bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytogenomic epileptology
Authors: Iourov Ivan Y. , Gerasimov Alexandr P. , Zelenova Maria A. , Ivanova Natalya E. , Kurinnaia Oksana S. , Zabrodskaya Yulia M. , Demidova Irina A. , Barantsevich Evgeny R. , Vasin Kirill S. , Kolotii Alexey D. , Ushanov Vseslav V. , Sitovskaya Darya A. , Lobzhanidze Timur B.-A. , Iuditskaia Maria E. , Iakushev Nikita S. , Zhumatov Muslim M. , Vorsanova Svetlana G. , Samochernyh Konstantin A.
Published: January 2023

Molecular cytogenetic and cytogenomic studies have made a contribution to genetics of epilepsy. However, current genomic research of this devastative condition is generally focused on the molecular genetic aspects (i.e. gene hunting, detecting mutations in known epilepsy-associated genes, searching monogenic causes of epilepsy). Nonetheless, chromosomal abnormalities and copy number variants (CNVs) represent an important part of genetic defects causing epilepsy. Moreover, somatic chromosomal mosaicism and genome/chromosome instability seem to be a possible mechanism for a wide spectrum of epileptic conditions. This idea becomes even more attracting taking into account the potential of molecular neurocytogenetic (neurocytogenomic) studies of the epileptic brain. Unfortunately, analyses of chromosome numbers and structure in the affected brain or epileptogenic brain foci are rarely performed. Therefore, one may conclude that cytogenomic area of genomic epileptology is poorly researched. Accordingly, molecular cytogenetic and cytogenomic studies of the clinical cohorts and molecular neurocytogenetic analyses of the epileptic brain appear to be required. Here, we have performed a theoretical analysis to define the targets of the aforementioned studies and to highlight future directions for molecular cytogenetic and cytogenomic research of epileptic disorders in the widest sense. To succeed, we have formed a consortium, which is planned to perform at least a part of suggested research. Taking into account the nature of the communication, “cytogenomic epileptology” has been introduced to cover the research efforts in this field of medical genomics and epileptology. Additionally, initial results of studying cytogenomic variations in the Russian neurodevelopmental cohort are reviewed with special attention to epilepsy. In total, we have concluded that (i) epilepsy-associated cytogenomic variations require more profound research; (ii) ontological analyses of epilepsy genes affected by chromosomal rearrangements and/or CNVs with unraveling pathways implicating epilepsy-associated genes are beneficial for epileptology; (iii) molecular neurocytogenetic (neurocytogenomic) analysis of postoperative samples are warranted in patients suffering from epileptic disorders.
S1PR1/S1PR3-YAP signaling and S1P-ALOX15 signaling contribute to an aggressive behavior in obesity-lymphoma
Authors: Wang Xingtong , Guo Wei , Shi Xiaoju , Chen Yujia , Yu Youxi , Du Beibei , Tan Min , Tong Li , Wang Anna , Yin Xianying , Guo Jing , Martin Robert C. , Bai Ou , Li Yan
Published: January 2023

Background

Excess body weight has been found to associate with an increased risk of lymphomas and some metabolic pathways are currently recognized in lymphomagenesis. Bioactive lipid metabolites such as sphingosine-1-phosphate (S1P) have been proposed to play an important role linking obesity and lymphomas. However, the underlying mechanism(s) of S1P signaling in obesity-lymphomagenesis have not been well addressed.

Methods

The gene expression of sphingosine kinase (SPHK), lymphoma prognosis, and S1P production were analyzed using Gene Expression Omnibus (GEO) and human lymphoma tissue array. Obesity-lymphoma mouse models and lymphoma cell lines were used to investigate the S1P/SPHK-YAP axis contributing to obesity-lymphomagenesis. By using the mouse models and a monocyte cell line, S1P-mediated polarization of macrophages in the tumor microenvironment were investigated.

Results

In human study, up-regulated S1P/SPHK1 was found in human lymphomas, while obesity negatively impacted progression-free survival and overall survival in lymphoma patients. In animal study, obesity-lymphoma mice showed an aggressive tumor growth pattern. Both in vivo and in vitro data suggested the existence of S1P-YAP axis in lymphoma cells, while the S1P-ALOX15 signaling mediated macrophage polarization towards TAMs exacerbated the lymphomagenesis. In addition, treatment with resveratrol in obesity-lymphoma mice showed profound effects of anti-lymphomagenesis, via down-regulating S1P-YAP axis and modulating polarization of macrophages.

Conclusion

S1P/S1PR initiated the feedback loops, whereby S1P-S1PR1/S1PR3-YAP signaling mediated lymphomagenesis contributing to tumor aggressive growth, while S1P-ALOX15 signaling mediated TAMs contributing to immunosuppressive microenvironment in obesity-lymphoma. S1P-targeted therapy could be potentially effective and immune-enhancive against obesity-lymphomagenesis.

Graphical Abstract
Plasma metabolomic characterization of premature ovarian insufficiency
Authors: Zhou Xing-Yu , Li Xin , Zhang Jun , Li Ying , Wu Xiao-Min , Yang Yi-Zhen , Zhang Xiao-Fei , Ma Lin-Zi , Liu Yu-Dong , Wang Zhe , Chen Shi-Ling
Published: January 2023

Background

Premature ovarian insufficiency (POI) patients are predisposed to metabolic disturbances, including in lipid metabolism and glucose metabolism, and metabolic disorders appear to be a prerequisite of the typical long-term complications of POI, such as cardiovascular diseases or osteoporosis. However, the metabolic changes underlying the development of POI and its subsequent complications are incompletely understood, and there are few studies characterizing the disturbed metabolome in POI patients. The aim of this study was to characterize the plasma metabolome in POI by using ultrahigh-performance liquid chromatography–mass spectrometry (UHPLC–MS/MS) metabolomics and to evaluate whether these disturbances identified in the plasma metabolome relate to ovarian reserve and have diagnostic value in POI.

Methods

This observational study recruited 30 POI patients and 30 age- and body mass index (BMI)-matched controls in the Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, from January 2018 to October 2020. Fasting venous blood was collected at 9:00 am on days 2–4 of the menstrual cycle and centrifuged for analysis. An untargeted quantitative metabolomic analysis was performed using UHPLC–MS/MS.

Results

Our study identified 48 upregulated and 21 downregulated positive metabolites, and 13 upregulated and 48 downregulated negative metabolites in the plasma of POI patients. The differentially regulated metabolites were involved in pathways such as caffeine metabolism and ubiquinone and other terpenoid-quinone biosynthesis. Six metabolites with an AUC value > 0.8, including arachidonoyl amide, 3-hydroxy-3-methylbutanoic acid, dihexyl nonanedioate, 18-HETE, cystine, and PG (16:0/18:1), were correlated with ovarian reserve and thus have the potential to be diagnostic biomarkers of POI.

Conclusion

This UHPLC–MS/MS untargeted metabolomics study revealed differentially expressed metabolites in the plasma of patients with POI. The differential metabolites may not only be involved in the aetiology of POI but also contribute to its major complications. These findings offer a panoramic view of the plasma metabolite changes caused by POI, which may provide useful diagnostic and therapeutic clues for POI disease.
The effect of blood pressure on mortality following out-of-hospital cardiac arrest: a retrospective cohort study of the United Kingdom Intensive Care National Audit and Research Centre database
Authors: McGuigan Peter J. , Giallongo Elisa , Blackwood Bronagh , Doidge James , Harrison David A. , Nichol Alistair D. , Rowan Kathryn M. , Shankar-Hari Manu , Skrifvars Markus B. , Thomas Karen , McAuley Danny F.
Published: January 2023

Background

Hypotension following out-of-hospital cardiac arrest (OHCA) may cause secondary brain injury and increase mortality rates. Current guidelines recommend avoiding hypotension. However, the optimal blood pressure following OHCA is unknown. We hypothesised that exposure to hypotension and hypertension in the first 24 h in ICU would be associated with mortality following OHCA.

Methods

We conducted a retrospective analysis of OHCA patients included in the Intensive Care National Audit and Research Centre Case Mix Programme from 1 January 2010 to 31 December 2019. Restricted cubic splines were created following adjustment for important prognostic variables. We report the adjusted odds ratio for associations between lowest and highest mean arterial pressure (MAP) and systolic blood pressure (SBP) in the first 24 h of ICU care and hospital mortality.

Results

A total of 32,349 patients were included in the analysis. Hospital mortality was 56.2%. The median lowest and highest MAP and SBP were similar in survivors and non-survivors. Both hypotension and hypertension were associated with increased mortality. Patients who had a lowest recorded MAP in the range 60–63 mmHg had the lowest associated mortality. Patients who had a highest recorded MAP in the range 95–104 mmHg had the lowest associated mortality. The association between SBP and mortality followed a similar pattern to MAP.

Conclusions

We found an association between hypotension and hypertension in the first 24 h in ICU and mortality following OHCA. The inability to distinguish between the median blood pressure of survivors and non-survivors indicates the need for research into individualised blood pressure targets for survivors following OHCA.

Graphical Abstract
Randomized control trial of prednisolone and doxycycline in patients with acute interstitial nephritis of unknown aetiology
Authors: Badurdeen Zeid , Ratnatunga Neelakanthi , Abeysekera Tilak , Wazil Abdul. W. M. , Rajakrishna Premil N. , Thinnarachchi Jalitha P. , Welagedera Dulani D. , Ratnayake Nadeeka , Alwis Adambarage. P. D. , Abeysundara Hemalika , Kumarasiri Ranjith , Taylor Richard , Nanayakkara Nishantha
Published: January 2023

Background

Patients presenting with acute interstitial nephritis (AIN) of unknown aetiology, probably the earliest presentation of chronic kidney disease of unknown aetiology (CKDu), have been treated with oral prednisolone and doxycycline by physicians in Sri Lanka. This trial assessed the effectiveness of prednisolone and doxycycline based on eGFR changes at 6 months in patients with AIN of unknown aetiology.

Method

A randomized clinical trial with a 2 × 2 factorial design for patients presenting with AIN of unknown aetiology (n = 59) was enacted to compare treatments with; A-prednisolone, B-doxycycline, C-both treatments together, and D-neither. The primary outcome was a recovery of patients’ presenting renal function to eGFR categories: 61–90 ml/min/1.73m2 (complete remission– CR) to 31–60 ml/min/1.73m2 (partial remission– PR) and 0–30 ml/min/1.73m2 no remission (NR) by 6 months. A secondary outcome was progression-free survival (not reaching < 30 ml/min/1.73m2 eGFR), by 6–36 months. Analysis was by intention to treat.

Results

Seventy patients compatible with a clinical diagnosis of AIN were biopsied for eligibility; 59 AIN of unknown aetiology were enrolled, A = 15, B = 15, C = 14 and D = 15 randomly allocated to each group. Baseline characteristics were similar between groups. The number of patients with CR, PR and NR, respectively, by 6 months, in group A 3:8:2, group B 2:8:3 and group C 8:5:0 was compared with group D 8:6:1. There were no significant differences found between groups A vs. D (p = 0.2), B vs. D (p = 0.1) and C vs. D (p = 0.4).

In an exploratory analysis, progression-free survival in prednisolone-treated (A + C) arms was 0/29 (100%) in comparison to 25/30 (83%) in those not so treated (B + D) arms, and the log-rank test was p = 0.02, whereas no such difference found (p = 0.60) between doxycycline-treated (B + C) arms 27/29 (93%) vs those not so treated (A + D) arms 27/30 (90%).

Conclusion

Prednisolone and doxycycline were not beneficial for the earliest presentation of CKDu at 6 months. However, there is a potential benefit of prednisolone on the long-term outcome of CKDu. An adequately powered steroid trial using patients reaching < 30 ml/min/1.73m2 eGFR by 3 years, as an outcome is warranted for AIN of unknown aetiology.

Trial registration

Sri Lanka Clinical Trial Registry SLCTR/2014/007, Registered on the 31st of March 2014.
CT and MRI features of hepatic epithelioid haemangioendothelioma: a multi-institutional retrospective analysis of 15 cases and a literature review
Authors: Luo Lianmei , Cai Zeyu , Zeng Sihui , Wang Lizhu , Kang Zhuang , Yang Ning , Zhang Yaqin
Published: January 2023

Objective

To improve the current imaging understanding of MRI or CT for hepatic epithelioid haemangioendothelioma (HEHE) to aid in its successful preoperative diagnosis.

Methods

The imaging features of 15 patients (median age 38.6, range 20–71; 7 M/8 F) from eight institutions with pathologically confirmed HEHE were retrospectively analysed. Additionally, the CT/MR imaging features of 180 patients in 15 literature publications were collected, analysed and compared with our case series.

Results

Fifteen patients underwent CT and MRI (n = 2), CT (n = 9) or MR (n = 8) scans. A total of 92.9% (13/14) of the patients were initially diagnosed with other lesions on imaging. A total of 86.7% (13/15) were multifocal. Nodules (11/15, 73.3%) were predominantly peripheral in distribution (12/15, 80.0%). Some cases were associated with hepatic capsular retraction (13/15, 86.7%), “target signs” (8/15, 53.3%) and “lollipop signs” (5/15, 33.3%). Peripheral enhancement of various shapes in the early phase with a progressive centripetal filling was the most common pattern of enhancement (12/15, 80.0%). Abnormal vascularity was seen in 50.7% (6/15) of the patients. Suspicious tumour thromboses in the inferior vena cava were seen in 3 (20.0%) of the patients. Two of the 15 patients (13.3%) had a history of smoking.

Conclusions

HEHEs have common distinctive features, including multifocal lesions that are predominantly peripheral, “target signs”, “lollipop signs”, hepatic capsular retraction and peripheral enhancement of various shapes in the early phase with progressive centripetal filling. Additional aggressive imaging features that may be valuable clues to the diagnosis can be identified by CT or MRI.
Automatic music signal mixing system based on one-dimensional Wave-U-Net autoencoders
Authors: Koszewski Damian , Görne Thomas , Korvel Grazina , Kostek Bozena
Published: January 2023

The purpose of this paper is to show a music mixing system that is capable of automatically mixing separate raw recordings with good quality regardless of the music genre. This work recalls selected methods for automatic audio mixing first. Then, a novel deep model based on one-dimensional Wave-U-Net autoencoders is proposed for automatic music mixing. The model is trained on a custom-prepared database. Mixes created using the proposed system are compared with amateur, state-of-the-art software, and professional mixes prepared by audio engineers. The results obtained prove that mixes created automatically by Wave-U-Net can objectively be evaluated as highly as mixes prepared professionally. This is also confirmed by the statistical analysis of the results of the conducted listening tests. Moreover, the results show a strong correlation between the experience of the listeners in mixing and the likelihood of a higher rating of the Wave-U-Net-based and professional mixes than the amateur ones or the mix prepared using state-of-the-art software. These results are also confirmed by the outcome of the similarity matrix-based analysis.
The interplay among self-assessment, using reflection for assessment, classroom enjoyment, and immunity: into prospects of effective language learning
Authors: Aldosari Mubarak , Heydarnejad Tahereh , Hashemifardnia Arash , Abdalgane Mohammed
Published: January 2023

Self-assessment and reflective thinking (RT) can arm learners to monitor and evaluate their learning progress. Despite the long history of the core of self-assessment (CSA) and RT, little is known about how they may contribute to learner enjoyment (LE) and learner immunity (LI). Therefore, the current research attempted to propose a model to depict the interplay among CSA, RT, LE, and LI. To this end, the Core of Self-Assessment Questionnaire (CSAQ), Reflective Thinking Questionnaire (RTQ), Foreign Language Enjoyment Scale (FLES), and Language Student Immunity Instrument (LSIS) were administered to 518 Iranian EFL university students. The results of confirmatory factor analysis (CFA) and structural equation modeling (SEM) indicated that EFL university students with higher levels of CSA and RT skills experienced more enjoyment and were immunized productively. Furthermore, the critical role of RT in CSA was discovered. The implications of this study may unveil new prospects for implementing learning-oriented assessment in the classroom and RT practices in educational programs.
Predictors of complex PTSD: the role of trauma characteristics, dissociation, and comorbid psychopathology
Authors: Guzman Torres E. , Krause-Utz A. , Sack M.
Published: January 2023

Background

Complex Posttraumatic Stress Disorder (CPTSD) has previously been associated with earlier trauma onset, repeated interpersonal traumatization, more dissociation, and more comorbid psychopathology. However, it is still debated if the afore-mentioned risk factors are related to CPTSD diagnosis or rather indicative of a more severe form of post-traumatic distress. The aim of this study was to compare patients with a CPTSD diagnosis to those with PTSD in trauma characteristics (onset, chronicity, interpersonal nature, familiarity with perpetrator), dissociation, and psychiatric comorbidities, while accounting for symptom severity.

Methods

In total, N = 81 patients with a trauma history (n = 43 with CPTSD; n = 37 with PTSD) underwent diagnostic interviews by trained clinicians and completed measures on CPTSD symptom severity, trauma characteristics, and dissociation (Screening for Complex PTSD; Dissociative Experience Scale Taxon).

Results

Patients with CPTSD reported earlier onset of trauma, more trauma perpetrated by acquaintances or family members, and more comorbidities than those with PTSD, also when accounting for symptom severity. No group differences in chronicity and dissociation were found. Severity of CPTSD was associated with earlier onset, familiarity with perpetrator, more comorbid (affective) disorders, and dissociation in both diagnostic groups.

Conclusion

Findings largely confirm earlier research, suggesting that CPTSD is associated with traumatic events that start earlier in life and are perpetrated by acquaintances. Focusing on transdiagnostic symptoms, such as dissociation, may help to detain symptom deterioration. Due to the small sample size, findings need to be interpreted with caution and further research is needed to replicate findings in larger samples. Future research should also elucidate possible working mechanisms besides dissociation, such as emotion dysregulation or negative self-image.
El-Gendi Fortress: a new military and religious geo-archaeological site, Sinai, Egypt: geomorphological and hydrogeological remarks
Authors: El-Asmar Hesham M. , El-Eraky Tamer H. , Taha Maysa M. N.
Published: January 2023

El-Gendi Fortress is a unique geo-archaeological site in Sinai, Egypt. It reflects the progress of the Islamic military architecture during Saladin’s reign (Salah ad-din al Ayyubi), the founder of the Ayyubid dynasty (1174-1260AD). The fortress's location met two major geo-criteria. One is geographical; it is located on a mound 655 m above sea level (a.s.l) and 152 m above El-Tih El-plateau; this elevation contributes to the exploration of the surrounding areas and provides the fortress with a strong defensive position against the Crusaders' invasions of Egypt (1163–1169 AD). The second is Hydro-geological; it provides exceptional access to both meteoric surface (via barrages) and groundwater (through Sudr spring). The latter is from deep aquifers of the Nubian sandstones (Malha Formation) across the fractured carbonates (Raha and Sudr Formations of Cenomanian to Maastrichtian age). Such water was accumulated since the Pleistocene pluvial age until the fortress’ most recent use. The barrages’ location upstream of a sub-basin “a” at Wadi Sudr, in a similar direction to the deep ditch side, confirms that the priority of their design is to protect the region from flash flood risks and to store water on a relatively flat-lying land. The study reveals that the fortress’ geographical location is used to safeguard the Hajj route in central Sinai and to provide facilities for pilgrims’ caravans when they travel from North Africa to Mecca. The study concludes that the fortress should be a part of the Sinai tourism itinerary and promoted globally as a geo-archaeological site for Geo-tourism. In addition, the government should implement a strategy for conserving, rehabilitating, and managing the heritage sites, to improve facilities and increase public awareness of these sites to maximize the outcomes.
Structural and immunohistochemical analysis of the cellular compositions of the liver of molly fish (Poecilia sphenops), focusing on its immune role
Authors: Hussein Marwa M. , Sayed Ramy K. A. , Mokhtar Doaa M.
Published: January 2023

The liver of fish is considered an ideal model for studying the collaboration between environmental agents and the health state of the fish, where it gives good indications about aquatic ecosystem status. Therefore, this study presented immune roles for the liver in molly fish (Poecilia sphenops), using immunohistochemistry and transmission electron microscopy (TEM). The hepatocytes’ sinusoidal structures of molly fish livers had taken two different forms; cord-like and tubular, while the biliary tract system showed two different types: isolated and biliary venous tract. The TEM showed that the hepatocytes possessed well-developed cytoplasmic organelles and numerous glycogen and lipid droplets of different sizes. Kupffer cells, Ito cells, aggregation of intrahepatic macrophages and melanomacrophages were also recognized. Melanomacrophages contained numerous phagosomes, many lysosomes, cytoplasmic vacuoles, and melanin pigments. Hepatocytes and Kupffer cells expressed immunoreactivity to APG5, indicating that these cells were involved in the process of autophagy. Telocytes (TCs) were also recognized in the liver of molly fish, and they shared the same morphological characteristics as those in mammals. However, TCs expressed strong immunoreactivity to APG5, TGF-β, and Nrf2, suggesting their possible role in cellular differentiation and regeneration, in addition to phagocytosis and autophagy. Both IL-1β and NF-KB showed immunoreactivity in the hepatocytes and in inflammatory cells (including intrahepatic macrophages and melanomacrophage center). Nrf2 and SOX9 showed immunoreactivity in hepatocytes, stem cells, and macrophages. The present study showed the spatial distribution of hepatic vascular-biliary tracts in molly fish. The liver of molly fish has unique functions in phagocytosis, autophagy, and cell regeneration. The expression of APG5 in hepatocytes, Kupffer cells, melanomacrophages, and telocytes supports the role of the liver in lymphocyte development and proliferation. The expression of TGF-β and NF-κB in hepatocytes, Kupffer cells, telocytes, and macrophages suggests the role of the liver in regulation of cell proliferation and immune response suppression. The expression of IL-1β and Sox9 in macrophages and melanomacrophages suggests the role of the liver in regulation of both innate and adaptive immunity, cell proliferation and apoptosis, in addition to stem cell maintenance.
Fluorescent in situ hybridization (FISH)—a quick screening tool for female children with palpable gonads for excluding androgen insensitivity syndrome
Authors: Arora Mrinal , Zargar Noor Ullah , Krishna Anurag
Published: January 2023

Background

The incidence of inguinal hernia in the pediatric population is 0.8–4.4% with a male to female ratio of 5:1.The reported incidence of sliding hernia containing an ovary in female infants and children is 15–20%.The complete androgen insensitivity syndrome occurs in 1–2% of girls with an inguinal hernia. Thus, the incidence of CAIS in females with hernias and palpable gonads is 4/1,000,000.

Results

This is a retrospective analysis of 694 children that had undergone inguinal hernia repair in last 11 years. Out of these, 123 were females, 36 cases had palpable gonads at the time of presentation. FISH analysis was done in 29 cases (80%). None of the cases showed the presence of the Y chromosome. An abnormal chromosomal pattern was seen in one case on complete karyotyping.

Conclusion

The reported incidence of CAIS in girls with inguinal hernia is low, thus subjecting every girl child with inguinal hernia to undergo karyotyping is distressing for the parents. FISH analysis is an effective screening modality to rule out CAIS in girls with an inguinal hernia. Thus, it is recommended to screen only high-risk cases with palpable gonads at presentation.
3D printing of microneedle arrays for hair regeneration in a controllable region
Authors: Li Rong , Yuan Xin , Zhang Li , Jiang Xuebing , Li Li , Zhang Yi , Guo Linghong , Dai Xide , Cheng Hao , Jiang Xian , Gou Maling
Published: January 2023

Hair loss is a common skin disease that causes intense emotional suffering. Hair regeneration in a personalized area is highly desirable for patients with different balding conditions. However, the existing pharmaceutical treatments have difficulty precisely regenerating hair in a desired area. Here, we show a method to precisely control the hair regeneration using customized microneedle arrays (MNAs). The MNA with a customized shape is fast fabricated by a static optical projection lithography process in seconds, which is a 3D printing technology developed by our group. In the mouse model, MNA treatment could induce hair regrowth in a defined area corresponding to the customized shape of MNA. And the regenerated hair promoted by MNAs had improved quality. Cellular and molecular analysis indicated that MNA treatment could recruit macrophages in situ and then initiate the proliferation of hair follicle stem cells, thereby improving hair regeneration. Meanwhile, the activation of the Wnt/β-catenin signaling pathway was observed in hair follicles. The expressions of Hgf, Igf 1 and Tnf-α were also upregulated in the treated skin, which may also be beneficial for the MNA-induced hair regeneration. This study provides a strategy to precisely control hair regeneration using customized microneedle arrays by recruiting macrophages in situ, which holds the promise for the personalized treatment of hair loss.
First molecular identification of multiple tick-borne pathogens in livestock within Kassena-Nankana, Ghana
Authors: Addo Seth Offei , Bentil Ronald Essah , Yartey Kevin Nii , Ansah-Owusu Jane , Behene Eric , Opoku-Agyeman Philip , Bruku Selassie , Asoala Victor , Mate Suzanne , Larbi John Asiedu , Baidoo Philip Kweku , Wilson Michael David , Diclaro Joseph W. , Dadzie Samuel K.
Published: January 2023

The risk of pathogen transmission continues to increase significantly in the presence of tick vectors due to the trade of livestock across countries. In Ghana, there is a lack of data on the incidence of tick-borne pathogens that are of zoonotic and veterinary importance. This study, therefore, aimed to determine the prevalence of such pathogens in livestock using molecular approaches. A total of 276 dry blood spots were collected from cattle (100), sheep (95) and goats (81) in the Kassena-Nankana Districts. The samples were analyzed using Polymerase Chain Reaction (qPCR) and conventional assays and Sanger sequencing that targeted pathogens including Rickettsia, Coxiella, Babesia, Theileria, Ehrlichia and Anaplasma. An overall prevalence of 36.96% was recorded from the livestock DBS, with mixed infections seen in 7.97% samples. Furthermore, the prevalence of infections in livestock was recorded to be 19.21% in sheep, 14.13% in cattle, and 3.62% in goats. The pathogens identified were Rickettsia spp. (3.26%), Babesia sp. Lintan (8.70%), Theileria orientalis (2.17%), Theileria parva (0.36%), Anaplasma capra (18.48%), Anaplasma phagocytophilum (1.81%), Anaplasma marginale (3.26%) and Anaplasma ovis (7.25%). This study reports the first molecular identification of the above-mentioned pathogens in livestock in Ghana and highlights the use of dry blood spots in resource-limited settings. In addition, this research provides an update on tick-borne pathogens in Ghana, suggesting risks to livestock production and human health. Further studies will be essential to establish the distribution and epidemiology of these pathogens in Ghana.
Multicenter Phase II Clinical Trial of Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy for Patients With High-Grade Upper Tract Urothelial Carcinoma
Authors: Coleman Jonathan A. , Yip Wesley , Wong Nathan C. , Sjoberg Daniel D. , Bochner Bernard H. , Dalbagni Guido , Donat S. Machele , Herr Harry W. , Cha Eugene K. , Donahue Timothy F. , Pietzak Eugene J. , Hakimi A. Ari , Kim Kwanghee , Al-Ahmadie Hikmat A. , Vargas H. Alberto , Alvim Ricardo G. , Ghafoor Soleen , Benfante Nicole E. , Meraney Anoop M. , Shichman Steven J. , Kamradt Jeffrey M. , Nair Suresh G. , Baccala Angelo A. , Palyca Paul , Lash Bradley W. , Rizvi Muhammad A. , Swanson Scott K. , Muina Antonio F. , Apolo Andrea B. , Iyer Gopa , Rosenberg Jonathan E. , Teo Min Y. , Bajorin Dean F.
Published: January 2023

PURPOSE

Neoadjuvant chemotherapy (NAC) has proven survival benefits for patients with invasive urothelial carcinoma of the bladder, yet its role for upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a multicenter, single-arm, phase II trial of NAC with gemcitabine and split-dose cisplatin (GC) for patients with high-risk UTUC before extirpative surgery to evaluate response, survival, and tolerability.

METHODS

Eligible patients with defined criteria for high-risk localized UTUC received four cycles of split-dose GC before surgical resection and lymph node dissection. The primary study end point was rate of pathologic response (defined as < ypT2N0). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety and tolerability.

RESULTS

Among 57 patients evaluated, 36 (63%) demonstrated pathologic response (95% CI, 49 to 76). A complete pathologic response (ypT0N0) was noted in 11 patients (19%). Fifty-one patients (89%) tolerated at least three complete cycles of split-dose GC, 27 patients (47%) tolerated four complete cycles, and all patients proceeded to surgery. With a median follow up of 3.1 years, 2- and 5-year PFS rates were 89% (95% CI, 81 to 98) and 72% (95% CI, 59 to 87), while 2- and 5-year OS rates were 93% (95% CI, 86 to 100) and 79% (95% CI, 67 to 94), respectively. Pathologic complete and partial responses were associated with improved PFS and OS compared with nonresponders (≥ ypT2N any; 2-year PFS 100% and 95% v 76%, P < .001; 2-year OS 100% and 100% v 80%, P < .001).

CONCLUSION

NAC with split-dose GC for high-risk UTUC is a well-tolerated, effective therapy demonstrating evidence of pathologic response that is associated with favorable survival outcomes. Given that these survival outcomes are superior to historical series, these data support the use of NAC as a standard of care for high-risk UTUC, and split-dose GC is a viable option for NAC.
Centralization of Initial Care and Improved Survival of Poor Patients With Breast Cancer
Authors: Nattinger Ann B. , Bickell Nina A. , Schymura Maria J. , Laud Purushottam , McGinley Emily L. , Fergestrom Nicole , Pezzin Liliana E.
Published: January 2023

PURPOSE

Poor women with breast cancer have worse survival than others, and are more likely to undergo surgery in low-volume facilities. We leveraged a natural experiment to study the effectiveness of a policy intervention undertaken by New York (NY) state in 2009 that precluded payment for breast cancer surgery for NY Medicaid beneficiaries treated in facilities performing fewer than 30 breast cancer surgeries annually.

METHODS

We identified 37,822 women with stage I-III breast cancer during 2004-2008 or 2010-2013 and linked them to NY hospital discharge data. A multivariable difference-in-differences approach compared mortality of Medicaid insured patients with that of commercially or otherwise insured patients unaffected by the policy.

RESULTS

Women treated during the postpolicy years had slightly lower 5-year overall mortality than those treated prepolicy; the survival gain was significantly larger for Medicaid patients ( P = .018). Women enrolled in Medicaid had a greater reduction than others in breast cancer–specific mortality ( P = .005), but no greater reduction in other causes of death ( P = .50). Adjusted breast cancer mortality among women covered by Medicaid declined from 6.6% to 4.5% postpolicy, while breast cancer mortality among other women fell from 3.9% to 3.8%. A similar effect was not observed among New Jersey Medicaid patients with breast cancer treated during the same years.

CONCLUSION

A statewide centralization policy discouraging initial care for breast cancer in low-volume facilities was associated with better survival for the Medicaid population targeted. Given these impressive results and those from prior research, other policymakers should consider adopting comparable policies to improve breast cancer outcomes. [Media: see text]
Rituximab Chimeric Anti-CD20 Monoclonal Antibody Therapy for Relapsed Indolent Lymphoma: Half of Patients Respond to a Four-Dose Treatment Program
Authors: McLaughlin P , Grillo-López A J , Link B K , Levy R , Czuczman M S , Williams M E , Heyman M R , Bence-Bruckler I , White C A , Cabanillas F , Jain V , Ho A D , Lister J , Wey K , Shen D , Dallaire B K
Published: January 2023

PURPOSE

The CD20 antigen is expressed on more than 90% of B-cell lymphomas. It is appealing for targeted therapy, because it does not shed or modulate. A chimeric monoclonal antibody more effectively mediates host effector functions and is itself less immunogenic than are murine antibodies.

PATIENTS AND METHODS

This was a multiinstitutional trial of the chimeric anti-CD20 antibody, IDEC-C2B8. Patients with relapsed low grade or follicular lymphoma received an outpatient treatment course of IDEC-C2B8 375 mg/m2 intravenously weekly for four doses.

RESULTS

From 31 centers, 166 patients were entered. Of this intent-to-treat group, 48% responded. With a median follow-up duration of 11.8 months, the projected median time to progression for responders is 13.0 months. Serum antibody levels were sustained longer after the fourth infusion than after the first, and were higher in responders and in patients with lower tumor burden. The majority of adverse events occurred during the first infusion and were grade 1 or 2; fever and chills were the most common events. Only 12% of patients had grade 3 and 3% grade 4 toxicities. A human antichimeric antibody was detected in only one patient.

CONCLUSION

The response rate of 48% with IDEC-C2B8 is comparable to results with single-agent cytotoxic chemotherapy. Toxicity was mild. Attention needs to be paid to the rate of antibody infusion, with titration according to toxicity. Further investigation of this agent is warranted, including its use in conjunction with standard chemotherapy.
Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: ASCO Endorsement of College of American Pathologists Guideline
Authors: Vikas Praveen , Messersmith Hans , Compton Carolyn , Sholl Lynette , Broaddus Russell R. , Davis Anjee , Estevez-Diz Maria , Garje Rohan , Konstantinopoulos Panagiotis A. , Leiser Aliza , Mills Anne M. , Norquist Barbara , Overman Michael J. , Sohal Davendra , Turkington Richard C. , Johnson Tyler
Published: January 2023

PURPOSE

The College of American Pathologists (CAP) has developed a guideline on testing for mismatch repair (MMR) and microsatellite instability (MSI) for patients considered for immune checkpoint inhibitor therapy. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations.

METHODS

The CAP guideline was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel subsequently reviewed the content and the recommendations.

RESULTS

The ASCO Endorsement Panel determined that the recommendations from the CAP guideline, published on August 3, 2022, are clear, thorough, and based on the most relevant scientific evidence. ASCO endorses Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: Guideline From the College of American Pathologists in Collaboration With the Association for Molecular Pathology and Fight Colorectal Cancer.

RECOMMENDATIONS

Within the guideline, MMR immunohistochemistry (IHC), MSI polymerase chain reaction, and MSI next-generation sequencing are all recommended testing options for colorectal cancer, MMR-IHC and MSI-polymerase chain reaction for gastroesophageal and small bowel cancer, and only MMR-IHC for endometrial cancer. No recommendation in favor of any testing method over another could be made for any other cancer. Tumor mutational burden was not recommended as a surrogate for DNA MMR deficiency. If MMR deficiency consistent with Lynch syndrome is detected, it should be communicated to the treating physician. Additional information is available at www.asco.org/molecular-testing-and-biomarkers-guidelines .
Current Issues in the Management of Patients With Newly Diagnosed Advanced-Stage High-Grade Serous Carcinoma of the Ovary
Authors: Penn Courtney A. , Alvarez Ronald D.
Published: January 2023

Ovarian cancer is the most common cause of mortality in patients with gynecologic malignancies. Advanced-stage high-grade serous carcinoma accounts for most ovarian cancer cases. Current issues in the management of patients with newly diagnosed advanced-stage high-grade serous ovarian cancer include decisions on primary versus interval cytoreduction, hyperthermic intraperitoneal chemotherapy, maintenance therapy, incorporation of bevacizumab, and germline and somatic genetic testing. Evidence and guidelines regarding these topics are addressed in this review.
STK11Inactivation Predicts Rapid Recurrence in Inoperable Early-Stage Non–Small-Cell Lung Cancer
Authors: Katipally Rohan R. , Spurr Liam F. , Gutiontov Stanley I. , Turchan William Tyler , Connell Philip , Juloori Aditya , Malik Renuka , Binkley Michael S. , Jiang Alice L. , Rouhani Sherin J. , Chervin Carolina Soto , Wanjari Pankhuri , Segal Jeremy P. , Ng Victor , Loo Billy W. , Gomez Daniel R. , Bestvina Christine M. , Vokes Everett E. , Ferguson Mark K. , Donington Jessica S. , Diehn Maximilian , Pitroda Sean P.
Published: January 2023

PURPOSE

Molecular factors predicting relapse in early-stage non–small-cell lung cancer (ES-NSCLC) are poorly understood, especially in inoperable patients receiving radiotherapy (RT). In this study, we compared the genomic profiles of inoperable and operable ES-NSCLC.

MATERIALS AND METHODS

This retrospective study included 53 patients with nonsquamous ES-NSCLC (stage I-II) treated at a single institution (University of Chicago) with surgery (ie, operable; n = 30) or RT (ie, inoperable; n = 23) who underwent tumor genomic profiling. A second cohort of ES-NSCLC treated with RT (Stanford, n = 39) was included to power clinical analyses. Prognostic gene alterations were identified and correlated with clinical variables. The primary clinical end point was the correlation of prognostic genes with the cumulative incidence of relapse, disease-free survival, and overall survival (OS) in a pooled RT cohort from the two institutions (N = 62).

RESULTS

Although the surgery cohort exhibited lower rates of relapse, the RT cohort was highly enriched for somatic STK11 mutations (43% v 6.7%). Receiving supplemental oxygen (odds ratio [OR] = 5.5), 20+ pack-years of tobacco smoking (OR = 6.1), and Black race (OR = 4.3) were associated with increased frequency of STK11 mutations. In the pooled RT cohort (N = 62), STK11 mutation was strongly associated with inferior oncologic outcomes: 2-year incidence of relapse was 62% versus 20% and 2-year OS was 52% versus 85%, remaining independently prognostic on multivariable analyses (relapse: subdistribution hazard ratio = 4.0, P = .0041; disease-free survival: hazard ratio, 6.8, P = .0002; OS: hazard ratio, 6.0, P = .022). STK11 mutations were predominantly associated with distant failure, rather than local.

CONCLUSION

In this cohort of ES-NSCLC, STK11 inactivation was associated with poor oncologic outcomes after RT and demonstrated a novel association with clinical hypoxia, which may underlie its correlation with medical inoperability. Further validation in larger cohorts and investigation of effective adjuvant systemic therapies may be warranted.
A Modified Approach to a Parasternal Block: A Case Report
Authors: Scimia Paolo , Gentili Luca , Tedesco Mario , Fusco Pierfrancesco , Sepolvere Giuseppe
Published: January 2023

The parasternal block is an ultrasound-guided interfascial plane block that provides anesthesia of the medial quadrants of the breast. The original approach provided injections in the fascial plane between the pectoral major and external intercostal muscles. We observed that this technique might limit an adequate diffusion of the injectate due to the anatomical convexity of the ribs, which might hinder fascial hydrodissection. We suggest a modified approach by positioning the tip of the needle on the rib dome to reduce the local anesthetic volume and obtain a more homogeneous and longitudinal spread into the target fascial compartment.
Lsp1 partially substitutes for Pil1 function in eisosome assembly under stress conditions
Authors: Vesela Petra , Zahumensky Jakub , Malinsky Jan
Published: January 2023

Eisosomes are large hemitubular structures that underlie the invaginated microdomains in the plasma membrane of various ascomycetous fungi, lichens and unicellular algae. In fungi, they are organized by BAR-domain containing proteins of the Pil1 family. Two such proteins, Pil1 and Lsp1, participate in eisosome formation in the yeast Saccharomyces cerevisiae. Under normal laboratory conditions, deletion of the PIL1 gene results in the inability of cells to assemble wild-type-like eisosomes. We found that under certain stress conditions, Lsp1 partially substitutes for the Pil1 function and mediates assembly of eisosomes, specifically following a decrease in the activity of serine palmitoyltransferase, for example, in response to hyperosmotic stress. Besides Lsp1, the assembly of eisosomes lacking Pil1 also requires Seg1 and Nce102 proteins. Using next-generation sequencing, we found that the seg1Δnce102Δpil1Δ strain, which is unable to form eisosomes, overexpresses genes coding for proteins of oxidative phosphorylation and tricarboxylic acid cycle. By contrast, genes involved in DNA repair, ribosome biogenesis and cell cycle are downregulated. Our results identify Lsp1 as a stress-responsive eisosome organizer and indicate several novel functional connections between the eisosome and essential cellular processes.
Characterization of RNA-based and protein-only RNases P from bacteria encoding both enzyme types
Authors: Gößringer Markus , Wäber Nadine B. , Wiegard Jana C. , Hartmann Roland K.
Published: January 2023

A small group of bacteria encode two types of RNase P, the classical ribonucleoprotein (RNP) RNase P as well as the protein-only RNase P HARP (homolog ofAquifexRNaseP). We characterized the dual RNase P activities of five bacteria that belong to three different phyla. All five bacterial species encode functional RNA (genernpB) and protein (genernpA) subunits of RNP RNase P, but only the HARP of the thermophileThermodesulfatator indicus(phylum Thermodesulfobacteria) was found to have robust tRNA 5′-end maturation activity in vitro and in vivo in anEscherichia coliRNase P depletion strain. These findings suggest that both types of RNase P are able to contribute to the essential tRNA 5′-end maturation activity inT. indicus, thus resembling the predicted evolutionary transition state in the progenitor of the Aquificaceae before the loss ofrnpAandrnpBgenes in this family of bacteria. Remarkably,T. indicusRNase P RNA is transcribed with a P12 expansion segment that is posttranscriptionally excised in vivo, such that the major fraction of the RNA is fragmented and thereby truncated by ∼70 nt in the nativeT. indicushost as well as in theE. colicomplementation strain. Replacing the native P12 element ofT. indicusRNase P RNA with the short P12 helix ofThermotoga maritimaRNase P RNA abolished fragmentation, but simultaneously impaired complementation efficiency inE. colicells, suggesting that intracellular fragmentation and truncation ofT. indicusRNase P RNA may be beneficial to RNA folding and/or enzymatic activity.
Antioxidant and phytometabolite profiles of ethanolic extract from the cascara pulp of Coffea arabica collected from Gayo Highland: A study for potential photoaging agent
Authors: Lestari Wahyu , Hasballah Kartini , Listiawan M. Yulianto , Sofia Sofia
Published: January 2023

Background: As the most abundant coffee by-product, cascara pulp has been considered a good source of antioxidants which could be used to prevent photoaging. The aim of this study was to determine the phytometabolite profiles, antioxidant and photoaging properties of the ethanolic extract of Coffea arabica cascara pulp.

Methods: Ethanolic maceration was performed on the fine powder of C. arabica cascara pulp collected from Gayo Highland, Aceh Province, Indonesia. The filtrate obtained was evaluated for its 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity, total phenolic content (TPC), and total flavonoid content (TFC). The phytometabolite profiling was conducted qualitatively using reagents and quantitatively using gas chromatography—mass spectroscopy (GC-MS). The potential of the cascara pulp phytometabolites in inhibiting activator protein-1 (AP-1) was evaluated through molecular docking.

Results: The extract had TPC and TFC of 2.04 mg gallic acid equivalent/g extract and 91.81 mg quercetin equivalent/g extract, respectively. The half-maximal inhibitory concentration (IC50) for the DPPH inhibition reached as low as 9.59 mg/L. Qualitative phytocompound screening revealed the presence of alkaloids, saponins, tannins, flavonoids, steroids, quinones, polyphenols, and triterpenoids. GC-MS revealed the extract containing 5-hydroxy-methylfurfural (22.31%); 2,5 dimethyl 4 hidroxy 3(2H) furanone (0.74%); and caffeine (21.07%), which could form interaction with AP-1 with binding energies of -172.8, -150.8, and -63.188 kJ/mol, respectively.

Conclusion: Ethanolic extract from C. arabica cascara pulp potentially have anti-photoaging properties which is worthy for further investigations in the future.