bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and characterization of FGFR2+ hematopoietic stem cell-derived fibrocytes as precursors of cancer-associated fibroblasts induced by esophageal squamous cell carcinoma
Authors: Qiu Haibo , Zhang Xu , Qi Jiali , Zhang Jiangwen , Tong Yin , Li Lei , Fu Li , Qin Yan-Ru , Guan Xinyuan , Zhang Liyi
Published: August 2022

Background

Cancer-associated fibroblast (CAF) is an ideal target for cancer treatment. Recent studies have focused on eliminating CAFs and their effects by targeting their markers or blocking individual CAF-secreted factors. However, these strategies have been limited by their specificity for targeting CAFs and effectiveness in blocking widespread influence of CAFs. To optimize CAF-targeted therapeutic strategies, we tried to explore the molecular mechanisms of CAF generation in this study.

Methods

Using FGFR2 as a tracing marker, we identified a novel origin of CAFs in esophageal squamous cell carcinoma (ESCC). Furthermore, we successfully isolated CAF precursors from peripheral blood of ESCC patients and explored the mechanisms underlying their expansion, recruitment, and differentiation via RNA-sequencing and bioinformatics analysis. The mechanisms were further verified by using different models both in vitro and in vivo.

Results

We found that FGFR2+ hematopoietic stem cell (HSC)-derived fibrocytes could be induced by ESCC cells, recruited into tumor xenografts, and differentiated into functional CAFs. They were mobilized by cancer-secreted FGF2 and recruited into tumor sites via the CXCL12/CXCR4 axis. Moreover, they differentiated into CAFs through the activation of YAP-TEAD complex, which is triggered by directly contracting with tumor cells. FGF2 and CXCR4 neutralizing antibodies could effectively block the mobilization and recruitment process of FGFR2+ CAFs. The YAP-TEAD complex-based mechanism hold promise for locally activation of genetically encoded therapeutic payloads at tumor sites.

Conclusions

We identified a novel CAF origin and systematically studied the process of mobilization, recruitment, and maturation of CAFs in ESCC under the guidance of tumor cells. These findings give rise to new approaches that target CAFs before their incorporation into tumor stroma and use CAF-precursors as cellular vehicles to target tumor cells.
Acylglycerol kinase promotes ovarian cancer progression and regulates mitochondria function by interacting with ribosomal protein L39
Authors: Sun Fei , Wei Yunjian , Liu Zheng , Jie Qiuling , Yang Xiaohui , Long Ping , Wang Jun , Xiong Ying , Li Qi , Quan Song , Ma Yanlin
Published: August 2022

Background

Epithelial ovarian cancer (EOC) is the leading cause of deaths among patients with gynecologic malignancies. In recent years, cancer stem cells (CSCs) have attracted great attention, which have been regarded as new biomarkers and targets in cancer diagnoses as well as therapies. However, therapeutic failure caused by chemotherapy resistance in late-stage EOC occurs frequently. The 5-year survival rate of patients with EOC remains at about 30%.

Methods

In this study, the expression of acylglycerol kinase (AGK) was analyzed among patients with EOC. The effect of AGK on EOC cell proliferation and tumorigenicity was studied using Western blotting, flow cytometry, EdU assay and in vivo xenotransplantation assays. Furthermore, AGK induced CSC-like properties and was resistant to cisplatin chemotherapy in the EOC cells, which were investigated through sphere formation assays and the in vivo model of chemoresistance. Finally, the relationship between AGK and RPL39 (Ribosomal protein L39) in mitochondria as well as their effect on the mitochondrial function was analyzed through methods including transmission electron microscopy, microarray, biotin identification and immunoprecipitation.

Results

AGK showed a markedly upregulated expression in EOC, which was significantly associated with the poor survival of patients with EOC, the expression of AGK-promoted EOC cell proliferation and tumorigenicity. AGK also induced CSC-like properties in the EOC cells and was resistant to cisplatin chemotherapy. Furthermore, the results indicated that AGK not only maintained mitochondrial cristae morphogenesis, but also increased the production of reactive oxygen species and Δψm of EOC cells in a kinase-independent manner. Finally, our results revealed that AGK played its biological function by directly interacting with RPL39.

Conclusions

We demonstrated that AGK was a novel CSC biomarker for EOC, which the stemness of EOC was promoted and chemotherapy resistance was developed through physical as well as functional interaction with RPL39.
Transcriptome analysis of immune cells from Behçet’s syndrome patients: the importance of IL-17-producing cells and antigen-presenting cells in the pathogenesis of Behçet’s syndrome
Authors: Okubo Mai , Sumitomo Shuji , Tsuchida Yumi , Nagafuchi Yasuo , Takeshima Yusuke , Yanaoka Haruyuki , Shirai Harumi , Kobayashi Satomi , Sugimori Yusuke , Maeda Junko , Hatano Hiroaki , Iwasaki Yukiko , Shoda Hirofumi , Okamura Tomohisa , Yamamoto Kazuhiko , Ota Mineto , Fujio Keishi
Published: August 2022

Background

Behçet’s syndrome (BS) is an immune-mediated disease characterized by recurrent oral ulcers, genital ulcers, uveitis, and skin symptoms. HLA-B51, as well as other genetic polymorphisms, has been reported to be associated with BS; however, the pathogenesis of BS and its relationship to genetic risk factors still remain unclear. To address these points, we performed immunophenotyping and transcriptome analysis of immune cells from BS patients and healthy donors.

Methods

ImmuNexUT is a comprehensive database consisting of RNA sequencing data and eQTL database of immune cell subsets from patients with immune-mediated diseases and healthy donors, and flow cytometry data and transcriptome data from 23 BS patients and 28 healthy donors from the ImmuNexUT study were utilized for this study. Differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) were performed to identify genes associated with BS and clinical features of BS. eQTL database was used to assess the relationship between genetic risk factors of BS with those genes.

Results

The frequency of Th17 cells was increased in BS patients, and transcriptome analysis of Th17 cells suggested the activation of the NFκB pathway in Th17 cells of BS patients. Next, WGCNA was used to group genes into modules with similar expression patterns in each subset. Modules of antigen-presenting cells were associated with BS, and pathway analysis suggested the activation of antigen-presenting cells of BS patients. Further examination of genes in BS-associated modules indicated that the expression of YBX3, a member of a plasmacytoid dendritic cell (pDC) gene module associated with BS, is influenced by a BS risk polymorphism, rs2617170, in pDCs, suggesting that YBX3 may be a key molecule connecting genetic risk factors of BS with disease pathogenesis. Furthermore, pathway analysis of modules associated with HLA-B51 indicated that the association of IL-17-associated pathways in memory CD8+ T cells with HLA-B51; therefore, IL-17-producing CD8+ T cells, Tc17 cells, may play a critical role in BS.

Conclusions

Various cells including CD4+ T cells, CD8+ T cells, and antigen-presenting cells are important in the pathogenesis of BS. Tc17 cells and YBX3 may be potential therapeutic targets in BS.
Regulation of type I interferon signature by VGLL3 in the fibroblast-like synoviocytes of rheumatoid arthritis patients via targeting the Hippo pathway
Authors: Du Yu , Cui Ran , Tian Na , Chen Miao , Zhang Xian-Long , Dai Sheng-Ming
Published: August 2022

Background

The upregulation of interferon (IFN)-stimulated genes induced by type I IFNs (namely type I IFN signature) in rheumatoid arthritis (RA) patients had implications in early diagnosis and prediction of therapy responses. However, factors that modulate the type I IFN signature in RA are largely unknown. In this study, we aim to explore the involvement of VGLL3, a homologue of the vestigial-like gene in Drosophila and a putative regulator of the Hippo pathway, in the modulation of type I IFN signature in the fibroblast-like synoviocytes (FLS) of RA patients.

Methods

FLS were isolated from RA and osteoarthritis (OA) patients. Expression of VGLL3 in the synovial tissues and FLS was analyzed by immunohistochemistry and PCR. RNA sequencing was performed in RA-FLS upon VGLL3 overexpression. The expression of IFN-stimulated genes was examined by PCR and Western blotting.

Results

VGLL3 was upregulated in the RA synovium and RA-FLS compared to OA. Overexpression of VGLL3 promoted the expression of IFN-stimulated genes in RA-FLS. The expression of STAT1 and MX1 was also upregulated in RA synovium compared to OA and was associated with the expression of VGLL3 in RA and OA patients. VGLL3 promoted the IRF3 activation and IFN-β1 expression in RA-FLS. Increased IFN-β1 induced the expression of IFN-stimulated genes in RA-FLS in an autocrine manner. VGLL3 also modulated the expression of the Hippo pathway molecules WWTR1 and AMOTL2, which mediated the regulation of IRF3 activation and IFN-β1 production by VGLL3 in RA-FLS.

Conclusions

VGLL3 drives the IRF3-induced IFN-β1 expression in RA-FLS by inhibiting WWTR1 expression and subsequently promotes the type I IFN signature expression in RA-FLS through autocrine IFN-β1 signaling.
Daphnia as a versatile model system in ecology and evolution
Authors: Ebert Dieter
Published: August 2022

Water fleas of the genus Daphnia have been a model system for hundreds of years and is among the best studied ecological model organisms to date. Daphnia are planktonic crustaceans with a cyclic parthenogenetic life-cycle. They have a nearly worldwide distribution, inhabiting standing fresh- and brackish water bodies, from small temporary pools to large lakes. Their predominantly asexual reproduction allows for the study of phenotypes excluding genetic variation, enabling us to separate genetic from non-genetic effects. Daphnia are often used in studies related to ecotoxicology, predator-induced defence, host–parasite interactions, phenotypic plasticity and, increasingly, in evolutionary genomics. The most commonly studied species are Daphnia magna and D. pulex, for which a rapidly increasing number of genetic and genomic tools are available. Here, I review current research topics, where the Daphnia model system plays a critical role.
Comparison of therapeutic effects of mesenchymal stem cells from umbilical cord and bone marrow in the treatment of type 1 diabetes
Authors: Zhang Wei , Ling Qing , Wang Bin , Wang Kai , Pang Jianbo , Lu Jing , Bi Yan , Zhu Dalong
Published: August 2022

Background

The therapeutic potential of mesenchymal stem cells (MSCs) in type 1 diabetes (T1D) has been demonstrated in both preclinical and clinical studies. MSCs that have been used in research on T1D are derived from various tissue sources, with bone marrow (BM) and umbilical cord (UC) tissues being the most commonly used. However, the influence of tissue origin on the functional properties and therapeutic effects of MSCs in T1D remains unclear. This study aimed to compare the therapeutic efficacy of UC-MSCs and BM-MSCs in a mouse model of T1D as well as in patients with T1D.

Methods

In non-obese diabetic (NOD) mice, the development of diabetes was accelerated by streptozotocin injections. Thereafter, diabetic mice were randomized and treated intravenously with UC-MSCs, BM-MSCs or phosphate-buffered saline as a control. Blood glucose and serum insulin were measured longitudinally after transplantation. At 14 days post-transplantation, pancreatic tissues were collected to assess insulitis and the β-cell mass. Flow cytometry was performed to evaluate the composition of T lymphocytes in the spleen and pancreatic lymph nodes of the NOD mice. In our retrospective study of patients with T1D, 28 recipients who received insulin therapy alone or a single transplantation of UC-MSCs or BM-MSCs were enrolled. The glycaemic control and β-cell function of the patients during the first year of follow-up were compared.

Results

In NOD mice, UC-MSC and BM-MSC transplantation showed similar effects on decreasing blood glucose levels and preserving β cells. The regulation of islet autoimmunity was examined, and no significant difference between UC-MSCs and BM-MSCs was observed in the attenuation of insulitis, the decrease in T helper 17 cells or the increase in regulatory T cells. In patients with T1D, MSC transplantation markedly lowered haemoglobin A1c (HbA1c) levels and reduced insulin doses compared to conventional insulin therapy. However, the therapeutic effects were comparable between UC-MSCs and BM-MSCs, and they also exerted similar effects on the endogenous β-cell function in the patients.

Conclusion

In conclusion, both UC-MSCs and BM-MSCs exhibited comparable therapeutic effects on improving glycaemic control and preserving β-cell function in T1D. Considering their abundance and higher cell yields, UC-MSCs appear to be more promising than BM-MSCs in clinical applications.

Trial registration NCT02763423. Registered on May 5, 2016—Retrospectively registered, https://www.clinicaltrials.gov/.
IFITM3 promotes malignant progression, cancer stemness and chemoresistance of gastric cancer by targeting MET/AKT/FOXO3/c-MYC axis
Authors: Chu Pei-Yi , Huang Wei-Chieh , Tung Shiao-Lin , Tsai Chung-Ying , Chen Chih Jung , Liu Yu-Chin , Lee Chia-Wen , Lin Yang-Hsiang , Lin Hung-Yu , Chen Cheng-Yi , Yeh Chau-Ting , Lin Kwang-Huei , Chi Hsiang-Cheng
Published: August 2022

Background

Targeting the HGF/MET signaling pathway has been a viable therapeutic strategy for various cancer types due to hyperactivation of HGF/MET axis occurs frequently that leads to detrimental cancer progression and recurrence. Deciphering novel molecule mechanisms underlying complex HGF/MET signaling network is therefore critical to development of effective therapeutics for treating MET-dependent malignancies.

Results

Using isobaric mass tag-based quantitative proteomics approach, we identified IFITM3, an interferon-induced transmembrane protein that was highly expressed in micro-dissected gastric cancer (GC) tumor regions relative to adjacent non-tumor epithelia. Analyses of GC clinical specimens revealed that expression IFITM3 was closely correlated to advanced pathological stages. IFITM3 has been reported as a PIP3 scaffold protein that promotes PI3K signaling. In present study, we unprecedentedly unraveled that IFITM3 associated with MET and AKT to facilitate HGF/MET mediated AKT signaling crosstalk in suppressing FOXO3, consequently leading to c-MYC mediated GC progression. In addition, gene ontology analyses of the clinical GC cohort revealed significant correlation between IFITM3-associated genes and targets of c-MYC, which is a crucial downstream effector of HGF/MET pathway in cancer progression. Moreover, we demonstrated ectopic expression of IFITM3 suppressed FOXO3 expression, consequently led to c-MYC induction to promote tumor growth, cell metastasis, cancer stemness as well as chemoresistance. Conversely, depletion of IFITM3 resulted in suppression of HGF triggered cellular growth and migration via inhibition of AKT/c-MYC signaling in GC.

Conclusions

In summary, our present study unveiled a novel regulatory mechanism for c-MYC-driven oncogenesis underlined by IFITM3-mediated signaling crosstalk between MET associated AKT signaling cascade.
Early prediction of hospital outcomes in patients tracheostomized for complex mechanical ventilation weaning
Authors: Cabrio Davy , Vesin Timothée , Lupieri Ermes , Messet Hélène , Sandu Kishore , Piquilloud Lise
Published: August 2022

Background

Tracheostomy is often performed in the intensive care unit (ICU) when mechanical ventilation (MV) weaning is prolonged to facilitate daily care. Tracheostomized patients require important healthcare resources and have poor long-term prognosis after the ICU. However, data lacks regarding prediction of outcomes at hospital discharge. We looked for patients’ characteristics, ventilation parameters, sedation and analgesia use (pre-tracheostomy) that are associated with favorable and poor outcomes (post-tracheostomy) using univariate and multivariate logistic regressions.

Results

Eighty tracheostomized patients were included (28.8% women, 60 [52–71] years). Twenty-three (28.8%) patients were intubated for neurological reasons. Time from intubation to tracheostomy was 14.7 [10–20] days. Thirty patients (37.5%) had poor outcome (19 patients deceased and 11 still tracheostomized at hospital discharge). All patients discharged with tracheostomy (n = 11) were initially intubated for a neurological reason. In univariate logistic regressions, older age and higher body-mass index (BMI) were associated with poor outcome (OR 1.18 [1.07–1.32] and 1.04 [1.01–1.08], p < 0.001 and p = 0.025). No MV parameters were associated with poor outcome. In the multiple logistic regression model higher BMI and older age were also associated with poor outcome (OR 1.21 [1.09–1.36] and 1.04 [1.00–1.09], p < 0.001 and p = 0.046).

Conclusions

Hospital mortality of patients tracheostomized because of complex MV weaning was high. Patients intubated for neurological reasons were frequently discharged from the acute care hospital with tracheostomy in place. Both in univariate and multivariate logistic regressions, only BMI and older age were associated with poor outcome after tracheostomy for patients undergoing prolonged MV weaning.
Changes in bone mineral density after bariatric surgery in patients of different ages or patients with different postoperative periods: a systematic review and meta-analysis
Authors: Ou Xiaodan , Chen Mingguang , Xu Lizhen , Lin Wei , Huang Huibin , Chen Gang , Wen Junping
Published: August 2022

To assess changes in bone mineral density (BMD) following bariatric surgery (BS) in patients with different bone sites, postoperative periods and ages. Twenty-two studies were included. Femoral neck (FN) BMD decreased after surgery (MD, − 0.05 g/cm2, CI − 0.10 to − 0.01, P = 0.03). Postoperative BMD decreased more in the FN and lumbar spine (LS) of patients older than 40 (FNBMD, − 0.07 g/cm2, CI − 0.13 to − 0.00, P = 0.04; LSBMD, − 0.03 g/cm2, CI − 0.05 to − 0.00, P = 0.02) or patients with a postoperative time of greater than 12 months (FNBMD, − 0.06 g/cm2, CI − 0.12 to − 0.01, P = 0.03; LSMD, − 0.04 g/cm2, CI − 0.09 to 0.01, P = 0.12); therefore, post-BS bone loss should be monitored among patients in these groups. Longer follow-ups are needed to determine whether BMD changes or stabilizes.
“Not everyone can do this”: childcare context and the practice of skill in emotional labor
Authors: Malhotra Ragini Saira
Published: August 2022

Scholarship remains divided about whether emotional labor is ‘skilled’. Interrogating gendered skill constructs that render emotions in work invisible, I examine two organizational contexts in the Early Childhood Education and Care (ECEC) sector: family and center-based care. I draw from 43 interviews, primarily with Latina and White women workers, reflecting feminized and racialized workplaces. I also draw from ethnographic and observational data. Challenging the particular devaluation of family-based care, findings reveal that the practice of skill in emotional labor is organizationally shaped across less and more institutionalized forms of ECEC. Examining worker critiques of professionalization norms and credential-based skill metrics, autonomy is also identified as a pre-requisite for embodied, tacit and discretionary skills in the emotional labor of ECEC.
Ultrasound joint examination by an automated system versus by a rheumatologist: from a patient perspective
Authors: Frederiksen Bill Aplin , Schousboe Maja , Terslev Lene , Iversen Nikolaj , Lindegaard Hanne , Savarimuthu Thiusius Rajeeth , Just Søren Andreas
Published: August 2022

Background

The Arthritis Ultrasound Robot (ARTHUR) is an automated system for ultrasound scanning of the joints of both hands and wrists, with subsequent disease activity scoring using artificial intelligence. The objective was to describe the patient’s perspective of being examined by ARTHUR, compared to an ultrasound examination by a rheumatologist. Further, to register any safety issues with the use of ARTHUR.

Methods

Twenty-five patients with rheumatoid arthritis (RA) had both hands and wrists examined by ultrasound, first by a rheumatologist and subsequently by ARTHUR. Patient-reported outcomes (PROs) were obtained after the examination by the rheumatologist and by ARTHUR. PROs regarding pain, discomfort and overall experience were collected, including willingness to be examined again by ARTHUR as part of future clinical follow-up. All ARTHUR examinations were observed for safety issues.

Results

There was no difference in pain or discomfort between the examination by a rheumatologist and by ARTHUR (p = 0.29 and p = 0.20, respectively). The overall experience of ARTHUR was described as very good or good by 92% (n = 23), with no difference compared to the examination by the rheumatologist (p = 0.50). All (n = 25) patients were willing to be examined by ARTHUR again, and 92% (n = 23) would accept ARTHUR as a regular part of their RA clinical follow up. No safety issues were registered.

Conclusions

Joint ultrasound examination by ARTHUR was safe and well-received, with no difference in PRO components compared to ultrasound examination by a rheumatologist. Fully automated systems for RA disease activity assessment could be important in future strategies for managing RA patients.

Trial registration: The study was evaluated by the regional ethics committee (ID: S-20200145), which ruled it was not a clinical trial necessary for their approval. It was a quality assessment project, as there was no intervention to the patient. The study was hereafter submitted and registered to Odense University Hospital, Region of Southern Denmark as a quality assessment project and approved (ID: 20/55294).
Systemic therapy response evaluation in prostate carcinoma with [68Ga]Ga-PSMA-11 PET/CT
Authors: Kucuker Kadir Alper , Yapar Zeynep , Guney Isa Burak , Paydas Semra
Published: August 2022

Background

Consensus statements was published by EAU and EANM to clarify some uncertainties on PSMA PET/CT response assessment in 2020. We aimed to investigate the response criteria for PSMA PET/CT according to published criteria by comparing with serum PSA changes and determine the factors affecting therapy response evaluation.

Results

A high concordance was found between [68Ga]Ga-PSMA-11 PET/CT and serum PSA responses and 0.84 of Gamma coefficient was obtained. Between concordant and discordant group, statistically significant difference was not found in terms of received therapies and castration resistance status. Statistically significant but low correlation was found between serum PSA and SUV values of prostate, moderate correlation was found serum PSA and SUVmax values of metastatic lymph nodes and bones.

Conclusions

The response evaluation of PSMA PET/CT according to the published criteria shows high concordance with serum PSA values without being affected by received therapies or castration resistance. This criteria can be used with contribution of serum PSA values in response evaluation of prostate cancer according to our results and literature data.
Post-traumatic stress disorder interventions for children and adolescents affected by war in low- and middle-income countries in the Middle East: systematic review
Authors: Alzaghoul Aseel F. , McKinlay Alison R. , Archer Marc
Published: August 2022

Background

Millions of children and adolescents are exposed to wars, affecting their psychological well-being. This review focuses on psychosocial interventions in low and middle-income countries (LMICs) in the Middle East, where mental health services are limited.

Aims

Our primary aim was to evaluate the effectiveness of trial-assessed psychosocial interventions in reducing post-traumatic stress disorder (PTSD) symptoms in children and adolescents aged ≤18 years who were exposed to war in LMICs in the Middle East. Changes in other psychological conditions and symptoms were evaluated where reported.

Method

PubMed, Cochrane Library and Ovid were searched without year restriction, in December 2021. Previous review reference lists were also checked. Only studies published in English were included. Each study was evaluated for risk of bias and results are presented as a narrative synthesis.

Results

Three group-based interventions were identified and evaluated across six studies: ‘Teaching Recovery Techniques’, ‘Writing for Recovery’ and ‘Advancing Adolescents’. Two studies took place in post-war settings, and four in a context of ongoing conflict. Positive experiences and improved social skills were indicated following most interventions, but Teaching Recovery Techniques was the only programme associated with a statistically significant reduction in PTSD score. Differences in follow-up interval limited comparability of outcomes.

Conclusions

This review highlights a paucity of evidence for effective treatment options for children and adolescents affected by war from LMICs in the Middle East. Promising indications of reductions in PTSD symptoms, specifically from Teaching Recovery Techniques, require further rigorous evaluation and long-term follow-up.
Clinicopathology and Treatment Patterns of Head and Neck Cancers in Ethiopia
Authors: Fekadu Adugna , Rick Tara J. , Tigeneh Wondemagegnhu , Kantelhardt Eva Johanna , Incrocci Luca , Jemal Ahmedin
Published: August 2022

PURPOSE

Head and neck cancers are the third most common cancers treated with radiation in Ethiopia. There is, however, a lack of published data on clinical and pathological characteristics and treatment patterns of head and neck cancers in the country. The objective of the study was to assess clinical and pathological characteristics and treatment patterns of head and neck cancers at Tikur Anbessa Specialized Hospital, which housed the only radiotherapy facility in Ethiopia during the study period.

MATERIALS AND METHODS

A retrospective cross-sectional study design with a simple random sampling of histologically confirmed head and neck cancers treated from 2014 to 2017 with analysis of descriptive data.

RESULTS

Three hundred twenty-one patient charts were analyzed in this study from a total population of 1,377 from the department cancer registry. The male to female ratio was 2:1. The median age was 45 years (interquartile range, 26-59). The most common primary site of head and neck cancers was nasopharynx (128 of 321, 40%), and the major histologic type was squamous cell carcinoma (285 of 321, 89%). Majority of the cases had advanced disease (stage III-IVC, 221 of 251, 88%), but 92% had potentially curable disease (231 of 321). Cobalt radiotherapy was used for 67% of all patients receiving treatment (184 of 273). Induction chemotherapy followed by radiotherapy was frequently used for curative intent patients (75 of 231, 32%). There was long duration between diagnosis and initiation of treatment, with 56% (148 of 264) waiting longer than 3 months.

CONCLUSION

Majority of patients with head and neck cancers seen in Ethiopia presented at advanced stage of disease, received cobalt radiotherapy, and had protracted treatment initiation. These findings underscore the need for additional investments to improve research capacity and increase the availability of high-quality radiotherapy and supportive services to deliver optimal care for patients with head and neck cancer and other cancer patients in the country.
Phase II Study of Afatinib in Patients With Tumors With Human Epidermal Growth Factor Receptor 2–Activating Mutations: Results From the National Cancer Institute–Molecular Analysis for Therapy Choice ECOG-ACRIN Trial (EAY131) Subprotocol EAY131-B
Authors: Bedard Philippe L. , Li Shuli , Wisinski Kari B. , Yang Eddy S. , Limaye Sewanti A. , Mitchell Edith P. , Zwiebel James A. , Moscow Jeffrey A. , Gray Robert J. , Wang Victoria , McShane Lisa M. , Rubinstein Larry V. , Patton David R. , Williams P. Mickey , Hamilton Stanley R. , Conley Barbara A. , Arteaga Carlos L. , Harris Lyndsay N. , O'Dwyer Peter J. , Chen Alice P. , Flaherty Keith T.
Published: August 2022

PURPOSE

National Cancer Institute–Molecular Analysis for Therapy Choice is a multicohort trial that assigns patients with advanced cancers to targeted therapies on the basis of central tumor genomic testing. Arm B evaluated afatinib, an ErbB family tyrosine kinase inhibitor, in patients with ERBB2-activating mutations.

METHODS

Eligible patients had selected ERBB2 single-nucleotide variants or insertions/deletions detected by the National Cancer Institute–Molecular Analysis for Therapy Choice next-generation sequencing assay. Patients had performance status ≤ 1, left ventricular ejection fraction > 50%, grade ≤ 1 diarrhea, and no prior human epidermal growth factor receptor 2 (HER2) therapy. Patients received afatinib 40 mg once daily in 28-day cycles. The primary end point was objective response rate (ORR). Secondary end points were 6-month progression-free survival, overall survival, toxicity, and molecular correlates.

RESULTS

A total of 59 patients were assigned and 40 were enrolled. The median age was 62 years, 78% were female, 68% had performance status = 1, and 58% had received > 3 prior therapies. The confirmed ORR was 2.7% (n = 1 of 37; 90% CI, 0.14 to 12.2), and 6-month progression-free survival was 12.0% (90% CI, 5.6 to 25.8). A confirmed partial response occurred in a patient with adenocarcinoma of extra-mammary Paget disease of skin who progressed after cycle 6. Two unconfirmed partial responses were observed (low-grade serous gynecological tract and estrogen receptor–positive/HER2-negative immunohistochemistry breast ductal carcinoma). Of 12 patients with breast cancer, 1 additional patient with lobular carcinoma (estrogen receptor–positive/HER2 fluorescent in situ hybridization) had a 51% reduction in target lesions but progressed because of a new lesion at cycle 6. The most common (> 20%) treatment-related adverse events were diarrhea (68%), mucositis (43%), fatigue (40%), acneiform rash (30%), dehydration (27%), vomiting (27%), nausea (27%), anemia (27%), and anorexia (22%). Four patients (11%) discontinued because of adverse events.

CONCLUSION

Although afatinib did not meet the prespecified threshold for antitumor activity in this heavily pretreated cohort, the response in a rare tumor type is notable. The safety profile of afatinib was consistent with prior studies.
Progressive Multiple Sclerosis
Authors: Amezcua Lilyana
Published: August 2022

PURPOSE OF REVIEW

This article provides an update on progressive forms of multiple sclerosis (MS) commonly referred to as primary progressive MS and secondary progressive MS. It discusses the importance of diagnosing and detecting progression early, the similarities between progressive forms, challenges in detecting progression, factors that could augment progression, and the importance of disease-modifying therapies in patients with evidence of active progressive MS. It also discusses the overall care of progressive MS.

RECENT FINDINGS

The pathogenesis of primary progressive MS and secondary progressive MS is overlapping, and in both presentations, patients with relapses or focal MRI activity are classified as having active, progressive MS. All currently approved disease-modifying therapies are indicated for active secondary progressive MS. The therapeutic opportunity of anti-inflammatory drugs for the treatment of progressive MS is enhanced in those who are younger and have a shorter disease duration. Vascular comorbidities may contribute to progression in MS.

Several challenges remain in the diagnosis, follow-up, and treatment of progressive MS. Early identification of active progressive MS is needed to maximize treatment benefit. The advantages of optimal comorbidity management (eg, hypertension, hyperlipidemia) in delaying progression are uncertain. Clinical care guidelines for advanced, severe MS are lacking.
White Cane Approach to Teaching Spinal Anesthesia
Authors: Lambert Donald H. , Sweitzer BobbieJean
Published: August 2022

With aging-associated obesity and osteoarthritis, anesthesiology trainees and their instructors face difficulties in identifying the surface anatomy and landmarks for spinal anesthesia, and successfully advancing the needle into the intrathecal space. Through a series of illustrations and instructions, this teaching tool suggests that using a spinal needle in the same way that a blind person uses a white cane may improve a trainee’s ability to successfully perform a lumbar puncture. Reviewing the technique and instructions with the trainee before approaching the patient can minimize verbal instructions in the patient’s presence and may lead to improved efficiency and trainee success.
Timely Schwann cell division drives peripheral myelination in vivo via the laminin/cAMP pathway
Authors: Mikdache Aya , Boueid Marie-José , Lesport Emilie , Delespierre Brigitte , Loisel-Duwattez Julien , Degerny Cindy , Tawk Marcel
Published: August 2022

Schwann cells (SCs) migrate along peripheral axons and divide intensively to generate the right number of cells prior to axonal ensheathment; however, little is known regarding the temporal and molecular control of their division and its impact on myelination. We report that Sil, a spindle pole protein associated with autosomal recessive primary microcephaly, is required for temporal mitotic exit of SCs. In sil-deficient cassiopeia (csp−/−) mutants, SCs fail to radially sort and myelinate peripheral axons. Elevation of cAMP, but not Rac1 activity, in csp−/− restores myelin ensheathment. Most importantly, we show a significant decrease in laminin expression within csp−/− posterior lateral line nerve and that forcing Laminin 2 expression in csp−/− fully restores the ability of SCs to myelinate. Thus, we demonstrate an essential role for timely SC division in mediating laminin expression to orchestrate radial sorting and peripheral myelination in vivo.
Energetics, but not development, is impacted in coral embryos exposed to ocean acidification
Authors: Chille E. E. , Strand E. L. , Scucchia F. , Neder M. , Schmidt V. , Sherman M. O. , Mass T. , Putnam H. M.
Published: August 2022

In light of the chronic stress and mass mortality reef-building corals face under climate change, it is critical to understand the processes driving reef persistence and replenishment, including coral reproduction and development. Here, we quantified gene expression and sensitivity to ocean acidification across a set of developmental stages in the rice coral, Montipora capitata. Embryos and swimming larvae were exposed to pH treatments of 7.8 (ambient), 7.6 (low) and 7.3 (extreme low) from fertilization to 9 days post-fertilization. Embryo and larval volume, and stage-specific gene expression were compared between treatments to determine the effects of acidified seawater on early development. Although there was no measurable size differentiation between pH treatments at the fertilized egg and prawn chip (9 h post-fertilization) stages, early gastrulae and larvae raised in reduced pH treatments were significantly smaller than those raised in ambient seawater, suggesting an energetic cost to developing under low pH. However, no differentially expressed genes were found until the swimming larval stage. Notably, gene expression patterns of larvae developing at pH 7.8 and pH 7.3 were more similar than those of larvae developing at pH 7.6. Larvae from pH 7.6 showed upregulation of genes involved in cell division, regulation of transcription, lipid metabolism and response to oxidative stress in comparison to the other two treatments. Although low pH appears to increase energetic demands and trigger oxidative stress in larvae, the developmental process is robust to this at a molecular level, with the swimming larval stage reached in all pH treatments.
Prevalence of responsible research practices among academics in The Netherlands
Authors: Gopalakrishna Gowri , Wicherts Jelte M. , Vink Gerko , Stoop Ineke , van den Akker Olmo R. , ter Riet Gerben , Bouter Lex M.
Published: August 2022

Background:Traditionally, research integrity studies have focused on research misbehaviors and their explanations. Over time, attention has shifted towards preventing questionable research practices and promoting responsible ones. However, data on the prevalence of responsible research practices, especially open methods, open codes and open data and their underlying associative factors, remains scarce.

Methods:We conducted a web-based anonymized questionnaire, targeting all academic researchers working at or affiliated to a university or university medical center in The Netherlands, to investigate the prevalence and potential explanatory factors of 11 responsible research practices.

Results:A total of 6,813 academics completed the survey, the results of which show that prevalence of responsible practices differs substantially across disciplines and ranks, with 99 percent avoiding plagiarism in their work but less than 50 percent pre-registering a research protocol. Arts and humanities scholars as well as PhD candidates and junior researchers engaged less often in responsible research practices. Publication pressure negatively affected responsible practices, while mentoring, scientific norms subscription and funding pressure stimulated them.

Conclusions:Understanding the prevalence of responsible research practices across disciplines and ranks, as well as their associated explanatory factors, can help to systematically address disciplinary- and academic rank-specific obstacles, and thereby facilitate responsible conduct of research.
Usefulness of vaccine boosters for Covid-19 in Italy and in UK and comparison between in intensive care admissions and deaths of vaccinated and unvaccinated patients. Surprises and implications
Authors: Alessandria Marco , Simion Claudio , Donzelli Alberto
Published: August 2022

Background: There is insufficient clarity about the different outcomes between unvaccinated and vaccinated people hospitalized with Covid-19, with reference to the variables “Intensive Care Unit” and “Deaths”. Moreover, it is unclear the real effectiveness of the vaccine boosters on the risks of infection and Covid-19 deaths, beyond the first few months after the booster. To verify the hypotheses that repeated vaccinations might expose to a progressively greater risk of severe Covid-19, and of a growing weakening of the immune response, primarily against infection, as the distance from the booster dose increases.

Methods: Through an analysis of the official Italian data we calculated significant differences, percentage variations and trends in the variables “Intensive Care Units” and “Deaths” in hospitalized patients among four groups with different vaccination status, and between the Unvaccinated and Vaccinated groups.

Through analyses of the UK Security Agency data in the weekly COVID-19 vaccine surveillance reports we explored the vaccine effectiveness against SARS-CoV-2 infections and against COVID-19 deaths in relation to the time elapsed from the booster doses.

Results: Repeated vaccinations seem to expose the recipients to a growing risk of severe Covid-19, and fewer vaccinations might be enough to protect persons at greater risk.

The vaccine effectiveness against infection vanished and reversed in the medium term, and vaccinated persons with three doses become increasingly more infected versus unvaccinated persons.

Conclusions: The starting hypotheses have been supported, together with the need to combine carefully rethought vaccination campaigns with the implementation of other strategies, with the achievement of a healthy living and working environment, healthy lifestyles, and effective, safe and sustainable care.
Dysbiosis: Gut feeling
Authors: Jalandra Rekha , Dhar Ruby , Pethusamy Karthikeyan , Sharma Minakshi , Karmakar Subhradip
Published: August 2022

A healthy host-microbiome relationship, crucial for intestinal homeostasis, is established early in postnatal life. Imbalance in the neonatal microbiome may lead to the development of chronic pathological conditions later in life. Dysbiosis of the gut microbiota is increasingly being linked to the etiology of both intestinal and systemic illnesses such as irritable bowel disease (IBD), cardiovascular diseases and diabetes, as well as kidney and neurological disorders. Gut dysbiosis also leads to the development of colorectal cancer (CRC). Despite substantial research, little is known about the interactions between microorganisms, their hosts, and their environments, or whether dysbiosis is a cause or consequence of disease. According to a recent hypothesis, bacterial species living in the mucus layer of the colon may determine whether cellular homeostasis is retained or inflammatory processes are elicited, either through direct interaction with intestinal epithelium or indirectly via bacterial metabolites. Recently, high throughput deep-sequencing technology has enabled the characterization of the microbiota in patients suffering from intestinal or extra-intestinal disorders, and a strong association between dysbiosis and disease development was found. However, specific disease drivers still need to be identified in most cases. Small compounds and metabolites produced by gut bacterial flora act as signaling molecules, such as neurotransmitters and neuropeptides that can profoundly influence host physiology. These metabolites play a crucial role in modulating gut-brain crosstalk. There is growing evidence that neurological disorders such as Alzheimer's disease, Parkinson’s and others, may originate or be exaggerated in response to microbial dysbiosis either directly or indirectly interfering with the drugs through metabolites. The present evidence on the role of the gut microbiota in disease development and drug metabolism is summarized in this review. Based on available studies, we can explore the potential of gut flora to alleviate disease progression.
Sustainability of the regional financial system: a case study of the Northwestern Federal District
Authors: Evgenievich Barykin Sergey , Aleksandrovich Mikheev Alexey , Grigorievna Kiseleva Elena , Evgenievich Putikhin Yuriy , De La Poza Plaza Elena , Sergeevna Alekseeva Natalia
Published: August 2022

Background: This article provides an assessment of the sustainability of Russian regions’ financial systems. The study is based on the methods of generalization and synthesis, correlation-regression analysis, and multivariate classification. Since the structure of the regional financial system is complex, several works are devoted to studying its sustainability issues. The relevance of the study topic is confirmed by the lack of a systematic approach to assessing the integral index of sustainability and the possibility of using various tools in determining the complex indicator.

Methods: This  methodology with application of mathematical statistics methods makes it possible to assess the financial system sustainability in four sectors, to include the leading indicators in the assessment, and to identify regions with extreme values of debt burden indicators. The method was tested for the regions of the Northwestern Federal District (NWFD) for the period 2010 - 2019  to classify the regions according to three levels of debt sustainability. Data collection from the 1st January to 30th April 2022 included statistical data from government open internet sources, sectors studied relate to government, and municipal budgets in the NWFD. Authors analyzed regional debt sustainability indicators and identified themes in the field of sustainability studies for the NWFD.

Results: An increased level of financial system sustainability was observed among the  NWFD regions in the corporative and personal finance sectors, indicating a significant contribution of businesses and households to maintaining the balance and sustainability of the financial system in Russia as a whole. The results of the study also identified that the NWFD regions belong to three clusters: cluster 1 - high debt sustainability; cluster 2 - medium debt sustainability; and cluster 3 - low debt sustainability.

Conclusions: The study results allowed the identification of regions with a constantly high level of debt, financial, and corporative sustainability.
Statistical models for the deterioration of kidney function in a primary care population: A retrospective database analysis
Authors: Oke Jason L , Feakins Benjamin G , Schlackow Iryna , Mihaylova Borislava , Simons Claire , O'Callaghan Chris A , Lasserson Daniel S , Hobbs F D Richard , Stevens Richard J , Perera Rafael
Published: August 2022

Background: Evidence for kidney function monitoring intervals in primary care is weak, and based mainly on expert opinion. In the absence of trials of monitoring strategies, an approach combining a model for the natural history of kidney function over time combined with a cost-effectiveness analysis offers the most feasible approach for comparing the effects of monitoring under a variety of policies. This study aimed to create a model for kidney disease progression using routinely collected measures of kidney function.

Methods: This is an open cohort study of patients aged ≥18 years, registered at 643 UK general practices contributing to the Clinical Practice Research Datalink between 1 April 2005 and 31 March 2014. At study entry, no patients were kidney transplant donors or recipients, pregnant or on dialysis. Hidden Markov models for estimated glomerular filtration rate (eGFR) stage progression were fitted to four patient cohorts defined by baseline albuminuria stage; adjusted for sex, history of heart failure, cancer, hypertension and diabetes, annually updated for age.

Results: Of 1,973,068 patients, 1,921,949 had no recorded urine albumin at baseline, 37,947 had normoalbuminuria (<3mg/mmol), 10,248 had microalbuminuria (3–30mg/mmol), and 2,924 had macroalbuminuria (>30mg/mmol). Estimated annual transition probabilities were 0.75–1.3%, 1.5–2.5%, 3.4–5.4% and 3.1–11.9% for each cohort, respectively. Misclassification of eGFR stage was estimated to occur in 12.1% (95%CI: 11.9–12.2%) to 14.7% (95%CI: 14.1–15.3%) of tests. Male gender, cancer, heart failure and age were independently associated with declining renal function, whereas the impact of raised blood pressure and glucose on renal function was entirely predicted by albuminuria.

Conclusions: True kidney function deteriorates slowly over time, declining more sharply with elevated urine albumin, increasing age, heart failure, cancer and male gender. Consecutive eGFR measurements should be interpreted with caution as observed improvement or deterioration may be due to misclassification.
An R-based reproducible and user-friendly preprocessing pipeline for CyTOF data
Authors: Crowell Helena L. , Chevrier Stéphane , Jacobs Andrea , Sivapatham Sujana ,   Tumor Profiler Consortium, Bodenmiller Bernd , Robinson Mark D.
Published: August 2022

Mass cytometry (CyTOF) has become a method of choice for in-depth characterization of tissue heterogeneity in health and disease, and is currently implemented in multiple clinical trials, where higher quality standards must be met. Currently, preprocessing of raw files is commonly performed in independent standalone tools, which makes it difficult to reproduce. Here, we present an R pipeline based on an updated version of CATALYST that covers all preprocessing steps required for downstream mass cytometry analysis in a fully reproducible way. This new version of CATALYST is based on Bioconductor’s SingleCellExperiment class and fully unit tested. The R-based pipeline includes file concatenation, bead-based normalization, single-cell deconvolution, spillover compensation and live cell gating after debris and doublet removal. Importantly, this pipeline also includes different quality checks to assess machine sensitivity and staining performance while allowing also for batch correction. This pipeline is based on open source R packages and can be easily be adapted to different study designs. It therefore has the potential to significantly facilitate the work of CyTOF users while increasing the quality and reproducibility of data generated with this technology.