bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Targeting BCL2 overcomes resistance and augments response to aurora kinase B inhibition by AZD2811 in small cell lung cancer
Authors: Ramkumar Kavya , Tanimoto Azusa , Della Corte Carminia M. , Stewart C. Allison , Wang Qi , Shen Li , Cardnell Robert J. , Wang Jing , Polanska Urszula M. , Andersen Courtney , Saeh Jamal , Pease J. Elizabeth , Travers Jon , Fabbri Giulia , Gay Carl M. , Urosevic Jelena , Byers Lauren A.
Published: June 2023

Abstract
Purpose: Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers of response. AURKB inhibition exploits an inherent genomic vulnerability in SCLC and is a promising therapeutic approach. Here, we identify biomarkers of response and develop rational combinations with AURKB inhibition to improve treatment efficacy. Experimental design: Selective AURKB inhibitor AZD2811 was profiled in a large panel of SCLC cell lines (n=57) and patient-derived xenograft (PDX) models. Proteomic and transcriptomic profiles were analyzed to identify candidate biomarkers of response and resistance. Effects on polyploidy, DNA damage and apoptosis were measured by flow cytometry and western blotting. Rational drug combinations were validated in SCLC cell lines and PDX models. Results: AZD2811 showed potent growth inhibitory activity in a subset of SCLC, often characterized by, but not limited to, high cMYC expression. Importantly, high BCL2 expression predicted resistance to AURKB inhibitor response in SCLC, independent of cMYC status. AZD2811-induced DNA damage and apoptosis were suppressed by high BCL2 levels, while combining AZD2811 with a BCL2 inhibitor significantly sensitized resistant models. In vivo, sustained tumor growth reduction and regression was achieved even with intermittent dosing of AZD2811 and venetoclax, an FDA approved BCL2 inhibitor. Conclusions: BCL2 inhibition overcomes intrinsic resistance and enhances sensitivity to AURKB inhibition in SCLC preclinical models.
Expression Levels of MicroRNA-300/BCL2L11 in Papillary Thyroid Cancer and Their Clinical Diagnostic Values
Authors: Shen Yi , Li Xiaoen , Xie Rongli , Chen Yupan , Hu Xun , Liu Yaping , Ma He
Published: June 2023

Introduction: This research aims to explore the expression levels of microRNA (miRNA)-300/BCL-2-like protein 11 (BCL2L11) and their values in the clinical diagnosis of papillary thyroid cancer (PTC). Methods: Pathological tissues that were surgically removed for thyroid disease were selected. miR-300 and BCL2L11 expression levels in the samples were measured. Receiver operating characteristic (ROC) curves were plotted to analyze miR-300 and BCL2L11 predictive values for PTC. Upon silencing miR-300 and silencing BCL2L11 in PTC cells, the corresponding miR-300 and BCL2L11 expression levels were tested, followed by examining PTC cell activities. The targeting relationship of miR-300 and BCL2L11 was detected by the bioinformatics website and luciferase activity assay. Results: miR-300 expression levels were elevated and BCL2L11 expression levels were reduced in PTC tissues. miR-300 and BCL2L11 expression levels in PTC tissues had a correlation with TNM stage and lymph node metastasis. The results of ROC curve revealed that both miR-300 and BCL2L11 had clinical predictive values for PTC. Mechanistically, miR-300 negatively regulated BCL2L11. The functional assays unveiled that silencing miR-300 impeded PTC cell activities, and silencing BCL2L11 induced PTC cell activities. In the rescue experiment, silencing BCL2L11 reversed the impacts of silencing miR-300 on PTC cell development. Conclusion: This study underlines that miR-300 expression is increased and BCL2L11 expression is declined in PTC. miR-300 and BCL2L11 both have clinical predictive values for diagnosing PTC.
Mechanistic and Clinical Comparison of the Erythropoietic Effects of SGLT2 Inhibitors and Prolyl Hydroxylase Inhibitors in Patients with Chronic Kidney Disease and Renal Anemia
Authors: Packer Milton
Published: June 2023

Renal anemia is treated with erythropoiesis-stimulating agents (ESAs), even though epoetin alfa and darbepoetin increase the risk of cardiovascular death and thromboembolic events, including stroke. Hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) inhibitors have been developed as an alternative to ESAs, producing comparable increases in hemoglobin. However, in advanced chronic kidney disease, HIF-PHD inhibitors can increase the risk of cardiovascular death, heart failure, and thrombotic events to a greater extent than that with ESAs, indicating that there is a compelling need for safer alternatives. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major cardiovascular events, and they increase hemoglobin, an effect that is related to an increase in erythropoietin and an expansion in red blood cell mass. SGLT2 inhibitors increase hemoglobin by ≈0.6–0.7 g/dL, resulting in the alleviation of anemia in many patients. The magnitude of this effect is comparable to that seen with low-to-medium doses of HIF-PHD inhibitors, and it is apparent even in advanced chronic kidney disease. Interestingly, HIF-PHD inhibitors act by interfering with the prolyl hydroxylases that degrade both HIF-1α and HIF-2α, thus enhancing both isoforms. However, HIF-2α is the physiological stimulus to the production of erythropoietin, and upregulation of HIF-1α may be an unnecessary ancillary property of HIF-PHD inhibitors, which may have adverse cardiac and vascular consequences. In contrast, SGLT2 inhibitors act to selectively increase HIF-2α, while downregulating HIF-1α, a distinctive profile that may contribute to their cardiorenal benefits. Intriguingly, for both HIF-PHD and SGLT2 inhibitors, the liver is likely to be an important site of increased erythropoietin production, recapitulating the fetal phenotype. These observations suggest that the use of SGLT2 inhibitors should be seriously evaluated as a therapeutic approach to treat renal anemia, yielding less cardiovascular risk than other therapeutic options.
The Qingdao Pattern and U.S.-Chinese Crisis Management: The KMT, the CCP, and the U.S. Marines in Qingdao during the Chinese Civil War (1945–1949)
Authors: Zhang Weizhen , Peng Tao
Published: June 2023

After the Second World War ended in 1945, the Chinese Communist Party (CCP) tried to seize Qingdao, a major port city on the Shandong Peninsula. The landing of U.S. Marines there foiled the CCP's attempt. With the support of the Kuomintang (KMT)—the CCP's main enemy—the U.S. Marines stayed in Qingdao throughout the civil war in China, from late 1945 to mid-1949. Drawing on archival sources from China, the United States, the former Soviet Union, Great Britain, and Japan, this article explores CCP-KMT-U.S. interactions regarding the presence of U.S. Marines in Qingdao. The KMT-CCP civil war influenced—and was influenced by—the presence of the Marines in Qingdao. The KMT government depended on the U.S. Marines for security, whereas the CCP, opposing the U.S. presence, took a tough propaganda stance but remained cautious in its actions. The United States ultimately decided to withdraw the Marines to avoid overt involvement in the Chinese civil war. This type of triangular engagement influenced the future pattern of Cold War confrontations among the three parties.
The Case of Mleh (1170–1175): Cilician Armenia between Nūr al-Dīn and Manuel I Komnenos
Authors: Takirtakoglou Konstantinos
Published: June 2023

The present paper discusses the reign of the Rubenid lord of Armenian Cilicia, Mleh (1170–1175), and examines his relations with the two great powers of the period, the Byzantine Empire and the Zengids under Nūr al-Dīn (1146–1174). Through examination of the contemporary sources of the period, the following conclusions may be drawn: Firstly, Manuel (1143–1180) did not send an expeditionary force against Mleh. On the contrary, Mleh faced and defeated the local Byzantine garrisons. Secondly, the Crusaders waged a campaign against Mleh in 1173, which was partially successful as it forced the Rubenid lord to recognize the suzerainty of the king of Jerusalem, albeit temporarily. Thirdly, a consequence of the Crusader success was the Byzantine re-conquest of the cities of the Cilician Plain. Finally, Mleh’s status as a client of Nur al-Din does not relate to his religious identity. The sources make it clear that he remained a Christian.
A Record of the Tea Retreat: The Chaliao ji by Lu Shusheng
Authors: Zanini Livio
Published: June 2023

The Chaliao ji 茶寮記 (A Record of the Tea Retreat) by the scholar-official Lu Shusheng 陸樹聲 (1509–1605) stands out in the vast corpus of essays on tea produced in the late Ming dynasty for two reasons. Firstly, the social status of its author, who held the highest official position among all tea writers of the period, shows that tea appreciation was actively discussed among the highest echelons of the late Ming gentry. Secondly, the Chaliao ji is the earliest publication to bring together the issues of the construction of a private tea room, prescriptions for the preparation of loose-leaf tea, as well as instructions for savouring the beverage, thus further delineating specific aspects of literati tea culture as social markers.

This study examines the background and content of Chaliao ji. It first provides an overview of Lu Shusheng’s biography, from his experience in officialdom to his later life in retirement, focusing on his construction of a garden and his commitment to Buddhism and tea appreciation. It then discusses the contents of the text, the several extant editions and issues regarding its authorship. Finally, it provides an English translation of the Chaliao ji accompanied by the Chinese text and commentary.
Comitatives and Instrumentals in Thai: A Diachronic Typological Perspective
Authors: Pothipath Vipas
Published: June 2023

Languages can be divided into three types with respect to the encoding of comitatives and instrumentals: identity, differentiation and mixed (Stolz, Stroh and Urdze 2013). Diachronic data from Thai dating from 13th to 21st centuries ce suggests that these three language types correspond to the three stages of development of the relation between the two categories in Thai, which progress as follows. Between the 13th and the mid-18th centuries, Thai employed the pattern of identity. In general, the preposition dûaj ‘with’ was the relator for the two categories. Later, in the late 18th and early 19th centuries, Thai displayed mixed structures. While the preposition dûaj was preserved to encode both categories, the preposition kàp ‘and/with’ was also the relator for the comitative. Still later, from the mid-19th century to the present, Thai favored differentiation. The preposition dûaj remains in its function as an instrumental relator, while the preposition kàp has been employed as a comitative relator.
Independence or Interdependence?: The Thai Self-Construal as Reflected by Linguistic Evidence
Authors: Panpothong Natthaporn , Phakdeephasook Siriporn
Published: June 2023

Self-construal can influence the ways people in distinct cultures think, perceive and interact with others. To date, scholars still present different arguments on the prominent self-construal of Thais. The present study aims at examining Thai linguistic data including proverbs, sayings, cultural key terms and interactional data in response to the question of whether Thai culture places emphasis on independent or interdependent perspectives of the self. The findings reveal that Thai sayings, proverbs and cultural key terms reflect both independent and interdependent self-construals. Yet, those that stress interdependency outnumber independency. As for interactional practices in daily exchanges, the usage of pronominal terms, final particles for (im)politeness and lexical variants marking interpersonal relationships make it mandatory for Thai speakers to pay attention to interpersonal relationships. Lastly, in task-based superior-subordinate conversations, collaborative and non-confrontational styles are preferred by Thai superiors. Their interactional style reflects features influenced by interdependent self-construal.
Whip it into shape: Revision of the Demansia psammophis (Schlegel, 1837) complex (Squamata: Elapidae), with a description of a new species from central Australia
Authors: NANKIVELL JAMES H. , MARYAN BRAD , BUSH BRIAN G. , HUTCHINSON MARK N.
Published: June 2023

The genus Demansia Günther is the most diverse genus of Australian terrestrial elapids. A phylogenetic framework for the familiar but problematic taxa D. psammophis and D. reticulata (Gray) has been long overdue to ascertain interspecific relationships and resolve unclear taxonomic issues. Here we present an integrated molecular phylogenetic and morphological analyses to review species delineation, resulting in confirmation that both D. psammophis and D. reticulata are full species and that some populations referred to D. r. cupreiceps Storr are not distinguishable from more typical D. reticulata. We also find the widespread central Australian population (treated by most authors as part of cupreiceps) to be specifically distinct. We redescribe D. psammophis and D. reticulata to clarify morphological and geographical boundaries and describe D. cyanochasma sp. nov. based on a combination of molecular genetic markers, details of colour and pattern, adult total length and a few morphometric attributes. We also designate a lectotype for D. psammophis from the original syntype series and comment on the necessity for further taxonomic refinement of this distinctive group.
A new species of Crasiella (Gastrotricha: Planodasyidae) from Capron Shoal, Florida, USA
Authors: ARAÚJO THIAGO QUINTÃO , HOCHBERG RICK
Published: June 2023

A new gastrotrich species of the genus Crasiella (Macrodasyida: Planodasyidae) is described from Capron Shoal, Florida, USA. The new species is up to 520 μm long and differs from its congeners in the position of adhesive tubes and the structure of its spermatozoa. There are nine TbA that insert ventrally on the head plus an additional pair of TBA that insert medially. Up to 42 TbVL per side. Six pairs of TbP insert on a pair of caudal pedicles. Animals are simultaneous hermaphrodites with an elongated frontal organ and large caudal organ. The spermatozoa have a tripartite acrosome unlike others in the genus that have a four-part acrosome.
A new species in the tortoise-beetle genus Dorynota s. str. Chevrolat (Coleoptera: Chrysomelidae: Cassidinae: Dorynotini) from Brazil
Authors: SIMÕES MARIANNA V. P. , SEKERKA LUKÁŠ
Published: June 2023

A new species Dorynota phoenix Simões and Sekerka, new species is described and figured from Mato Grosso state of Brazil. The new species belongs to the D. monoceros species-group and is compared to morphologically similar taxa. Updated key to the nominotypical subgenus of Dorynota is provided.
Transfer RNA-derived fragments as novel biomarkers of the onset and progression of gastric cancer
Authors: Xie Yaoyao , Zhang Shuangshuang , Yu Xiuchong , Ye Guoliang , Guo Junming
Published: June 2023

Gastric cancer (GC) is a particularly malignant disease; thus, early diagnosis and treatment are especially important. Transfer RNA-derived small RNAs (tsRNAs) have been implicated in the onset and progression of various cancers. Therefore, the aim of this study was to explore the role of tRF-18-79MP9P04 (previously named tRF-5026a) in the onset and progression of GC. Expression levels of tRF-18-79MP9P04 were quantified in gastric mucosa specimens of healthy controls and plasma samples of patients with different stages of GC. The results showed that plasma levels of tRF-18-79MP9P04 were significantly decreased in the early and advanced stages of GC. The results of the nucleocytoplasmic separation assay found that tRF-18-79MP9P04 was localized in the nuclei of GC cells. High-throughput transcriptome sequencing identified genes regulated by tRF-18-79MP9P04 in GC cells, and the function of tRF-18-79MP9P04 was predicted by bioinformatics. Collectively, the findings of this study suggest that tRF-18-79MP9P04 would be useful as non-invasive biomarker for early diagnosis of GC and is related to cornification, the type I interferon signaling pathway, RNA polymerase II activities, and DNA binding.
Resolving therapy resistance mechanisms in multiple myeloma by multiomics subclone analysis
Authors: Poos Alexandra M. , Prokoph Nina , Przybilla Moritz J. , Mallm Jan-Philipp , Steiger Simon , Seufert Isabelle , John Lukas , Tirier Stephan M. , Bauer Katharina , Baumann Anja , Rohleder Jennifer , Munawar Umair , Rasche Leo , Kortüm K. Martin , Giesen Nicola , Reichert Philipp , Huhn Stefanie , Müller-Tidow Carsten , Goldschmidt Hartmut , Stegle Oliver , Raab Marc S. , Rippe Karsten , Weinhold Niels
Published: June 2023

Intratumor heterogeneity as a clinical challenge becomes most evident after several treatment lines, when multidrug-resistant subclones accumulate. To address this challenge, the characterization of resistance mechanisms at the subclonal level is key to identify common vulnerabilities. In this study, we integrate whole-genome sequencing, single-cell (sc) transcriptomics (scRNA sequencing), and chromatin accessibility (scATAC sequencing) together with mitochondrial DNA mutations to define subclonal architecture and evolution for longitudinal samples from 15 patients with relapsed or refractory multiple myeloma. We assess transcriptomic and epigenomic changes to resolve the multifactorial nature of therapy resistance and relate it to the parallel occurrence of different mechanisms: (1) preexisting epigenetic profiles of subclones associated with survival advantages, (2) converging phenotypic adaptation of genetically distinct subclones, and (3) subclone-specific interactions of myeloma and bone marrow microenvironment cells. Our study showcases how an integrative multiomics analysis can be applied to track and characterize distinct multidrug-resistant subclones over time for the identification of molecular targets against them.
Soluble CD163 predicts outcome in both chemoimmunotherapy and targeted therapy–treated mantle cell lymphoma
Authors: Nikkarinen Anna , Lokhande Lavanya , Amini Rose-Marie , Jerkeman Mats , Porwit Anna , Molin Daniel , Enblad Gunilla , Kolstad Arne , Räty Riikka , Hutchings Martin , Weibull Caroline E. , Hollander Peter , Ek Sara , Glimelius Ingrid
Published: June 2023

The outcome for patients with mantle cell lymphoma (MCL) has drastically improved with new treatments directed toward the tumor immune microenvironment, where macrophages play an important role. In MCL, the presence of M2 macrophages defined by CD163 expression in diagnostic biopsies has been associated with a worse prognosis. An alternative way to assess the abundance of M2 macrophages is by measuring the level of soluble CD163 in serum (sCD163). We aimed to investigate the prognostic value of sCD163 in 131 patients with MCL. We found that high sCD163 at diagnosis was associated with shorter progression-free survival (PFS) and shorter overall survival (OS) in 81 patients who were newly diagnosed and subsequently treated with chemoimmunotherapy. The same was seen in a cohort of 50 patients with relapsed MCL that were mainly treated within the phase 2 Philemon-trial with rituximab, ibrutinib, and lenalidomide. In patients who were newly diagnosed and had low levels of sCD163, 5-year survival was 97%. There was a moderate correlation between sCD163 and tissue CD163. The association with a poor prognosis was independent of MCL international prognostic index, Ki67, p53 status, and blastoid morphology, as assessed in a multivariable Cox proportional hazards model. In this study, high sCD163 was associated with both shorter PFS and shorter OS, showing that high levels of the M2 macrophage marker sCD163 is an independent negative prognostic factor in MCL, both in the chemoimmunotherapy and ibrutinib/lenalidomide era. In addition, low sCD163 levels identify patients with MCL with a very good prognosis.
Attenuated immunogenicity of SARS-CoV-2 vaccines and risk factors in stem cell transplant recipients: a meta-analysis
Authors: Meejun Tanaporn , Srisurapanont Karan , Manothummetha Kasama , Thongkam Achitpol , Mejun Nuthchaya , Chuleerarux Nipat , Sanguankeo Anawin , Phongkhun Kasidis , Leksuwankun Surachai , Thanakitcharu Jaedvara , Lerttiendamrong Bhoowit , Langsiri Nattapong , Torvorapanit Pattama , Worasilchai Navaporn , Plongla Rongpong , Hirankarn Nattiya , Nematollahi Saman , Permpalung Nitipong , Moonla Chatphatai , Kates Olivia S.
Published: June 2023

Immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is diminished in hematopoietic stem cell transplant (HSCT) recipients. To summarize current evidence and identify risk factors for attenuated responses, 5 electronic databases were searched since database inceptions through 12 January 2023 for studies reporting humoral and/or cellular immunogenicity of SARS-CoV-2 vaccination in the HSCT population. Using descriptive statistics and random-effects models, extracted numbers of responders and pooled odds ratios (pORs) with 95% confidence intervals (CIs) for risk factors of negative immune responses were analyzed (PROSPERO: CRD42021277109). From 61 studies with 5906 HSCT recipients, after 1, 2, and 3 doses of messenger RNA (mRNA) SARS-CoV-2 vaccines, the mean antispike antibody seropositivity rates (95% CI) were 38% (19-62), 81% (77-84), and 80% (75-84); neutralizing antibody seropositivity rates were 52% (40-64), 71% (54-83), and 78% (61-89); and cellular immune response rates were 52% (39-64), 66% (51-79), and 72% (52-86). After 2 vaccine doses, risk factors (pOR; 95% CI) associated with antispike seronegativity were male recipients (0.63; 0.49-0.83), recent rituximab exposure (0.09; 0.03-0.21), haploidentical allografts (0.46; 0.22-0.95), <24 months from HSCT (0.25; 0.07-0.89), lymphopenia (0.18; 0.13-0.24), hypogammaglobulinemia (0.23; 0.10-0.55), concomitant chemotherapy (0.48; 0.29-0.78) and immunosuppression (0.18; 0.13-0.25). Complete remission of underlying hematologic malignancy (2.55; 1.05-6.17) and myeloablative conditioning (1.72; 1.30-2.28) compared with reduced-intensity conditioning were associated with antispike seropositivity. Ongoing immunosuppression (0.31; 0.10-0.99) was associated with poor cellular immunogenicity. In conclusion, attenuated humoral and cellular immune responses to mRNA SARS-CoV-2 vaccination are associated with several risk factors among HSCT recipients. Optimizing individualized vaccination and developing alternative COVID-19 prevention strategies are warranted.
Significant race and gender differences in anterior cruciate ligament tibial footprint location: a 3D-based analysis
Authors: Zhang Lihang , Li Changzhao , Zhang Jiaying , Zou Diyang , Dimitriou Dimitris , Xing Xing , Tsai Tsung-Yuan , Li Pingyue
Published: June 2023

Background

The aim of the present study was to identify potential race- or gender-specific differences in anterior cruciate ligament (ACL) tibial footprint location from the tibia anatomical coordinate system (tACS) origin, investigate the distances from the tibial footprint to the anterior root of the lateral meniscus (ARLM) and the medial tibial spine (MTS), determine how reliable the ARLM and MTS can be in locating the ACL tibial footprint, and assess the risk of iatrogenic ARLM injuries caused by using reamers with various diameters (7–10 mm).

Patients and methods

Magnetic resonance images of 91 Chinese and 91 Caucasian subjects were used for the reconstruction of three-dimensional (3D) tibial and ACL tibial footprint models. The anatomical coordinate system was applied to reflect the anatomical locations of scanned samples.

Results

The average anteroposterior (A/P) tibial footprint location was 17.1 ± 2.3 mm and 20.0 ± 3.4 mm in Chinese and Caucasians, respectively (P < .001). The average mediolateral (M/L) tibial footprint location was 34.2 ± 2.4 mm and 37.4 ± 3.6 mm in Chinese and Caucasians, respectively (P < .001). The average difference between men and women was 2 mm in Chinese and 3.1 mm in Caucasians. The safe zone for tibial tunnel reaming to avoid ARLM injury was 2.2 mm and 1.9 mm away from the central tibial footprint in the Chinese and Caucasians, respectively. The probability of damaging the ARLM by using reamers with various diameters ranged from 0% for Chinese males with a 7 mm reamer to 30% in Caucasian females with a 10 mm reamer.

Conclusions

The significant race- and gender-specific differences in the ACL tibial footprint should be taken in consideration during anatomic ACL reconstruction. The ARLM and MTS are reliable intraoperative landmarks for identifying the tibial ACL footprint. Caucasians and females might be more prone to iatrogenic ARLM injury.

Level of evidence: III, cohort study.

Trial registration: This study has been approved by the ethical research committee of the General Hospital of Southern Theater Command of PLA under the code: [2019] No.10.
The decreased of peripheral blood natural killer cell is associated with serum IL-2 level in the renal tubular acidosis in patients with primary sjogren’s syndrome
Authors: Cheng Liyun , Liu Lu , Su Ronghui , Yan Huanhuan , Zi Xiaoyu , Gao Chong , Li Xiaofeng , Wang Caihong
Published: June 2023

Background

Primary Sjogren’s Syndrome (pSS) is a lymphoproliferative disease with autoimmune characteristics, which is characterized by lymphocyte infiltration of exocrine glands and involvement and dysfunction of extraglandular organs. Renal tubular acidosis (RTA) is a common renal involvement in pSS. This study investigated the phenotypic characteristics of peripheral blood lymphocyte subsets and cytokines in pSS patients complicated with RTA (pSS-RTA).

Method

This retrospective study included 25 pSS patients complicated with RTA and 54 pSS patients without RTA (pSS-no-RTA). To examine the level of peripheral lymphocytes subsets, flow cytometry analysis was used. The level of serum cytokines were detected by flow cytometry bead array(CBA). The influencing factors related to the occurrence of pSS-RTA were identified through logistic regression analyze.

Results

The absolute number of CD4 + T cells and Th2 cells in peripheral blood were decreased in pSS-RTA patients than pSS-no-RTA patients. Moreover, the absolute number of NK cells and Treg cells were also decreased in pSS-RTA patients than pSS-no-RTA. The level of serum IL-2 was higher in pSS-RTA patients than pSS-no-RTA patients, and is negatively correlated with the number of NK cells, the number and percentage of Th17 cells, and Th17/Treg. Serum IL-2 level is also correlated with various cytokines. Multivariate logistic analysis proved that elevated ESR and ALP were risk factors for pSS complicated with RTA, while Treg was a protective factor.

Conclusion

The increase of serum IL-2 level and the decrease of peripheral blood NK cells and Treg cells may be the immune mechanism of the development of pSS-RTA disease.
The revealing of a novel double bond reductase related to perilla ketone biosynthesis in Perilla frutescens
Authors: Zhou Peina , Shao Yongfang , Jiang Zheng , Dang Jingjie , Qu Cheng , Wu Qinan
Published: June 2023

Background

Perilla frutescens is widely used as both a medicine and a food worldwide. Its volatile oils are its active ingredients, and, based on the different volatile constituents, P. frutescens can be divided into several chemotypes, with perilla ketone (PK) being the most common. However, the key genes involved in PK biosynthesis have not yet been identified.

Results

In this study, metabolite constituents and transcriptomic data were compared in leaves of different levels. The variation in PK levels was the opposite of that of isoegoma ketone and egoma ketone in leaves at different levels. Based on transcriptome data, eight candidate genes were identified and successfully expressed in a prokaryotic system. Sequence analysis revealed them to be double bond reductases (PfDBRs), which are members of the NADPH-dependent, medium-chain dehydrogenase/reductase (MDR) superfamily. They catalyze the conversion of isoegoma ketone and egoma ketone into PK in in vitro enzymatic assays. PfDBRs also showed activity on pulegone, 3-nonen-2-one, and 4-hydroxybenzalacetone. In addition, several genes and transcription factors were predicted to be associated with monoterpenoid biosynthesis, and their expression profiles were positively correlated with variations in PK abundance, suggesting their potential functions in PK biosynthesis.

Conclusions

The eight candidate genes encoding a novel double bond reductase related to perilla ketone biosynthesis were identified in P. frutescens, which carries similar sequences and molecular features as the MpPR and NtPR from Nepeta tenuifolia and Mentha piperita, respectively. These findings not only reveal the pivotal roles of PfDBR in exploring and interpreting PK biological pathway but also contribute to facilitating future studies on this DBR protein family.
Genome-wide association study of dilated cardiomyopathy-induced heart failure associated with renal insufficiency in a Chinese population
Authors: Hu Yuexin , Jin Liangli , Wang Zhi
Published: June 2023

Background

As it is unclear whether there is genetic susceptibility to cardiorenal syndrome (CRS), we conducted a genome-wide association study of dilated cardiomyopathy (DCM)-induced heart failure (HF) associated with renal insufficiency (RI) in a Chinese population to identify putative susceptibility variants and culprit genes.

Methods

A total of 99 Han Chinese patients with DCM-induced chronic HF were selected and divided into one of three groups, namely, HF with normal renal function (Group 1), HF with mild RI (Group 2) and HF with moderate to severe RI (Group 3). Genomic DNA was extracted from each subject for genotyping.

Results

According to Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, top 10 lists of molecular function, cell composition and biological process of differential target genes and 15 signalling pathways were discriminated among the three groups. Additionally, sequencing results identified 26 significantly different single-nucleotide polymorphisms (SNPs) in the 15 signalling pathways, including three SNPs (rs57938337, rs6683225 and rs6692782) in ryanodine receptor 2 (RYR2) and two SNPs (rs12439006 and rs16958069) in RYR3. The genotype and allele frequencies of the five SNPs in RYR2 and RYR3 were significantly differential between HF (Group 1) and CRS (Group 2 + 3) patients.

Conclusion

Twenty-six significantly different SNP loci in 17 genes of the 15 KEGG pathways were found in the three patient groups. Among these variants, rs57938337, rs6683225 and rs6692782 in RYR2 and rs12439006 and rs16958069 in RYR3 are associated with RI in Han Chinese patients with heart failure, suggesting that these variants may be used to identify patients susceptible to CRS in the future.
Non-response to first-line hormonal treatment for symptomatic endometriosis: overcoming tunnel vision. A narrative review
Authors: Cetera Giulia Emily , Merli Camilla Erminia Maria , Facchin Federica , Viganò Paola , Pesce Elisa , Caprara Francesca , Vercellini Paolo
Published: June 2023

One-fourth to one-third of women with endometriosis receiving first-line hormonal treatment lacks an adequate response in terms of resolution of painful symptoms. This phenomenon has been ascribed to “progesterone resistance”, an entity that was theorized to explain the gap between the ubiquity of retrograde menstruation and the 10% prevalence of endometriosis among women of reproductive age.

Nevertheless, the hypothesis of progesterone resistance is not free of controversies. As our understanding of endometriosis is increasing, authors are starting to set aside the traditionally accepted tunnel vision of endometriosis as a strictly pelvic disease, opening to a more comprehensive perspective of the condition. The question is: are patients not responding to first-line treatment because they have an altered signaling pathway for such treatment, or have we been overlooking a series of other pain contributors which may not be resolved by hormonal therapy?

Finding an answer to this question is evermore impelling, for two reasons mainly. Firstly, because not recognizing the presence of further pain contributors adds a delay in treatment to the already existing delay in diagnosis of endometriosis. This may lead to chronicity of the untreated pain contributors as well as causing adverse consequences on quality of life and psychological health. Secondly, misinterpreting the consequences of untreated pain contributors as a non-response to standard first-line treatment may imply the adoption of second-line medical therapies or of surgery, which may entail non-negligible side effects and may not be free of physical, psychological and socioeconomic repercussions.

The current narrative review aims at providing an overview of all the possible pain contributors in endometriosis, ranging from those strictly organic to those with a greater neuro-psychological component. Including these aspects in a broader psychobiological approach may provide useful suggestions for treating those patients who report persistent pain symptoms despite receiving first-line hormonal medical treatment.
How many mosquito nets are needed to maintain universal coverage: an update
Authors: Koenker Hannah , Yukich Josh , Erskine Marcy , Opoku Robert , Sternberg Eleanore , Kilian Albert
Published: June 2023

Background

Insecticide-treated nets (ITNs) have served as the cornerstone of malaria vector control in sub-Saharan Africa for the past two decades. Over 2.5 billion ITNs have been delivered since 2004 primarily through periodic mass distribution campaigns scheduled at approximately three-year intervals, aligning with the expected lifespan of nets. Recent work indicates that ITN retention times are less than two years in most countries, raising key questions for quantification approaches and delivery frequency for ITN distribution. This paper models several quantification approaches for five typical ITN distribution strategies, estimates the proportion of the population with access to an ITN, and presents recommended quantification approaches to meet global targets for ITN access and use.

Methods

A stock and flow model with annual timesteps was used to model ITN distribution and resulting ITN access for 2020–2035 under five scenarios in 40 countries: (1) three-year mass campaigns, (2) full-scale annual continuous distribution, (3) three-year mass campaigns plus continuous distribution in the years between campaigns, (4) three-year mass campaigns at different quantification approaches, (5) two-year mass campaigns at different quantification approaches. All scenarios included ITN distribution to pregnant women at antenatal clinics and infants at immunization visits.

Results

The current status quo of conducting mass campaigns every three years using a population/1.8 quantifier is insufficient to achieve or maintain targets of 80% population access to ITNs in most malaria-endemic countries, given most estimated retention times are less than three years. Tailored three- or two-year mass campaigns were less efficient than annual continuous distribution strategies in nearly all settings. For countries with at least 2.5 year median ITN retention times, full scale continuous distribution provided better ITN access while needing 20-23% fewer ITNs compared to current mass campaigns.

Conclusion

Given variation in ITN retention times across countries, tailored quantification approaches for mass campaigns and continuous distribution strategies are warranted. Continuous distribution strategies are likely to offer more efficient ways to maintain ITN coverage, with fewer nets, where ITN retention times are at least two and a half years. National malaria programmes and their funding partners should work to increase the number of ITNs available to those vulnerable to malaria, while at the same time working to extend the useful life of these critical commodities.
Efficacy of the PainVision apparatus for assessment of axial neck pain after cervical laminoplasty: a prospective study
Authors: Inoue Takeshi , Soshi Shigeru , Yamamoto Shun , Saito Mitsuru
Published: June 2023

Background

Axial neck pain is one of the complications of posterior cervical surgeries such as laminoplasty. This study aimed to investigate the efficiency of the PainVision apparatus for axial neck pain assessment by comparing it with other methods.

Methods

This prospective study included 118 patients (90 men and 28 women; average age: 66.9 (32–86) years) with cervical myelopathy who underwent open-door laminoplasty at our medical center between April 2009 and August 2019. Pain degree (PD) measured by PainVision, visual analog scale (VAS), and bodily pain (BP), a subitem of the MOS 36-Item Short-Form Health Survey (SF36), were used to evaluate axial neck pain, which was investigated preoperatively and at 3, 6, 12, 18, and 24 months postoperatively.

Results

Comparison of the scores at each evaluation time point found significant improvement between the pre- and post-operative values for all assessment methods. Further, on comparing the amounts of change between pre- and post-operative scores in each pain assessment method, we found significant differences in PD and VAS but not in BP. We also found significant positive correlations between PD and VAS at each time point (all p < 0.001) and significant negative correlations between PD and BP (all p < 0.05) and between VAS and BP (all p < 0.01)  at each time point.

Conclusions

In this study, we demonstrated that PD and VAS are more sensitive indicators of changes in axial neck pain than BP and also that PD has an excellent correlation with VAS. These results suggest that the PainVision apparatus may be an effective instrument for quantifying axial neck pain after cervical laminoplasty, though its superiority over VAS needs to be verified in future studies.
Factors affecting nutritional knowledge, attitude, practices and dietary intake among national players in Kathmandu, Nepal: a cross-sectional study
Authors: Thapa Madhu , Neupane Arjun , Shrestha Sailendra Kumar Duwal , Nepal Prabin , Upadhyaya Atul , Niraula Pratik , Shrestha Ram Kumar , Sunuwar Dev Ram
Published: June 2023

Introduction

Good nutrition knowledge and nutrient intake have been regarded as significant determinants in enhancing athletes’ performance and overall health status. This study aimed to assess knowledge, attitude, and practices of nutrition and dietary intake among athletes.

Methods

A cross-sectional study was conducted from January to April 2022 among national athletes from two sports clubs in Kathmandu Metropolitan City, Nepal. A semi-structured questionnaire was used to collect the data. Anthropometric measurements and dietary intake were recorded. Bivariate and multivariate binary logistic regression was used to estimate the crude odds ratios (cOR), and adjusted odds ratios (aOR) with 95% confidence intervals (CIs).

Results

A total of 270 players were included in this study (mean age, 25 years; 49.6% male, 50.4% female). Almost half of the athletes had good nutrition knowledge [54.1% (146/270)], attitude [56.7% (153/270)], and practices [50% (135/270)] scores. The mean energy, carbohydrate, protein, and fat intake were 35.0 kcal/kg/day, 5.6, 0.9, and 0.9 g/kg/day, respectively. Likewise, mean calcium and iron intake were 370, and 12.5 mg, respectively. In the multivariate model, families with monthly household income less than 50,000 Nepalese rupees ($400) (adjusted Odds Ratio/aOR = 2.58; 95% CI: 1.12 to 5.96), and those who did not receive diet plan (aOR = 3.14; 95% CI: 1.25 to 7.84) were more likely to have poor nutrition knowledge. Players who did not check food labelling (aOR = 1.44; 95% CI: 0.78 to 2.63) were more likely to have negative attitude towards nutrition. Players who did not ever attend nutrition class (aOR = 3.54; 95% CI: 1.46 to 8.54) and those who did not consume different food during off and on the season of sports (aOR = 2.36; 95% CI: 1.39 to 4.01) were more likely to have poor nutrition practice.

Conclusions

Half of the athletes’ nutritional knowledge, attitudes, and practices score were satisfactory. Nutrient intake among athletes was suboptimal. Nutrition intervention programs are critical to improve nutritional knowledge, attitude and practice related to dietary intake among national athletes in Nepal.
Blau syndrome with persistent fetal vasculature: a case report
Authors: Liu Miao , Zeng Yong , Zhong Jie
Published: June 2023

Background

Blau Syndrome (BS) is a rare autosomal dominant noncaseous granulomatous disease caused by mutations in the NOD2 gene. The disease is characterized by granulomatous dermatitis, symmetrical arthritis, and uveitis, which, if left untreated, can progress to blindness. The diagnosis of BS can be challenging because of its rarity and overlap with other rheumatologic disorders. Early detection of ocular involvement is critical to prevent vision loss and improve the prognosis of patients with BS.

Case presentation

In this report, we present a case of a five-year-old Chinese girl diagnosed with BS one year ago after presenting with a systemic rash and urinary calculi. Genetic testing was recommended by a physician, and a heterozygous mutation of the NOD2 gene c.1538T > C (p.M513T) was identified. Eight months ago, due to bilateral corneal punctate opacity, we had examined and diagnosed bilateral uveitis, bilateral corneal zonal degeneration, persistent fetal vasculature (PFV) in the right eye, and perivascular granuloma in the right eye. As a result, Vitrectomy was performed on the right eye, resulting in a significant improvement in visual acuity from 1/50 on the first day after surgery to 3/10 after 1 week. After 6 months, the visual acuity of the right eye was maintained at 3/20, but opacification of the lens posterior capsule was observed. Follow-up appointments are ongoing to monitor the condition of the affected eyes. Our report underscores the importance of prompt detection and management of ocular involvement in BS accompany with PFV to prevent vision loss and improve patient outcomes.

Conclusions

This report details the case of a child diagnosed with BS who accompanied a periretinal granuloma and PFV in the right eye. Regrettably, the left eye was observed to have no light perception (NLP) with the fundus not being visible. The occurrence of ocular complications in patients with BS, must be closely monitored to prevent vision loss and enhance treatment outcomes. This case underscores the importance of prompt diagnosis and management of ocular complications in patients with BS to prevent further damage and optimize patient outcomes.
Multi-omics analysis of DNA replication-associated primase polymerase (PRIMPOL) in pan-cancer: a potential target for prognosis and immune response
Authors: Deng Langmei , Thakur Abhimanyu , Peng Jinwu , Song Liying , Li Zhilan
Published: June 2023

Background

It is critical to understand the mechanisms of human cancers in order to develop the effective anti-cancer therapeutic strategies. Recent studies indicated that primase polymerase (PRIMPOL) is strongly associated with the development of human cancers. Nevertheless, a systematic pan-cancer analysis of PRIMPOL remains to be further clarified.

Method

Comprehensive multi-omics bioinformatics algorithms, such as TIMER2.0, GEPIA2.0 and cBioPortal, were utilized to evaluate the biological roles of PRIMPOL in pan-cancer, including the expression profiles, genomic alterations, prognostic values and immune regulation.

Results

PRIMPOL was upregulated in glioblastoma multiforme and kidney renal clear cell carcinoma. The brain lower grade glioma patients with enhanced PRIMPOL expression displayed poor prognostic values. We also demonstrated the PRIMPOL's immunomodulating effects on pan-cancer as well as its genomic changes and methylation levels. The aberrant expression of PRIMPOL was linked to various cancer-associated pathways, including DNA damage response, DNA repair, and angiogenesis, according to single-cell sequencing and function enrichment.

Conclusions

This pan-cancer analysis offers a thorough review of the functional roles of PRIMPOL in human cancers, suggesting PRIMPOL as a potentially important biomarker for the progression and immunotherapy of various cancers.
Benzylpenicillin concentrations in umbilical cord blood and plasma of premature neonates following intrapartum doses for group B streptococcal prophylaxis
Authors: Samb Amadou , Dierikx Thomas H. , Bijleveld Yuma A. , de Haan Timo R. , Hodiamont Caspar J. , van Leeuwen Elisabeth , van Kaam Anton H. L. C. , Mathôt Ron A. A. , Visser Douwe H.
Published: June 2023

Background and method

Dutch obstetrics guideline suggest an initial maternal benzylpenicillin dose of 2,000,000 IU followed by 1,000,000 IU every 4 h for group-B-streptococci (GBS) prophylaxis. The objective of this study was to evaluate whether concentrations of benzylpenicillin reached concentrations above the minimal inhibitory concentrations (MIC) in umbilical cord blood (UCB) and neonatal plasma following the Dutch guideline.

Results

Forty-six neonates were included. A total of 46 UCB samples and 18 neonatal plasma samples were available for analysis. Nineteen neonates had mothers that received intrapartum benzylpenicillin. Benzylpenicillin in UCB corresponded to concentrations in plasma drawn directly postpartum (R2 = 0.88, p < 0.01). A log-linear regression suggested that benzylpenicillin concentrations in neonates remained above the MIC threshold 0.125 mg/L up to 13.0 h after the last intrapartum dose.

Conclusions

Dutch intrapartum benzylpenicillin doses result in neonatal concentrations above the MIC of GBS.