bluuebunny/crossref_metadata_2025 huggingface dataset:
The FACT-targeted drug CBL0137 enhances the effects of rituximab to inhibit B-cell non-Hodgkin’s lymphoma tumor growth by promoting apoptosis and autophagy
Authors: Lv Yan , Du Yuxin , Li Kening , Ma Xiao , Wang Juan , Du Tongde , Ma Yuxin , Teng Yue , Tang Weiyan , Ma Rong , Wu Jianqiu , Wu Jianzhong , Feng Jifeng
Published: January 2023

Background

Aggressive B-cell non-Hodgkin’s lymphoma (B-NHL) patients often develop drug resistance and tumor recurrence after conventional immunochemotherapy, for which new treatments are needed.

Methods

We investigated the antitumor effects of CBL0137. In vitro, cell proliferation was assessed by CCK-8 and colony formation assay. Flow cytometry was performed to analyze cell cycle progression, apoptosis, mitochondrial depolarization, and reactive oxygen species (ROS) production. Autophagy was detected by transmission electron microscopy and mGFP-RFP-LC3 assay, while western blotting was employed to detect proteins involved in apoptosis and autophagy. RNA-sequencing was conducted to analyze the transcription perturbation after CBL0137 treatment in B-NHL cell lines. Finally, the efficacy and safety of CBL0137, rituximab, and their combination were tested in vivo.

Results

CBL0137, a small molecule anticancer agent that has significant antitumor effects in B-NHL. CBL0137 sequesters the FACT (facilitates chromatin transcription) complex from chromatin to produce cytotoxic effects in B-NHL cells. In addition, we discovered novel anticancer mechanisms of CBL0137. CBL0137 inhibited human B-NHL cell proliferation by inducing cell cycle arrest in S phase via the c-MYC/p53/p21 pathway. Furthermore, CBL0137 triggers ROS generation and induces apoptosis and autophagy in B-NHL cells through the ROS-mediated PI3K/Akt/mTOR and MAPK signaling pathways. Notably, a combination of CBL0137 and rituximab significantly suppressed B-NHL tumor growth in subcutaneous models, consistent with results at the cellular level in vitro.

Conclusions

CBL0137 has potential as a novel approach for aggressive B-NHL, and its combination with rituximab can provide new therapeutic options for patients with aggressive B-NHL.
Resistin-like molecules: a marker, mediator and therapeutic target for multiple diseases
Authors: Shi Yaning , Zhu Neng , Qiu Yun , Tan Junlan , Wang Feiying , Qin Li , Dai Aiguo
Published: January 2023

Resistin-like molecules (RELMs) are highly cysteine-rich proteins, including RELMα, RELMβ, Resistin, and RELMγ. However, RELMs exhibit significant differences in structure, distribution, and function. The expression of RELMs is regulated by various signaling molecules, such as IL-4, IL-13, and their receptors. In addition, RELMs can mediate numerous signaling pathways, including HMGB1/RAGE, IL-4/IL-4Rα, PI3K/Akt/mTOR signaling pathways, and so on. RELMs proteins are involved in wide range of physiological and pathological processes, including inflammatory response, cell proliferation, glucose metabolism, barrier defense, etc., and participate in the progression of numerous diseases such as lung diseases, intestinal diseases, cardiovascular diseases, and cancers. Meanwhile, RELMs can serve as biomarkers, risk predictors, and therapeutic targets for these diseases. An in-depth understanding of the role of RELMs may provide novel targets or strategies for the treatment and prevention of related diseases.
Observation of the delineation of the target volume of radiotherapy in adult-type diffuse gliomas after temozolomide-based chemoradiotherapy: analysis of recurrence patterns and predictive factors
Authors: Liu Hongbo , Zhang Lu , Tan Ye , Jiang Yanxia , Lu Haijun
Published: January 2023

Background

Radiation therapy is the cornerstone of treatment for adult-type diffuse gliomas, but recurrences are inevitable. Our study assessed the prognosis and recurrence pattern of different radiotherapy volumes after temozolomide-based chemoradiation in our institution.

Methods

The treatment plans were classified into two groups, the plan 1 intentionally involved the entire edema area while plan 2 did not. Retrospectively investigate the differences in outcomes of 118 adult-type diffuse gliomas patients between these two treatment plans. Then, patients who underwent relapse were selected to analyze their recurrence patterns. Continuous dynamic magnetic resonance images (MRI) were collected to categorized the recurrence patterns into central, in-field, marginal, distant, and cerebrospinal fluid dissemination (CSF-d) recurrence. Finally, the clinical and molecular characteristics which influenced progression were analyzed.

Results

Plan 1 (n = 63) showed a median progression-free survival (PFS) and overall survival (OS) of 9.5 and 26.4 months while plan 2 (n = 55) showed a median PFS and OS of 9.4 and 36.5 months (p = 0.418; p = 0.388). Treatment target volume had no effect on the outcome in patients with adult-type diffuse gliomas. And there was no difference in radiation toxicity (p = 0.388). Among the 90 relapsed patients, a total of 58 (64.4%) patients had central recurrence, 10 (11.1%) patients had in-field recurrence, 3 (3.3%) patients had marginal recurrence, 11 (12.2.%) patients had distant recurrence, and 8 (8.9%) patients had CSF-d recurrence. By treatment plans, the recurrence patterns were similar and there was no significant difference in survival. Reclassifying the progression pattern into local and non-local groups, we observed that oligodendroglioma (n = 10) all relapsed in local and no difference in PFS and OS between the two groups (p > 0.05). Multivariable analysis showed that subventricular zone (SVZ) involvement was the independent risk factor for non-local recurrence in patients with GBM (p < 0.05).

Conclusion

In our study, deliberately including or not the entire edema had no impact on prognosis and recurrence. Patients with varied recurrence patterns had diverse clinical and genetic features.
Education as a protective factor for mental health risks among youth living in highly dangerous regions in Afghanistan
Authors: Kovess-Masfety V. , Frounfelker R. L. , Keyes K. , Karam E. , Sabawoon Ajmal , Sarwari Bashir Ahmad , Husky M. , Kaur N. , Rousseau C.
Published: January 2023

Background

Children in Afghanistan live in dangerous areas, and have been exposed to traumatic events and chaotic education. Progress has been made on access to education for girls who were the most affected by traditional attitudes against engagement in education.

Objectives

The objectives were to evaluate the mental health of Afghan children living in regions of conflict and the association of mental health with school attendance for girls and boys.

Method

The study included 2707 school aged children in eight regions of Afghanistan (16 provinces) residing in households recruited through a multi-stage stratified cluster sampling strategy in 2017. The level of terrorist threat was evaluated by the intensity of terrorist attacks recorded that year in each province. Child mental health was assessed with the parental report Strengths and Difficulties Questionnaire (SDQ) along with information on school attendance, sociodemographic characteristics and geographic location.

Results

A total of 52.75% of children had scores above threshold for the SDQ total difficulties score, 39.19% for emotional difficulties, 51.98% for conduct challenges, and 15.37% for hyperactivity/inattention. Peer relationship problems were high (82.86%) and 12.38% reported that these problems impacted daily life. The level of terrorist threat was associated with SDQ total difficulties (Adjusted Odds Ratio [AOR] = 4.08, P < 0.0001), with youth in regions with high levels of terrorist threat more likely to have problems than youth in regions with low or medium levels of danger, independent of region and ethnicity. School attendance was negatively associated with emotional symptoms (AOR = 0.65, P < 0.0001) and mental health difficulties with impairment (AOR = 0.67, P = 0.007), but positively associated with peer relationships difficulties (AOR = 1.96, P > 0.0001). Conduct (AOR = 1.66, P < .0001) and SDQ total difficulties (AOR = 1.22, P = 0.019) were higher among boys. Overall, gender did not modify the relationship between school attendance and child mental health.

Conclusion

Attending school is essential for children’s mental health, across gender, and should be supported as a priority in Afghanistan despite the return of the Taliban.
Mesothelioma-associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c-Met/PI3K and WNT signaling but do not protect against cisplatin
Authors: Ries Alexander , Flehberger Daniela , Slany Astrid , Pirker Christine , Mader Johanna C. , Mohr Thomas , Schelch Karin , Sinn Katharina , Mosleh Berta , Hoda Mir Alireza , Dome Balazs , Dolznig Helmut , Krupitza Georg , Müllauer Leonhard , Gerner Christopher , Berger Walter , Grusch Michael
Published: January 2023

Background

Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Unlike many other cancers, PM is mostly characterized by inactivation of tumor suppressor genes. Its highly malignant nature in absence of tumor driving oncogene mutations indicates an extrinsic supply of stimulating signals by cells of the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are an abundant cell type of the TME and have been shown to drive the progression of several malignancies. The aim of the current study was to isolate and characterize patient-derived mesothelioma-associated fibroblasts (Meso-CAFs), and evaluate their impact on PM cells.

Methods

Meso-CAFs were isolated from surgical specimens of PM patients and analyzed by array comparative genomic hybridization, next generation sequencing, transcriptomics and proteomics. Human PM cell lines were retrovirally transduced with GFP. The impact of Meso-CAFs on tumor cell growth, migration, as well as the response to small molecule inhibitors, cisplatin and pemetrexed treatment was investigated in 2D and 3D co-culture models by videomicroscopy and automated image analysis.

Results

Meso-CAFs show a normal diploid genotype without gene copy number aberrations typical for PM cells. They express CAF markers and lack PM marker expression. Their proteome and secretome profiles clearly differ from normal lung fibroblasts with particularly strong differences in actively secreted proteins. The presence of Meso-CAFs in co-culture resulted in significantly increased proliferation and migration of PM cells. A similar effect on PM cell growth and migration was induced by Meso-CAF-conditioned medium. Inhibition of c-Met with crizotinib, PI3K with LY-2940002 or WNT signaling with WNT-C59 significantly impaired the Meso-CAF-mediated growth stimulation of PM cells in co-culture at concentrations not affecting the PM cells alone. Meso-CAFs did not provide protection of PM cells against cisplatin but showed significant protection against the EGFR inhibitor erlotinib.

Conclusions

Our study provides the first characterization of human patient-derived Meso-CAFs and demonstrates a strong impact of Meso-CAFs on PM cell growth and migration, two key characteristics of PM aggressiveness, indicating a major role of Meso-CAFs in driving PM progression. Moreover, we identify signaling pathways required for Meso-CAF-mediated growth stimulation. These data could be relevant for novel therapeutic strategies against PM.
Single-nucleus RNA sequencing and deep tissue proteomics reveal distinct tumour microenvironment in stage-I and II cervical cancer
Authors: Liu Xiaosong , Ni Guoying , Zhang Pingping , Li Hejie , Li Junjie , Cavallazzi Sebold Bernardo , Wu Xiaolian , Chen Guoqiang , Yuan Songhua , Wang Tianfang
Published: January 2023

Background

Cervical cancer (CC) is the 3rd most common cancer in women and the 4th leading cause of deaths in gynaecological malignancies, yet the exact progression of CC is inconclusive, mainly due to the high complexity of the changing tumour microenvironment (TME) at different stages of tumorigenesis. Importantly, a detailed comparative single-nucleus transcriptomic analysis of tumour microenvironment (TME) of CC patients at different stages is lacking.

Methods

In this study, a total of 42,928 and 29,200 nuclei isolated from the tumour tissues of stage-I and II CC patients and subjected to single-nucleus RNA sequencing (snRNA-seq) analysis. The cell heterogeneity and functions were comparatively investigated using bioinformatic tools. In addition, label-free quantitative mass spectrometry based proteomic analysis was carried out. The proteome profiles of stage-I and II CC patients were compared, and an integrative analysis with the snRNA-seq was performed.

Results

Compared with the stage-I CC (CCI) patients, the immune response relevant signalling pathways were largely suppressed in various immune cells of the stage-II CC (CCII) patients, yet the signalling associated with cell and tissue development was enriched, as well as metabolism for energy production suggested by the upregulation of genes associated with mitochondria. This was consistent with the quantitative proteomic analysis that showed the dominance of proteins promoting cell growth and intercellular matrix development in the TME of CCII group. The interferon-α and γ responses appeared the most activated pathways in many cell populations of the CCI patients. Several collagens, such as COL12A1, COL5A1, COL4A1 and COL4A2, were found significantly upregulated in the CCII group, suggesting their roles in diagnosing CC progression. A novel transcript AC244205.1 was detected as the most upregulated gene in CCII patients, and its possible mechanistic role in CC may be investigated further.

Conclusions

Our study provides important resources for decoding the progression of CC and set the foundation for developing novel approaches for diagnosing CC and tackling the immunosuppressive TME.
Management of Borderline ovarian tumors (BOT): results of a retrospective, single center study in Switzerland
Authors: Kipp B. , Vidal A. , Lenick D. , Christmann-Schmid C.
Published: January 2023

Background

Borderline tumors are malignant epithelial ovarian tumors with a very low incidence. Thus experience in diagnostics and treatment is still rare. The aim of this study was to present and analyze data of women with borderline ovarian tumor (BOT) regarding clinical features, histological characteristics, diagnostics and treatment management.

Methods

In this single center retrospective study women with BOT treated at the Departement of Gynecology and Obstetrics at the Kantonsspital Luzern between 2011 and 2018 were analyzed according to their clinical and histological reports.

Results

A total of 42 women were enrolled. The median age was 58.5 with a range from 26 to 85, of which 31 (73.8%) were postmenopausal. Regarding the histological subtypes, 23 women (54.8%) had serous and 15 (35.7%) had mucinous BOT. Seromucinous histology was found in 3 patients (7.1%) and endometrioid in 1 woman (2.4%), respectively. All women underwent surgery. In a total of 39 women (92.9%) a complete surgical staging for BOT was performed. In 29 women (69.0%) staging was performed by laparoscopy, 13 (31.0%) underwent laparotomy. The mean follow up was 52 months (range = 16.3–101.4 months). During this period two patients, initially diagnosed in FIGO stage 1, recurred after 21.7 and 44 months, respectively, the second woman died after 53 months because of the BOT.

Conclusion

In the present study women were treated according to the international therapy recommendations and the rate of recurrence was very low. The most common risk factors for relapse are known to be FIGO stage, incomplete staging and peritoneal implants but were not present in our group. Thus further studies are necessary to investigate additional recurrence risks.
Index theory and multiple solutions for asymptotically linear second-order delay differential equations
Authors: Shan Yuan
Published: January 2023

This paper is concerned with the existence of periodic solutions for asymptotically linear second-order delay differential equations. We will establish an index theory for the linear system directly in the sense that we do not need to change the problem of the original linear system into the problem of an associated Hamiltonian system. By using the critical point theory and the index theory, some new existence results are obtained.
Impact of nutrition counseling on anthropometry and dietary intake of multiple sclerosis patients at Kasr Alainy Multiple Sclerosis Unit, Cairo, Egypt 2019–2020: randomized controlled clinical trial
Authors: Afifi Zeinab , Hassan Amr , Abdelrahman Nebal , El Sayed Asmaa , Salem Marwa
Published: January 2023

Background

Faulty dietary habits and overnutrition are prevalent among Egyptian patients with multiple sclerosis (MS) who do not receive nutrition care as part of treatment. Thus, this study was conducted to identify the effect of nutrition counseling on the nutritional status of patients with MS. This endeavor might provide evidence for the value of counseling in such a setting and advance the integration of nutrition counseling into the routine management of patients with MS.

Methods

A single-blinded, parallel-randomized controlled clinical trial was conducted at Kasr Alainy MS Unit on 120 eligible patients with MS from September 2019 to February 2020. Patients were randomly allocated to either the nutrition counseling intervention group (IG) or the control group (CG). Allocation concealment was performed by using sequentially numbered opaque sealed envelopes. All patients were assessed initially and complied with the Kasr Alainy MS Unit standard management protocol for the study period. Only patients in the IG underwent initial nutrition counseling sessions followed by a monthly evaluation. All patients were assessed at the end of the 3-month follow-up period. Sociodemographic data were gathered through a structured interview. Nutritional status was assessed anthropometrically and via 24-h recall. The 2 groups were compared initially and at the end of the follow-up. Both intention-to-treat and per-protocol analyses were conducted.

Results

At baseline assessment, the prevalence of overweight and obesity was 31.7% and 32.5%, respectively, and the mean body mass index was 27.7 ± 5.7 kg/m2. Mean waist circumference was 93.5 ± 11.9 and 99.2 ± 13.1 cm for males and females, respectively. Approximately 27.3% of males and 83.9% of females showed abdominal obesity. After 3 months of counseling, weight, body mass index, waist circumference, nutrient intake and adequacy significantly improved in the IG (p < 0.05).

Conclusion

Nutrition counseling significantly improved anthropometric measurements, dietary habits, nutrient intake and adequacy.

Trial registration

The study was registered on ClinicalTrial.gov and was given a code (NCT04217564).
Ubiquitin protein E3 ligase ASB9 suppresses proliferation and promotes apoptosis in human spermatogonial stem cell line by inducing HIF1AN degradation
Authors: Li Ning , Zhou Qianyin , Yi Zhang , Zhang Huan , Zhou Dai
Published: January 2023

Background

Spermatogonial stem cells (SSCs) are critical for sustaining spermatogenesis. Even though several regulators of SSC have been identified in rodents, the regulatory mechanism of SSC in humans has yet to be discovered.

Methods

To explore the regulatory mechanisms of human SSCs, we analyzed publicly available human testicular single-cell sequencing data and found that Ankyrin repeat and SOCS box protein 9 (ASB9) is highly expressed in SSCs. We examined the expression localization of ASB9 using immunohistochemistry and overexpressed ASB9 in human SSC lines to explore its role in SSC proliferation and apoptosis. Meanwhile, we used immunoprecipitation to find the target protein of ASB9 and verified its functions. In addition, we examined the changes in the distribution of ASB9 in non-obstructive azoospermia (NOA) patients using Western blot and immunofluorescence.

Results

The results of uniform manifold approximation and projection (UMAP) clustering and pseudotime analysis showed that ASB9 was highly expressed in SSCs, and its expression gradually increased during development. The immunohistochemical and dual-color immunofluorescence results displayed that ASB9 was mainly expressed in nonproliferating SSCs. Overexpression of ASB9 in the SSC line revealed significant inhibition of cell proliferation and increased apoptosis. We predicted the target proteins of ASB9 and verified that hypoxia-inducible factor 1-alpha inhibitor (HIF1AN), but not creatine kinase B-type (CKB), has a direct interaction with ASB9 in human SSC line using protein immunoprecipitation experiments. Subsequently, we re-expressed HIF1AN in ASB9 overexpressing cells and found that HIF1AN reversed the proliferative and apoptotic changes induced by ASB9 overexpression. In addition, we found that ABS9 was significantly downregulated in some NOA patients, implying a correlation between ASB9 dysregulation and impaired spermatogenesis.

Conclusion

ASB9 is predominantly expressed in human SSCs, it affects the proliferation and apoptotic process of the SSC line through HIF1AN, and its abnormal expression may be associated with NOA.
Gangrenous ischemic colitis localized to the cecum: a case report
Authors: Tateno Kohei , Motegi Yoko , Ogawa Hiroomi , Suga Kunihiko , Okada Takuhisa , Osone Katsuya , Katoh Ryuji , Ubukata Yasunari , Saito Hideyuki , Hara Keigo , Sakai Makoto , Ogata Kyoichi , Sohda Makoto , Murakami Chiaki , Shirabe Ken , Saeki Hiroshi
Published: January 2023

Background

Ischemic colitis affects the left colon in elderly individuals and localization on the right side, especially in the cecum, is rare. We report a case of gangrenous ischemic colitis localized in the cecum of a patient undergoing hemodialysis.

Case presentation

A 73-year-old man had been undergoing hemodialysis for chronic renal failure caused by diabetic nephropathy. He experienced frequent vomiting, diarrhea, and abdominal pain. Contrast-enhanced computed tomography revealed thickening of the cecal wall, poor enhancement, dilation of the cecum, and intrahepatic portal emphysema. No obvious abnormal findings were observed in the appendix. The patient was diagnosed with cecal necrosis and ileocecal resection was performed. Histopathological examination revealed gangrenous ischemic colitis of the cecum. He was discharged 12 days after surgery without postoperative complications.

Conclusion

It is important to consider the possibility of ischemic colitis of the right colon in the event of renal failure requiring dialysis, to ensure that opportunities for surgical intervention are not missed.
A multi-center, randomized, 12-month, parallel-group, feasibility study to assess the acceptability and preliminary impact of family navigation plus usual care versus usual care on attrition in managing pediatric obesity: a study protocol
Authors: Ball Geoff D. C. , O’Neill Marcus G. , Noor Rafat , Alberga Angela , Azar Rima , Buchholz Annick , Enright Michelle , Geller Josie , Ho Josephine , Holt Nicholas L. , Lebel Tracy , Rosychuk Rhonda J. , Tarride Jean-Eric , Zenlea Ian
Published: January 2023

Background

Pediatric obesity management can be successful, but some families discontinue care prematurely (i.e., attrition), limiting treatment impact. Attrition is often a consequence of barriers and constraints that limit families’ access to obesity management. Family Navigation (FN) can improve access, satisfaction with care, and treatment outcomes in diverse areas of healthcare. To help our team prepare for a future effectiveness trial, the objectives of our randomized feasibility study are to (i) explore children’s and caregivers’ acceptability of FN and (ii) examine attrition, measures of study rigor and conduct, and responses to FN + Usual Care vs Usual Care by collecting clinical, health services, and health economic data.

Methods

In our 2.5-year study, 108 6–17-year-olds with obesity and their caregivers will be randomized (1:1) to FN + Usual Care or Usual Care after they enroll in obesity management clinics in Calgary and Mississauga, Canada. Our Stakeholder Steering Committee and research team will use Experience-Based Co-Design to design and refine our FN intervention to reduce families’ barriers to care, maximizing the intervention dose families receive. FN will be delivered by a navigator at each site who will use logistical and relational strategies to enhance access to care, supplementing obesity management. Usual Care will be offered similarly at both clinics, adhering to expert guidelines. At enrollment, families will complete a multidisciplinary assessment, then meet regularly with a multidisciplinary team of clinicians for obesity management. Over 12 months, both FN and Usual Care will be delivered virtually and/or in-person, pandemic permitting. Data will be collected at 0, 3, 6, and 12 months post-baseline. We will explore child and caregiver perceptions of FN acceptability as well as evaluate attrition, recruitment, enrolment, randomization, and protocol integrity against pre-set success thresholds. Data on clinical, health services, and health economic outcomes will be collected using established protocols. Qualitative data analysis will apply thematic analysis; quantitative data analysis will be descriptive.

Discussion

Our trial will assess the feasibility of FN to address attrition in managing pediatric obesity. Study data will inform a future effectiveness trial, which will be designed to test whether FN reduces attrition.

Trial registration

This trial was registered prospectively at ClinicalTrials.gov (#NCT05403658; first posted: June 3, 2022).
Adaptation and validation of the Adult Dispositional Hope Scale in the Ecuadorian context
Authors: Vinueza-Solórzano Andrea M. , Campoverde Ronald Enrique , Portalanza-Chavarría Cecilia Alexandra , de Freitas Clarissa P. P. , Hutz Claudio Simon , Vazquez Ana Claudia Souza
Published: January 2023

This study aimed to evidence the validity and reliability of the Ecuadorian version of the Adult Dispositional Hope Scale, one of the most studied concepts of positive psychology. The adaptation process included translation and semantic and idiomatic validation. For content validation, an expert review and focus group were conducted. The questionnaire was applied to 2423 workers in Ecuador with a mean age of 37 years (SD = 9.04), and 65.6% were women. A confirmatory factor analysis was conducted to assess the validity of the scale’s dimensionality. The reliability and convergent and discriminant validity were also evaluated. In order to investigate the best solution for an Ecuadorian version of the Adult Dispositional Hope Scale, four structural models were assessed. The unidimensional solution was the most adequate structure for the scale. The internal consistency of the scale was adequate. The Adult Dispositional Hope Scale (ADHS) was developed to assess this positive psychological state and has been the most used tool in many contexts. To our knowledge, this study is the first to adapt the Adult Dispositional Hope Scale into the Ecuadorian context and evaluate its validity. The findings support its reliability, factorial, and construct validity in the Ecuadorian context. Furthermore, the results show that dispositional hope acts as a protective factor, promoting work engagement and preventing burnout.
Evaluation of P-glycoprotein-targeting circulating microRNAs as peripheral biomarkers for medically intractable epilepsy
Authors: Xie Yangmei , Shao Yiye , Gong Xue , Wang Ming , Chen Yinghui
Published: January 2023

Background

Early diagnosis of medically intractable epilepsy is challenging in clinical work. P-glycoprotein (P-gp) is one of the most important multidrug efflux transporters, which has been demonstrated to contribute to the drug resistance of intractable epilepsy. The present study was aimed to explore the diagnostic value of microRNAs (miRNAs) targeting P-gp for medically intractable epilepsy.

Methods

Thirty-six patients with intractable epilepsy and 36 epilepsy patients responsive to anti-epilepsy drugs, who visited Jinshan Hospital of Fudan University from September 2014 to September 2016, were enrolled in this study. Clinical information of the patients was obtained by retrospectively reviewing medical records. MiRNAs with differential serum expression between the two groups of patients were detected by microarray assay. Meanwhile, miRNAs that were confirmed to regulate P-gp in vitro by western blot were selected for further validation. In the validation phase, reverse transcription quantitative PCR (RT-qPCR) was conducted to confirm the differential expression of the candidate miRNAs in the epilepsy cohorts. Receiver operating characteristic (ROC) curve analysis was carried out to evaluate the diagnostic value of the miRNAs for intractable epilepsy.

Results

Three miRNAs including miR-6514-3p, miR-6076-5p, and miR-6855-3p were identified to be candidate miRNAs by microarray assay. The results of western blotting validated that miR-146a-5p and miR-138-5p could regulate P-gp expression in vitro, so they were included in the candidate miRNAs for further validation. In the validation phase, the results of RT-qPCR indicated that compared with drug-responsive patients, the patients with intractable epilepsy showed decreased level of miR-138-5p and increased level of miR-146a-5p. The results of ROC curve analysis indicated that miR-138-5p (AUC = 0.877) and miR-146a-5p (AUC = 0.866) had high diagnostic value for intractable epilepsy. In addition, the miR-panel composed of miR-138-5p and miR-146a-5p showed higher diagnostic value (AUC = 0.926) than the miRNAs selected by microarray assay.

Conclusions

Our results indicated that the dysregulated miR-138-5p and miR-146a-5p which target P-gp expression have high potential as peripheral biomarkers for medically intractable epilepsy.
A thermo-hydro-mechanical model to evaluate the seismic properties of geothermal reservoirs
Authors: Li Nianqi , Fu Li-Yun , Deng Wubing , Carcione José M. , Yang Jian
Published: January 2023

Fractured-vuggy thermal reservoirs with complex pore spaces (stiff pores, cracks, and fractures) are typical geothermal resources for development and utilization in China. The cyclic recovery of such thermal reservoirs involves a complex thermo-hydro-mechanical (THM) coupling process. Insights into the thermoelastic effects of heating-cooling cycles on the seismic response have great potential for seismic monitoring in the cyclic recovery, which remains largely unaddressed in the literature. We intend to fill this gap by applying the double-porosity thermoelasticity theory to interpret ultrasonic measurements on granite under water-cooling conditions. We consider an isotropic porous host embedded with fractures. A plane-wave analysis yields the classical P and S waves and three slow P waves, namely the slow (Biot) P1, the slow (Biot) P2, and a thermal P. We investigate the combined effect of temperature, porous structure, and pore fluid on the thermoelastic properties of the THM process for typical granite reservoirs that experience a cold-shock process. Fractures provide the main channels for heat exchange and fluid flow. Our THM thermoelastic model describes the reservoir properties as a function of temperature associated with thermal-induced cracking, where fracture porosity is more important than the stiff (host) pore to describe the reservoir quality. We find that the thermal conductivity and specific heat have negligible effects in the seismic frequency band for the temperature range of less than 400°C, whereas the crack density significantly affects the seismic response in the heating-cooling cycles because of the additional contribution of thermal- and cold-shock-induced cracks. We further determine that the P-wave velocity and attenuation due to thermal effects under water cooling offer an important index to monitor the thermal-induced cracking and operation efficiency of the enhanced geothermal system. The THM thermoelastic model lays the foundation for active (or passive) seismic monitoring of the cyclic recovery of thermal reservoirs.
Short-Term Surgical Mission in Sub-Saharan Country, Experience of a Breast-Dedicated Team: Reviewing the Past and Stepping Toward the Last Mission
Authors: Djedjo Luís , Martins Maria do Céu Oliveira , Bicho Luís , Andrade David , Sidiropoulou Zacharoula
Published: January 2023

PURPOSE

The present article aims to present the data of a Breast Cancer Team Short-Term Surgical Mission in Guinea-Bissau in the setting of the National Bissau Hospital, Hospital Nacional Simão Mendes, level A referral health structure.

PATIENTS AND METHODS

Patients with breast disease have been presented to our team for in loco consultation during the total of three missions in 1 year. We have observed a total of 97 female patients with age ranging from 12 to 70 years. We performed 21 excisional biopsies, five radical surgeries, and 28 needle biopsies.

RESULTS

There have been diagnosed 19 invasive breast cancer cases in stage IV, and in seven patients, the biopsy resulted in malignancy. On the recall consultation of the needle biopsied patients, just two returned and accepted the proposed treatment. Major issue has been the lack of trained pathology technicians for adequate sampling conditioning, a fact that led to a poor quality of 18 samples.

CONCLUSION

Access to surgical care is disparate across the world, and short-term surgical missions are often call-in action to deliver not only patient care but also local staff training. Complex disease management, such as cancer, may create several problems being conditioned by the lack of basic resources required. In Guinea-Bissau, a poor country with very few inhabitants, the need to implement an anticancer national strategy is urgent but seems feasible. Any action should prioritize local team training and enhance specialization. No external intervention can provide any long-term benefit for patients if they are detached from local health workers.
Clinicopathologic and Molecular Analysis of Normal Karyotype Therapy-Related and De Novo Acute Myeloid Leukemia: A Multi-Institutional Study by the Bone Marrow Pathology Group
Authors: Cantu Miguel D. , Kanagal-Shamanna Rashmi , Wang Sa A. , Kadia Tapan , Bueso-Ramos Carlos E. , Patel Sanjay S. , Geyer Julia T. , Tam Wayne , Madanat Yazan , Li Peng , George Tracy I. , Nichols Meredith M. , Rogers Heesun J. , Liu Yen-Chun , Aggarwal Nidhi , Kurzer Jason H. , Maracaja Danielle L.V. , Hsi Eric D. , Zaiem Feras , Babu Daniel , Foucar Kathryn , Laczko Dorottya , Bagg Adam , Orazi Attilio , Arber Daniel A. , Hasserjian Robert P. , Weinberg Olga K.
Published: January 2023

PURPOSE

Therapy-related acute myeloid leukemias (t-AML) are a heterogenous group of aggressive neoplasms that arise following exposure to cytotoxic chemotherapy and/or ionizing radiation. Many therapy-related myeloid neoplasms (t-MN) are associated with distinct chromosomal aberrations and/or TP53 alterations, but little is known about the clinicopathologic and molecular features of normal karyotype t-AML (NK-t-AML) and whether this t-MN subtype is distinctly different from NK de novo AML (NK-dn-AML).

METHODS

This multi-institutional study by the Bone Marrow Pathology Group retrospectively evaluated clinicopathologic and molecular characteristics of 335 patients with NK-AML, comprising 105 t-AML and 230 dn-AML cases.

RESULTS

Patients with t-AML compared with dn-AML exhibit significantly shorter overall survival (OS; median months: 17.6 v 44.2; P < .0001) and relapse-free survival (RFS; median months: 9.1 v 19.2; P = .0018). Frequency of NPM1, FLT3, KRAS, and GATA2 mutations were significantly different in NK-t-AML compared with NK-dn-AML ( NPM1 35% v 49%; P = .0493; FLT3 23% v 36%; P = 0494; KRAS 12% v 5%; P = .0465; GATA2 9% v 2% P = .0105), while TP53 mutations were rare. Patients with t-AML more often stratified into intermediate or adverse 2017 ELN genetic risk groups. Favorable ELN risk predicted favorable OS (hazard ratio [HR], 0.4056; 95% CI, 0 to 0.866; P = .020) and RFS (HR, 0.355; 95% CI, 0 to 0.746; P = .006). Among all patients with NK-AML, stem-cell transplant and favorable ELN risk both significantly affected RFS, while therapy-relatedness and age had a borderline significant impact on OS (HR, 1.355; 95% CI, 0.975 to 1.882; P = .070).

CONCLUSION

To our knowledge, this is the largest study to date to comprehensively evaluate NK-t-AML and provides a framework that may inform our understanding of NK-t-AML disease biology and could potentially help guide therapeutic management and improved disease classification in t-MNs that lack cytogenetic aberrations.
Survival Outcomes of Patients With Tropomyosin Receptor Kinase Fusion-Positive Cancer Receiving Larotrectinib Versus Standard of Care: A Matching-Adjusted Indirect Comparison Using Real-World Data
Authors: Bokemeyer Carsten , Paracha Noman , Lassen Ulrik , Italiano Antoine , Sullivan Sean D. , Marian Marisca , Brega Nicoletta , Garcia-Foncillas Jesus
Published: January 2023

PURPOSE

Larotrectinib, a highly specific tropomyosin receptor kinase (TRK) inhibitor, previously demonstrated high response rates in single-arm trials of patients with TRK fusion-positive cancer, but there are limited data on comparative effectiveness against standard-of-care (SoC) regimens used in routine health care practice, before widespread adoption of TRK inhibitors as SoC for TRK fusion-positive cancers. Matching-adjusted indirect comparison, a validated methodology that balances population characteristics to facilitate cross-trial comparisons, was used to compare the overall survival (OS) of larotrectinib versus non–TRK-inhibitor SoC.

MATERIALS AND METHODS

Individual patient data from three larotrectinib trials (ClinicalTrials.gov identifiers: NCT02122913 , NCT02637687 , and NCT02576431 ) were compared with published aggregate real-world data from patients with locally advanced/metastatic TRK fusion-positive cancer identified in the Flatiron Health/Foundation Medicine database. OS was defined as the time from advanced/metastatic disease diagnosis to death. After matching population characteristics, the analyses included (1) a log-rank test of equality to test whether the two groups were similar before larotrectinib initiation; and (2) estimation of treatment effect of larotrectinib versus non–TRK-inhibitor SoC. These analyses are limited to prognostic variables available in real-world data.

RESULTS

Eighty-five larotrectinib patients and 28 non-TRK-inhibitor SoC patients were included in the analyses. After matching, log-rank testing showed no difference in baseline characteristics between the two groups ( P = .31). After matching, larotrectinib was associated with a 78% lower risk of death, compared with non–TRK-inhibitor SoC (adjusted hazard ratio, 0.22 [95% CI, 0.09 to 0.52]; P = .001); median OS was 39.7 months (95% CI: 16.4, NE [not estimable]) for larotrectinib and 10.2 months (95% CI: 7.2, 14.1) for SoC.

CONCLUSION

Matching-adjusted indirect comparison analyses suggest longer OS with larotrectinib, compared with non–TRK-inhibitor SoC, in adult patients with TRK fusion-positive cancer.
Fibronectin and JMJD6 Signature in Circulating Placental Extracellular Vesicles for the Detection of Preeclampsia
Authors: Alahari Sruthi , Ausman Jonathan , Porter Tyler , Park Chanho , Pettersson Ante B V , Klemetti Miira M , Zhang Jianhong , Post Martin , Caniggia Isabella
Published: January 2023

Preeclampsia (PE) is a major obstetric complication that is challenging to predict. Currently, there are limited tools to assess placental health/function in crucial gestational periods for diagnosis and early prediction. The glycoprotein fibronectin (FN) is augmented in PE placentae, and associated with reduced activity of JMJD6, an oxygen sensor that regulates placental FN processing. Evidence implicates placenta-derived small extracellular vesicles (sEVs) in the pathogenesis of pregnancy-associated disorders. Here, we examined the utility of FN and JMJD6 in placental sEVs as putative markers for early- and late-onset PE (E-PE and L-PE). Maternal plasma was obtained from venous blood collected longitudinally during pregnancy (10-14, 16-22, and 26-32 weeks of gestation and at delivery) in normotensive term control, preterm control, L-PE, E-PE, and gestational hypertensive individuals. Placenta-derived sEVs were isolated and their FN and JMJD6 content and JMJD6 activity were measured. In women that went on to develop preeclampsia, FN content of circulating placental sEVs was significantly elevated as early as 10 to 14 weeks of gestation and remained augmented until the time of delivery. This was accompanied by a depletion in JMJD6 content. Multivariate receiver operating characteristic analysis revealed high predictive power for FN and JMJD6 as early markers of E-PE and L-PE. In vitro, hypoxia or JMJD6 loss promoted FN accumulation in sEVs that was reverted on restoring cellular iron balance with the natural compound, Hinokitiol. Elevated FN, along with diminished JMJD6 in circulating placental sEVs, serves as an early molecular signature for the detection of different hypertensive disorders of pregnancy and their severity.
The Effects of Global Alignment and Proportionality Scores on Postoperative Outcomes After Adult Spinal Deformity Correction
Authors: Passias Peter G. , Krol Oscar , Owusu-Sarpong Stephane , Tretiakov Peter , Passfall Lara , Kummer Nicholas , Ani Fares , Imbo Bailey , Joujon-Roche Rachel , Williamson Tyler K. , Sagoo Navraj S. , Vira Shaleen , Schoenfeld Andrew , De la Garza Ramos Rafael , Janjua Muhammad Burhan , Sciubba Daniel , Diebo Bassel G. , Paulino Carl , Smith Justin , Lafage Renaud , Lafage Virginie
Published: January 2023

BACKGROUND:

Recent studies have suggested achieving global alignment and proportionality (GAP) alignment may influence mechanical complications after adult spinal deformity (ASD) surgery.

OBJECTIVE:

To investigate the association between the GAP score and mechanical complications after ASD surgery.

METHODS:

Patients with ASD with at least 5-level fusion to pelvis and minimum 2-year data were included. Multivariate analysis was used to find an association between proportioned (P), GAP-moderately disproportioned, and severely disproportioned (GAP-SD) states and mechanical complications (inclusive of proximal junctional kyphosis [PJK], proximal junctional failure [PJF], and implant-related complications [IC]). Severe sagittal deformity was defined by a “++” in the Scoliosis Research Society (SRS)-Schwab criteria for sagittal vertebral axis or pelvic incidence and lumbar lordosis.

RESULTS:

Two hundred ninety patients with ASD were included. Controlling for age, Charlson comorbidity index, invasiveness and baseline deformity, and multivariate analysis showed no association of GAP-moderately disproportioned patients with proximal junctional kyphosis, PJF, or IC, while GAP-SD patients showed association with IC (odds ratio [OR]: 1.7, [1.1-3.3]; P = .043). Aligning in GAP-relative pelvic version led to lower likelihood of all 3 mechanical complications (all P < .04). In patients with severe sagittal deformity, GAP-SD was predictive of IC (OR: 2.1, [1.1-4.7]; P = .047), and in patients 70 years and older, GAP-SD was also predictive of PJF development (OR: 2.5, [1.1-14.9]; P = .045), while improving in GAP led to lower likelihood of PJF (OR: 0.2, [0.02-0.8]; P = .023).

CONCLUSION:

Severely disproportioned in GAP is associated with development of any IC and junctional failure specifically in older patients and those with severe baseline deformity. Therefore, incorporation of patient-specific factors into realignment goals may better strengthen the utility of this novel tool.
On the identity of The Serbian endemic spring snail Belgrandiella serbica Glöer, 2008 (Gastropoda: Truncatelloidea: Hydrobiidae)
Authors: Gojšina Vukašin
Published: January 2023

In this paper, the Serbian endemic spring snail Belgrandiella serbica Glöer, 2008 which was described from a small spring in Rsovci village (SE Serbia) and known only from the type locality, is synonymised with Grossuana codreanui (Grossu, 1946) based on similarities in shell morphology and morphology of the penis.
Υπολογιστικές μεθοδολογίες κατάταξης ευπαθών πληθυσμών με αναπηρία και ασυμπτωματικό προφίλ βιοδεικτών σε ομάδες υψηλού ρίσκου
Authors: Σαγιαδινού Μαρία-Μαγδαληνή
Published: January 2023

Η συγκεκριμένη διατριβή επικεντρώνεται στη μοντελοποποίηση συμπεριφορικών δεδομένων, προερχόμενων από πολυπολιτισμικό πληθυσμό και βιοδεικτών φυσιολογίας (δείκτες αναπηρίας) από Άτομα με Αναπηρία, με στόχο την πρώιμη ανίχνευση άνοιας και την κατάταξη των πληθυσμών σε ομάδες υψηλού ρίσκου ανάπτυξης άνοιας. Στόχος της έρευνας ήταν η δημιουργία ενός καινοτόμου πρωτοκόλλου, το οποίο συνδυάζει ετερογενείς παράγοντες συμπεριφορικών κριτηρίων, γνωστικών δεικτών και βιοδεικτών για την ανίχνευση της πρώιμης άνοιας σε ευπαθείς ομάδες πληθυσμών, όπως τα Άτομα με Αναπηρία και ο πολυπολιτισμικός πληθυσμός. Για την εφαρμογή του πρωτοκόλλου αναπτύχθηκε κατάλληλη εφαρμογή, που περιλαμβάνει ένα σύνολο εξετάσεων, με το οποίο αξιολογήθηκε ο παραπάνω πληθυσμός. Διαμορφώθηκε μοντέλο λειτουργίας της ανίχνευσης άνοιας σ’ ευάλωτο πληθυσμό και σε πληθυσμό με διαπολιτισμικές διαφορές. Με βάση τα ερευνητικά δεδομένα, που προέκυψαν, προτάθηκε ένας μηχανισμός για την ανίχνευση άνοιας, ως μια πιθανή πρόταση στην υποδιάγνωση αυτών των πληθυσμών από επαγγελματίες πρωτοβάθμιου τομέα υγείας. Η πρόταση μοντελοποίησης της ανίχνευσης πρώιμης άνοιας σε πολυπολιτισμικό πληθυσμό και Άτομα με Αναπηρία απευθύνεται σε πρωτοβάθμιο υγειονομικό προσωπικό, χωρίς ν’ απαιτείται επιπλέον εκπαίδευση, είναι κατάλληλη για πληθυσμό απομακρυσμένων/αγροτικών περιοχών, καθώς και για ευάλωτες ομάδες πληθυσμού ηλικιωμένων και ατόμων με χωρίς ή ελάχιστη επίσημη εκπαίδευση.
Enabling artificial intelligence analytics on the edge
Authors: Τσακανίκας Βασίλειος
Published: January 2023

Αυτή η διατριβή εισάγει ένα νέο κατανεμημένο μοντέλο για χειρισμό σε πραγματικό χρόνο, αναλυτικών βίντεο στα άκρα του δικτύου. Η καινοτομία του μοντέλου βασίζεται στην αποσύνδεση και τη διανομή των υπηρεσιών σε πολλές αποσυντεθειμένες συναρτήσεις, δημιουργώντας αλυσίδες εικονικών λειτουργιών (μοντέλο VFC). Το μοντέλο λαμβάνει υπόψη τόσο τους υπολογιστικούς περιουρισμούς όσο και τους περιορισμούς επικοινωνίας. Θεωρητικά αποτελέσματα, αποτελέσματα προσομοιώσεων και πειραματικά αποτελέσματα έχουν δείξει ότι το μοντέλο VFC μπορεί να επιτρέψει την υποστήριξη υπηρεσιών βαρέως φορτίου σε περιβάλλον στα άκρα του δικτύου βελτιώνοντας παράλληλα το αποτύπωμα της υπηρεσίας σε σύγκριση με πλαίσια τελευταίας τεχνολογίας. Αναλυτικά, τα αποτελέσματα στο μοντέλο VFC έδειξαν ότι μπορεί να μειώσει το συνολικό κόστος των άκρων, σε σύγκριση με μοντέλα διανομής μονολιθικού και απλού πλαισίου. Για πειραματισμούς σε ένα πραγματικό σενάριο, έχει αναπτυχθεί ένα δοκιμαστικό περιβάλλον δικτύου στα άκρα, όπου έχουν αναπτυχθεί τα προαναφερθέντα μοντέλα, καθώς και ένα γενικό πλαίσιο διανομής (Apache Spark ©). Εξετάστηκε επίσης μια υπηρεσία υπολογιστικού νέφους. Τα πειράματα έχουν δείξει ότι το VFC μπορεί να ξεπεράσει όλες τις εναλλακτικές προσεγγίσεις, μειώνοντας το λειτουργικό κόστος και βελτιώνοντας την ποιότητα της υπηρεσίας. Τέλος, εισάγεται ένα μοντέλο μετεγκατάστασης, ένα μοντέλο προσωρινής αποθήκευσης και μια υπηρεσία παρακολούθησης της ποιότητας υπηρεσίας που βασίζεται σε μοντέλα τεχνητής νοημοσύνης (LSTM).