published: December 2022

Diabetic retinopathy (DR) is a challenging public health problem mainly because of its growing prevalence and risk of blindness. In general, our current knowledge and practice have failed to prevent the onset or progression of DR to sight-threatening complications. While there are treatment options for sight-threatening complications of DR, it is crucial to pay more attention to the early stages of DR to decrease its prevalence. Growing evidence suggests many pathologic changes occur before clinical presentations of DR in euglycemic hyperinsulinemia, prediabetes, and diabetes. These pathological changes occur in retinal neurons, glia, and microvasculature. A new focus on these preclinical pathologies – especially on hyperinsulinemia – may provide further insight into disease mechanisms, endpoints for clinical trials, and druggable targets in early disease. Here, we review the current evidence on the pathophysiological changes reported in preclinical DR and appraise preventive and treatment options for DR.
Assessing Heuristic Bias During Care for Patients Hospitalized for Heart Failure: Get With The Guidelines-Heart Failure
Authors: Selvaraj Senthil , Greene Stephen J. , Ayodele Iyanuoluwa , Alhanti Brooke , Allen Larry A. , Lewsey Sabra C. , Adusumalli Srinath , Reza Nosheen , Hernandez Adrian F. , Yancy Clyde W. , Jena Anupam B. , Fonarow Gregg C. , Bhatt Deepak L.
Published: December 2022

Background:

Heuristic biases are increasingly recognized, and potentially modifiable, contributors to patient care and outcomes. Left digit bias is a cognitive bias where continuous variables are categorized by their left-most digit. The impact of this heuristic bias applied to patient age on quality of care in heart failure has not been explored.

Methods:

We examined participants admitted from 2005 to 2021 in the Get With The Guidelines-Heart Failure registry. To create 2 naturally randomized groups, isolating the effect of left digit bias, we dichotomized patients into those discharged within 60 days prior to their 80th birthday (N=4238) and those discharged within 60 days after their 80th birthday (N=4329). We performed multivariable logistic regression to assess the association between discharge date relative to 80th birthday and several in-hospital quality metrics and in-hospital outcomes. Among Medicare participants (N=2759), we performed adjusted Cox regression to analyze the relationship between discharge date and risk of 1-year mortality or readmission.

Results:

Among 8567 patients, 50.4% were female, 73% were non-Hispanic White, and 42.9% had an ejection fraction ≤40%. Discharge date relative to 80th birthday was not associated with numerous in-hospital quality metrics or in-hospital outcomes on unadjusted or adjusted logistic regression. Among Medicare beneficiaries, there was no association between discharge date and risk of mortality or readmission at 1-year postdischarge (hazard ratio, 1.03 [95% CI, 0.95–1.12];
P
=0.52).

Conclusions:

In a large registry of patients hospitalized for heart failure, we did not detect a left digit bias‚ with respect to age at discharge, which resulted in differential quality of care or outcomes.
TSPAN12 (Tetraspanin 12) Is a Novel Negative Regulator of Aldosterone Production in Adrenal Physiology and Aldosterone-Producing Adenomas
Authors: Gong Siyuan , Tetti Martina , Kemter Elisabeth , Peitzsch Mirko , Mulatero Paolo , Bidlingmaier Martin , Eisenhofer Graeme , Wolf Eckhard , Reincke Martin , Williams Tracy Ann
Published: December 2022

Background:

Aldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism, a condition of low-renin hypertension, in which aldosterone overproduction is usually driven by a somatic activating mutation in an ion pump or channel.
TSPAN12
is differentially expressed in different subgroups of APAs suggesting a role in APA pathophysiology. Our objective was to determine the function of TSPAN12 (tetraspanin 12) in adrenal physiology and pathophysiology.

Methods:

APA specimens, pig adrenals under dietary sodium modulation, and a human adrenocortical cell line HAC15 were used for functional characterization of TSPAN12 in vivo and in vitro.

Results:

Gene ontology analysis of 21 APA transcriptomes dichotomized according to high versus low
TSPAN12
transcript levels highlighted a function for
TSPAN12
related to the renin-angiotensin system.
TSPAN12
expression levels in a cohort of 30 APAs were inversely correlated with baseline plasma aldosterone concentrations (
R
=−0.47;
P
=0.009). In a pig model of renin-angiotensin system activation by dietary salt restriction,
TSPAN12
mRNA levels and TSPAN12 immunostaining were markedly increased in the zona glomerulosa layer of the adrenal cortex. In vitro stimulation of human adrenocortical human adrenocortical cells with 10 nM angiotensin II for 6 hours caused a 1.6-fold±0.13 increase in
TSPAN12
expression, which was ablated by 10 μM nifedipine (
P
=0.0097) or 30 μM W-7 (
P
=0.0022). Gene silencing of
TSPAN12
in human adrenocortical cells demonstrated its inverse effect on aldosterone secretion under basal and angiotensin II stimulated conditions.

Conclusions:

Our findings show that TSPAN12 is a negative regulator of aldosterone production and could contribute to aldosterone overproduction in primary aldosteronism.
Representations of Abstract Relations in Infancy
Authors: Hochmann Jean-Rémy
Published: December 2022

Abstract relations are considered the pinnacle of human cognition, allowing for analogical and logical reasoning, and possibly setting humans apart from other animal species. Recent experimental evidence showed that infants are capable of representing the abstract relations same and different, prompting the question of the format of such representations. In a propositional language of thought, abstract relations would be represented in the form of discrete symbols. Is this format available to pre-lexical infants? We report six experiments (N = 192) relying on pupillometry and investigating how preverbal 10- to 12-month-old infants represent the relation same. We found that infants’ ability to represent the relation same is impacted by the number of individual entities taking part in the relation. Infants could represent that four syllables were the same and generalized that relation to novel sequences (Experiments 1 and 4). However, they failed to generalize the relation same when it involved 5 or 6 syllables (Experiments 2–3), showing that infants’ representation of the relation same is constrained by the limits of working memory capacity. Infants also failed to form a representation equivalent to all the same, which could apply to a varying number of same syllables (Experiments 5–6). These results highlight important discontinuities along cognitive development. Contrary to adults, preverbal infants lack a discrete symbol for the relation same, and rather build a representation of the relation by assembling symbols for individual entities.
Modeling Individual Differences in Children’s Information Integration During Pragmatic Word Learning
Authors: Bohn Manuel , Schmidt Louisa S. , Schulze Cornelia , Frank Michael C. , Tessler Michael Henry
Published: December 2022

Pragmatics is foundational to language use and learning. Computational cognitive models have been successfully used to predict pragmatic phenomena in adults and children – on an aggregate level. It is unclear if they can be used to predict behavior on an individual level. We address this question in children (N = 60, 3- to 5-year-olds), taking advantage of recent work on pragmatic cue integration. In Part 1, we use data from four independent tasks to estimate child-specific sensitivity parameters to three information sources: semantic knowledge, expectations about speaker informativeness, and sensitivity to common ground. In Part 2, we use these parameters to generate participant-specific trial-by-trial predictions for a new task that jointly manipulated all three information sources. The model accurately predicted children’s behavior in the majority of trials. This work advances a substantive theory of individual differences in which the primary locus of developmental variation is sensitivity to individual information sources.
An isolated crested newt population in Dutch coastal dunes: distribution relict or introduction?
Authors: de Brouwer Jurian , Helder Bas , France James , de Visser Manon C. , Struijk Richard P.J.H. , Wielstra Ben
Published: December 2022

Isolated distribution patches may represent local remnants of a formerly wider range or could have originated by human-mediated expansion beyond the natural range. Distinguishing between these two scenarios is not always straightforward. Northern crested newts (Triturus cristatus) in the Dutch coastal dunes are disconnected from the main species range by over 40 kilometres and whether they have been present historically is unclear. We genotyped crested newts from throughout the Netherlands for an mtDNA marker to determine the provenance of the coastal dune population. Because a closely related species, the Italian crested newt (T. carnifex), has an introduction history in the Netherlands, we also screened eight nuclear DNA SNP markers diagnostic for T. cristatus vs. T. carnifex. The crested newts from the coastal dunes carry a single T. cristatus mtDNA haplotype that naturally occurs in the south, but not the east, of the Netherlands. Therefore, we cannot distinguish if the population represents a natural distribution relict or is derived from an introduction. We find no evidence of genetic admixture with T. carnifex in the coastal dunes, but such admixture is apparent at another Dutch locality (far removed from a previously known genetically admixed population). Our study illustrates how difficult it can be to determine the origin of isolated populations.
Path Modification and Adjustments in Individual Behaviour? Evidence from Female Employment after the German Reunification
Authors: Fechter Charlotte
Published: December 2022

This paper is concerned with the question, how individuals behave during periods of institutional re-designs in welfare states. To understand behaviour after an institutional path modification, this article collects evidence on employment characteristics after the German reunification. East German women show to experience care activities for the first time later compared to West German women. Younger cohorts stay in care activities for a shorter period of time. Developments imply, that preferences have changed for women from both regions, proposing new forms of female employment standardisation in today’s Germany. At the same time, divergences from male employment characteristics are evident, implying rising gender inequality. Individual behaviour seems to be adaptive to new social processes proposed by institutions despite of former cultural beliefs.
Aspidistra nikitensis (Asparagaceae, Nolinoideae), a new species from Vietnam
Authors: KALYUZHNY SERGEY S. , VISLOBOKOV NIKOLAY A. , LUU HONG TRUONG , PLUGATAR YURY V. , KUZNETSOV ANDREY N. , KUZNETSOVA SVETLANA P. , KORZHENEVSKY VLADISLAV V. , VIN’KOVSKAYA OKSANA P.
Published: December 2022

Aspidistra nikitensis is described and illustrated as a new species from Gia Lai province of Vietnam. The new species possesses linear leaves and trimerous flowers with a mushroom-shaped pistil. In these features, the new species is morphologically similar to A. hainanensis species complex but differs in its convex stigma with projections. In stigma structure, A. nikitensis resembles A. longanensis but differs in shape of leaves and flower merism.
Revision of the Ambrysus signoreti Stål species complex (Heteroptera: Naucoridae: Ambrysinae). Section 1.
Authors: REYNOSO-VELASCO DANIEL , SITES ROBERT W.
Published: December 2022

The species-rich Ambrysus signoreti Stål species complex is diagnosed and subdivided into three sections based on morphology of the female subgenital plate. The species in the first section, characterized by the posterior margin of the subgenital plate with posterolateral corners extending posteriorly further than the central lobe, are revised. The group includes four species: two previously described from Mexico (Ambrysus cosmius La Rivers, A. schuhi Reynoso & Sites), one from Costa Rica (A. variegatus Usinger), and a new species, A. morelosensis n. sp., from central Mexico. The description of the new species and transfer of A. mormon Montandon to the A. guttatipennis Stål species complex brings the total number of species in the complex to 24 and the total number of described species of Ambrysus to 68. Also, an illustrated key to the species in this first section of the complex is provided. Finally, we present new state records from Mexico for A. cosmius and new province records from Costa Rica for A. variegatus.
Global Lagrangian Tracking of Continental Precipitation Recycling, Footprints, and Cascades
Authors: Cheng Tat Fan , Lu Mengqian
Published: December 2022

This study addresses how moisture in continental precipitation is recycled globally from a moisture-tracking perspective. Using a state-of-the-art three-dimensional Lagrangian model and optimized water accounting diagnostics, we complete a 40-yr (1971–2010) tracking of moisture from continental precipitation in the present-day climate. Climatologically, we conclude that 62% of continental precipitation stems from evapotranspiration through Lagrangian tracking—a measure is known as the global “continental precipitation recycling (CPR)” ratio. The result bridges the long-standing gap between the explicit (i.e., moisture trajectory–based) and implicit (i.e., water budget–based) estimates of the global CPR ratio in the literature. On the 1° grid scale, nonlocal terrestrial sources dominate precipitation in almost 70% of the land areas, most prominent in the continental interior. The CPR ratio consistently exhibits a contrasting seasonality between the mid-to-high latitudes and monsoon regions worldwide, from which two kinds of moisture source–regulated hydroclimate are generalized. Given the importance of CPR, we identify terrestrial source hotspots for continental precipitation that deserve careful governance. Using the backward “WaterSip” and a newly proposed forward “WaterDrip” diagnostics, we conceptualize and quantify two important types of cascading moisture recycling (CMR), whereby the moisture from an earlier source precipitates over an intermediate source and then re-evaporates to sustain precipitation farther downwind. The watershed-scale CMR metrics uncover the interdependence among the regional water cycles. Findings here advance the scientific understanding of the atmospheric water cycle as seen through Lagrangian tracking, and offer insights into transboundary watershed management and land-use planning to improve freshwater sustainability.

Significance Statement

Water is crucial for human civilization. There has been a century-long discussion on the moisture sources of continental precipitation. Using Lagrangian tracking, we show that 62% of continental precipitation stems from evapotranspiration, closing the gap with the budget-based estimate. Terrestrial sources dominate precipitation in 70% of Earth’s surface, especially in the interior of South America, Africa, and Eurasia. Global monsoon regions and the mid-to-high latitudes share a completely different source-regulated hydroclimate. Terrestrial source hotspots for continental precipitation that deserve conservation are identified. Two types of processes that formulate a cascade of regional water cycles are proposed and evaluated. Findings here advance the understanding of the origin of continental precipitation, offering insights into water and land management for freshwater sustainability.