bluuebunny/crossref_metadata_2025 huggingface dataset:
Rationale and design of Children’s Oncology Group (COG) study ACCL20N1CD: financial distress during treatment of acute lymphoblastic leukemia in the United States
Authors: Beauchemin Melissa , Santacroce Sheila Judge , Bona Kira , Dang Ha , Alexander Sarah , Allen Kamala , De Los Santos Crystal , Fisher Beth , Muñeton-Castaño Yudy , Ponce Olivia , Vargas Sarah , Sugalski Aaron , Sung Lillian , Parsons Susan
Published: June 2022

Background

The study purpose is to describe trajectories of financial distress for parents of children (ages 1–14.9 years) with newly diagnosed acute lymphoblastic leukemia (ALL). The secondary aim is to identify multilevel factors (child, parent, household, treating institution) that influence change in financial distress over time.

Methods

The study uses a prospective cohort design, repeated measurements, and mixed methods. The settings are Children’s Oncology Group (COG) institutions participating in the National Cancer Institute Community Oncology Research Program (NCORP). Eligible participants are English- and/or Spanish-speaking parents or legal guardians (hereafter “parents”) of index children. Parents are asked to complete a survey during their child’s induction (T1) and maintenance therapy (T2), and near treatment completion (T3). Study surveys include items about (a) the child’s cancer and clinical course, (b) parental socio-economic status, financial distress and financial coping behaviors, and (c) household material hardships. At least 15 parents will be invited to participate in an optional semi-structured interview. NCORP institutions that enroll at least one parent must complete an annual survey about institution resources that could influence parental financial distress.

Discussion

The results will inform future interventions to mitigate financial distress for parents of children diagnosed with ALL and could be instructive beyond this disease group.

Trial registration

This trial was initially registered with the NCI Clinical Trial Reporting Program ID: NCI-2021–03,567 on June 16, 2021. The study can be found on clinicaltrials.gov, IdentifierNCT04928599.
Cost-effectiveness of voretigene neparvovec in the treatment of patients with inherited retinal disease with RPE65 mutation in Switzerland
Authors: Bhadhuri Arjun , Dröschel Daniel , Guldimann Mike , Jetschgo Claudia , Banhazi Judit , Schwenkglenks Matthias , Sutherland C. Simone
Published: June 2022

Objective

We aimed to evaluate the cost-effectiveness of voretigene neparvovec (VN) compared with standard of care (SoC) for patients with inherited retinal disease (IRD) caused by a biallelic RPE65-mutation. VN is a live, non-replicating adeno-associated virus serotype 2 (AAV2). SoC is best supportive care provided to patients with visual impairment. Patients under SoC may experience progressive vision loss leading to complete blindness.

Methods

We adapted a previously published Markov cohort model for IRD. An annual cycle length, life-long time horizon, discount rate of 3% for cost and health outcomes, and Swiss health system perspective were used. Data from a randomised controlled phase III trial of VN versus SoC (ClinicalTrials.gov: NCT00999609) were used to estimate transitions between health states in the first year, after which VN patients were assumed to remain for 39 subsequent years in the health state they were in at the end of the first year. After the 40th year for VN patients and 1st year for SoC patients, visual decline was modelled based on observational data on the natural progression of the disease. Quality-adjusted life years (QALYs) were calculated based on an external study which elicited clinicians’ EQ-5D-5L-based utility estimates for IRD patients with a RPE65-mutation. Costs (Swiss Francs (CHF), year 2018-2019) included drug acquisition/ administration, adverse events, testing for sufficient viable retinal cells, and healthcare-related costs of blindness. Societal costs of blindness were added in a complementary analysis. Robustness of the model results were tested in sensitivity and scenario analyses.

Results

For the base-case, VN resulted in incremental costs per patient of CHF 764’402 (VN: CHF 901’654, SoC: CHF 137’252), incremental blindness-free years of 7.67 (VN: 28.32, SoC: 20.65) and incremental QALYs of 6.73 (VN: 18.35, SoC: 11.62), leading to an incremental cost-effectiveness ratio of CHF 113’526 per QALY gained. In probabilistic sensitivity analysis, the cost-effectiveness of VN was better than CHF 100,000 per QALY gained in 41% of iterations. For the scenario analysis in which a societal perspective was adopted and for which a 50% work-related productivity loss from blindness was assumed, incremental costs of CHF 423,837 and an ICER of CHF 62’947 per QALY gained were produced. The scenario assuming VN treatment effect lasts for 20 years produced an ICER of CHF 156’171 per QALY gained, whereas assuming a life-long VN treatment effect resulted in an ICER of CHF 96’384 per QALY gained.

Conclusion

The incremental cost-effectiveness ratio of VN compared to the SoC was estimated to be CHF 113’526 and CHF 62’947 per QALY gained, respectively, from a Swiss healthcare system, and societal perspective assuming a 50% productivity loss.
Patient and health system level barriers to and facilitators for tuberculosis treatment initiation in Uganda: a qualitative study
Authors: Zawedde-Muyanja Stella , Manabe Yukari C. , Cattamanchi Adithya , Castelnuovo Barbara , Katamba Achilles
Published: June 2022

Background

The WHO END TB strategy targets to place at least 90% of all patients diagnosed with Tuberculosis (TB) on appropriate treatment. In Uganda, approximately 20% of patients diagnosed with TB are not initiated on TB treatment. We sought to identify the patient and health system level barriers to and facilitators for TB treatment initiation in Uganda.

Methods

We conducted the study at ten public health facilities (three primary care, four district and three tertiary referral hospitals). We carried out in-depth interviews with patients diagnosed with TB and key informant interviews with health managers. In addition, we held focus group discussions with healthcare workers involved in TB care. Data collection and thematic analysis of transcripts was informed by the Capability, Opportunity, Motivation and Behavior (COM-B) model. We identified relevant intervention functions using the Behavior Change Wheel.

Results

We interviewed 79 respondents (31 patients, 10 health managers and 38 healthcare workers). Common barriers at the health facility level included; lack of knowledge about the proportion of patients not initiated on TB treatment (psychological capability); difficulty accessing sputum results from the laboratory as well as difficulty tracing patients due to inadequate recording of patient addresses (physical opportunity). At the patient level, notable barriers included long turnaround time for sputum results and lack of transport funds to return to health facilities (physical opportunity); limited TB knowledge (psychological capability) and stigma (social opportunity). The most important facilitators identified were quick access to sputum test results either on the date of first visit (same-day diagnosis) or on the date of first return and availability of TB treatment (physical opportunity). We identified education, restructuring of the service environment to improve sputum results turnaround time and enablement to improve communication of test results as relevant intervention functions to alleviate these barriers to and enhance facilitators for TB treatment initiation.

Conclusion

We found that barriers to treatment initiation existed at both the patient and health facility-level across all levels of the (Capability, Opportunity and Motivation) model. The intervention functions identified here should be tested for feasibility.
Unusual diagnosis of feline cardiac lymphoma using cardiac needle biopsy
Authors: Tanaka S. , Suzuki R. , Hirata M. , Kagawa Y. , Koyama H.
Published: June 2022

Background

Cardiac tumors in cats are relatively rare, with lymphoma accounting for more than half of all cases. However, feline cardiac lymphoma is often diagnosed post-mortem, and it is difficult to diagnose while the cat is still alive. It is the first report of a direct, rather than estimative, diagnosis with cardiac needle biopsy of a living cat with cardiac lymphoma.

Case presentation

A 3-year-old domestic short-haired male cat experienced loss of energy and loss of appetite. Thoracic radiography and transthoracic echocardiography showed cardiomegaly with slight pleural effusion and cardiac tamponade due to pericardial effusion, respectively. In addition, partial hyperechoic and hypertrophy of the papillary muscle and myocardium were observed. Blood test showed an increase in cardiac troponin I levels. Pericardial fluid, removed by pericardiocentesis, was analyzed; however, the cause could not be determined. With the owner’s consent, pericardiectomy performed under thoracotomy revealed a discolored myocardium. Cardiac needle biopsy was performed with a 25G needle, and a large number of large atypical lymphocytes were collected; therefore, a direct diagnosis of cardiac lymphoma was made. Pathological examination of the pericardium diagnosed at a later date revealed T-cell large cell lymphoma. The cat underwent chemotherapy followed by temporary remission but died 60 days after the diagnosis. Postmortem, two-dimensional speckle-tracking echocardiography (data when alive) revealed an abnormal left ventricular myocardial deformation, which corresponded to the site of cardiac needle biopsy.

Conclusions

This rare case demonstrates that cardiac lymphoma should be added to the differential diagnosis in cats with myocardial hypertrophy and that the diagnosis can be made directly by thoracotomy and cardiac needle biopsy. In addition, the measurement of cardiac troponin I levels and local deformation analysis of the myocardium by two-dimensional speckle-tracking echocardiography may be useful in the diagnosis of cardiac tumors.
Somatic targeted mutation profiling of colorectal cancer precursor lesions
Authors: dos Santos Wellington , dos Reis Mariana Bisarro , Porto Jun , de Carvalho Ana Carolina , Matsushita Marcus , Oliveira Gabriela , Syrjänen Kari , Reis Rui Manuel , Guimarães Denise Peixoto
Published: June 2022

Background

Most colorectal cancers (CRC) arise from precursor lesions. This study aimed to characterize the mutation profile of colorectal cancer precursor lesions in a Brazilian population.

Methods

In total, 90 formalin-fixed paraffin-embedded colorectal precursor lesions, including 67 adenomas, 7 sessile serrated lesions, and 16 hyperplastic polyps, were analyzed by next-generation sequencing using a panel of 50 oncogenes and tumor suppressor genes. The genetic ancestry of the patients was estimated.

Results

Somatic driver mutations were identified in 66.7% of cases, including alterations in APC (32.2%), TP53 (20.0%), KRAS (18.9%), BRAF (13.3%) and EGFR (7.8%). Adenomas displayed a higher number of mutations, mainly in APC, compared to serrated polyps (73.1% vs. 47.8%, p = 0.026). Advanced adenomas had a significantly higher frequency of mutation in KRAS and a high overall mutation rate than early adenomas (92.9% vs. 59%, p = 0.006). A high degree of ancestry admixture was observed in the population studied, with a predominance of European components (mean of 73%) followed by African (mean of 11.3%). No association between genetic ancestry and type of lesions was found. The mutation profile of Brazilian colorectal precursor lesions exhibits alteration in APC, KRAS, TP53, and BRAF at different frequencies according to lesion type.

Conclusions

These results bestow the knowledge of CRC's biologic history and support the potential of these biomarkers for precursor lesions detection in CRC screening of the Brazilian population.
Heart rate variability as a biomarker in patients with Chronic Chagas Cardiomyopathy with or without concomitant digestive involvement and its relationship with the Rassi score
Authors: Silva Luiz Eduardo Virgilio , Moreira Henrique Turin , de Oliveira Marina Madureira , Cintra Lorena Sayore Suzumura , Salgado Helio Cesar , Fazan Rubens , Tinós Renato , Rassi Anis , Schmidt André , Marin-Neto J. Antônio
Published: June 2022

Background

Dysautonomia plays an ancillary role in the pathogenesis of Chronic Chagas Cardiomyopathy (CCC), but is the key factor causing digestive organic involvement. We investigated the ability of heart rate variability (HRV) for death risk stratification in CCC and compared alterations of HRV in patients with isolated CCC and in those with the mixed form (CCC + digestive involvement). Thirty-one patients with CCC were classified into three risk groups (low, intermediate and high) according to their Rassi score. A single-lead ECG was recorded for a period of 10–20 min, RR series were generated and 31 HRV indices were calculated. The HRV was compared among the three risk groups and regarding the associated digestive involvement. Four machine learning models were created to predict the risk class of patients.

Results

Phase entropy is decreased and the percentage of inflection points is increased in patients from the high-, compared to the low-risk group. Fourteen patients had the mixed form, showing decreased triangular interpolation of the RR histogram and absolute power at the low-frequency band. The best predictive risk model was obtained by the support vector machine algorithm (overall F1-score of 0.61).

Conclusions

The mixed form of Chagas' disease showed a decrease in the slow HRV components. The worst prognosis in CCC is associated with increased heart rate fragmentation. The combination of HRV indices enhanced the accuracy of risk stratification. In patients with the mixed form of Chagas disease, a higher degree of sympathetic autonomic denervation may be associated with parasympathetic impairment.
Interaction of alginate with nano-hydroxyapatite-collagen using strontium provides suitable osteogenic platform
Authors: Hassani Ayla , Avci Çığır Biray , Kerdar Sajed Nazif , Amini Hassan , Amini Meisam , Ahmadi Mahdi , Sakai Shinji , Bagca Bakiye Goker , Ozates Neslihan Pınar , Rahbarghazi Reza , Khoshfetrat Ali Baradar
Published: June 2022

Background

Hydrogels based on organic/inorganic composites have been at the center of attention for the fabrication of engineered bone constructs. The establishment of a straightforward 3D microenvironment is critical to maintaining cell-to-cell interaction and cellular function, leading to appropriate regeneration. Ionic cross-linkers, Ca2+, Ba2+, and Sr2+, were used for the fabrication of Alginate-Nanohydroxyapatite-Collagen (Alg-nHA-Col) microspheres, and osteogenic properties of human osteoblasts were examined in in vitro and in vivo conditions after 21 days.

Results

Physicochemical properties of hydrogels illustrated that microspheres cross-linked with Sr2+ had reduced swelling, enhanced stability, and mechanical strength, as compared to the other groups. Human MG-63 osteoblasts inside Sr2+ cross-linked microspheres exhibited enhanced viability and osteogenic capacity indicated by mineralization and the increase of relevant proteins related to bone formation. PCR (Polymerase Chain Reaction) array analysis of the Wnt (Wingless-related integration site) signaling pathway revealed that Sr2+ cross-linked microspheres appropriately induced various signaling transduction pathways in human osteoblasts leading to osteogenic activity and dynamic growth. Transplantation of Sr2+ cross-linked microspheres with rat osteoblasts into cranium with critical size defect in the rat model accelerated bone formation analyzed with micro-CT and histological examination.

Conclusion

Sr2+ cross-linked Alg-nHA-Col hydrogel can promote functionality and dynamic growth of osteoblasts.

Graphical Abstract
Unveiling the improved targeting migration of mesenchymal stem cells with CXC chemokine receptor 3-modification using intravital NIR-II photoacoustic imaging
Authors: Lin Yuejun , Zhou Hui-chao , Chen Ningbo , Ren Yaguang , Gao Rongkang , Li Qiaojia , Deng Yiwen , Han Xuejiao , Zhang Xiaoran , Xiang Andy Peng , Guo Bing , Liu Chengbo , Ren Jie
Published: June 2022

Background

Therapy with genetically modified mesenchymal stem cells (MSCs) has clinical translation promise. Optimizing the targeting migratory ability of MSCs relies on accurate imaging of the distribution and extravasation kinetics of MSCs, and the corresponding imaging results could be used to predict therapeutic outcomes and guide the optimization of the treatment program. Among the different imaging modalities, second near-infrared (NIR-II) optical-resolution photoacoustic microscopy (OR-PAM) has merits, including a fine resolution, a deep penetration, a high sensitivity, and a large signal-to-background ratio. It would be an ideal candidate for precise monitoring of MSCs, although it has not been tested for this purpose so far.

Results

Penetrating peptide-decorated conjugated polymer nanoparticles (TAT-CPNPs) with strong NIR-II absorbance were used to label chemokine-receptor genetically modified MSCs, which were subsequently evaluated under intravital NIR-II OR-PAM regarding their targeting migratory ability. Based on the upregulation of chemokine (C-X-C motif) ligand 10 in the inflamed ears of contact hypersensitivity mice, MSCs with overexpression of corresponding receptor, chemokine (C-X-C motif) receptor 3 (Cxcr3) were successfully generated (MSCCxcr3). TAT-CPNPs labeling enabled NIR-II photoacoustic imaging to discern MSCCxcr3 covered by 1.2 cm of chicken breast tissue. Longitudinal OR-PAM imaging revealed enhanced inflammation-targeting migration of MSCCxcr3 over time attributed to Cxcr3 gene modification, which was further validated by histological analysis.

Conclusions

TAT-CPNPs-assisted NIR-II PA imaging is promising for monitoring distribution and extravasation kinetics of MSCs, which would greatly facilitate optimizing MSC-based therapy.

Graphical Abstract
MiR-21 regulating PVT1/PTEN/IL-17 axis towards the treatment of infectious diabetic wound healing by modified GO-derived biomaterial in mouse models
Authors: Chen Xi , Peng Yizhong , Xue Hang , Liu Guohui , Wang Ning , Shao Zengwu
Published: June 2022

Background

Diabetic foot ulcer (DFU), persistent hyperglycemia and inflammation, together with impaired nutrient and oxygen deficiency, can present abnormal angiogenesis following tissue injury such that these tissues fail to heal properly. It is critical to design a new treatment method for DFU patients with a distinct biomechanism that is more effective than current treatment regimens.

Method

Graphene oxide (GO) was combined with a biocompatible polymer as a kind of modified GO-based hydrogel. The characterization of our biomaterial was measured in vitro. The repair efficiency of the biomaterial was evaluated in the mouse full-skin defect models. The key axis related to diabetic wound (DW) was identified and investigated using bioinformatics analyses and practical experiments.

Result

In the study, we found that our modified GO-based wound dressing material is a promising option for diabetic wound. Secondly, our biomaterial could enhance the secretion of small EVs (sEVs) with more miR-21 by adipose-derived mesenchymal stem cells (AD-MSCs). Thirdly, the PVT1/PTEN/IL-17 axis was found to be decreased to promote DFU wound healing by modifying miR-21 with the discovery of PVT1 as a critical LncRNA by bioinformatics analysis and tests.

Conclusion

These findings could aid in the development of clinical care strategies for DFU wounds.
Transthoracic, thoracoabdominal, and transabdominal surgical approaches for gastric cardia adenocarcinomas: a survival evaluation based on a cohort of 7103 patients
Authors: Chen Yao , Zhao Xue Ke , Xu Rui Hua , Song Xin , Yang Miao Miao , Zhou Fu You , Lei Ling Ling , Fan Zong Min , Han Xue Na , Gao She Gan , Wang Xian Zeng , Liu Zhi Cai , Li Li Ai , Gao Wen Jun , Hu Jing Feng , Zhang Li Guo , Wei Jin Chang , Jiao Fu Lin , Zhong Kan , Wang Wei Peng , Li Liu Yu , Ji Jia Jia , Li Xue Min , Wang Li Dong
Published: June 2022

Background

This study compared the survival outcomes of different surgical approaches to determine the optimal approach for gastric cardia adenocarcinoma (GCA) and aimed to standardize the surgical treatment guidelines for GCA.

Methods

A total of 7103 patients with GCA were enrolled from our previously established gastric cardia and esophageal carcinoma databases. In our database, when the epicenter of the tumor was at or within 2 cm distally from the esophagogastric junction, the adenocarcinoma was considered to originate from the cardia and was considered a Siewert type 2 cancer. The main criteria for the enrolled patients included treatment with radical surgery, no radio- or chemotherapy before the operation, and detailed clinicopathological information. Follow-up was mainly performed by telephone or through home interviews. According to the medical records, the surgical approaches included transthoracic, thoracoabdominal, and transabdominal approaches. Kaplan–Meier and Cox proportional hazards regression models were applied to correlate the surgical approach with survival in patients with GCA.

Results

There were marked differences in age and tumor stage among the patients who underwent the three surgical approaches (P < 0.001). Univariate analysis showed that survival was related to sex, age, tumor stage, and N stage (P < 0.001 for all). Cox regression model analysis revealed that thoracoabdominal approach (P < 0.001) and transabdominal approach (P < 0.001) were significant risk factors for poor survival. GCA patients treated with the transthoracic approach had the best survival (5-year survival rate of 53.7%), and survival varied among the different surgical approaches for different tumor stages.

Conclusion

Thoracoabdominal approach and transabdominal approach were shown to be poor prognostic factors. Patients with (locally advanced) GCA may benefit from the transthoracic approach. Further prospective randomized clinical trials are necessary.
Do oral combined contraceptive pills modify body image and sexual function?
Authors: Nowosielski Krzysztof
Published: June 2022

Background

The effect of hormonal contraceptives on sexual function and body image is still controversial. Existing studies have not come to definite conclusions on the association between hormonal contraceptive use and sexual function/presence of sexual dysfunction or changes in body image perception. Thus, this study aimed to evaluate the prevalence of sexual problems/dysfunction in Polish women of reproductive age (18–45 years) and to assess to what extent oral combined contraceptive pills (OCCP) impact body image, sexual function and the prevalence of female sexual dysfunction (FSD).

Methods

A total of 495 women were included in this cross-sectional questionnaire-based study. Sexual function was assessed by the Changes in Sexual Function Questionnaire (CSFQ), the prevalence of FSD was assessed by DSM-5 criteria, and body image was assessed by the Body Exposure during Sexual Activity Questionnaire (BESAQ). A total of 237 women using OCCP were the study group (HC), and the rest were controls (CG). A regression model was used to evaluate the influence of the selected variables on sexual function and the presence of FSD.

Results

The prevalence of FSD was 7.5% in HC and 2.6% in CG, and 22% compared to 14% of women in HC and CG, respectively, reported sexual problems (CSFQ). The demographic characteristics of those using other contraception methods or not using any contraception (control group) were similar. The contraceptive group was characterized by significantly higher importance of sex (4.03 vs. 3.79), worse partner’s attitude toward sex (4.35 vs. 4.47), worse self-attitude toward sex (4.35 vs. 4.47), and worse body image (BESAQ) compared to controls. Among all of the variables, a lower level of anxiety (t = -1.99), positive attitudes toward sex (t = 2.05), watching erotic videos (t = 5.58) and a higher importance of sex (t = 5.66) were predictive of better sexual function (R2–0.38, F = 28.9, p = 0.0001).

Conclusion

Sexual behaviors and function are different in those using OCCP compared to nonusers. The prevalence of sexual problems and dysfunction was higher in those using this hormonal method of contraception; however, using OCCP was not a risk factor for either worse sexual function or sexual dysfunction. Partners’ attitudes toward sex and general anxiety level were factors contributing to sexual function and the risk of sexual dysfunction in the population of women of reproductive age and should be routinely evaluated in clinical practice, especially before prescribing hormonal contraceptives.
Determinants and reasons for switching anti-retroviral regimen among HIV-infected youth in a large township of South Africa (2002–2019)
Authors: Kabarambi Anita , Balinda Sheila , Abaasa Andrew , Cogill Dolphina , Orrell Catherine
Published: June 2022

Background

There are limited data exploring antiretroviral therapy (ART) changes and time to change among South Africa young people living with HIV/AIDS.

Objective

We describe the time to first drug switch, which includes ART regimen change (three drug switch) and substitutions (single drug switch). We describe common reasons for ART switch among young people aged 10 to 24 years in South Africa.

Methods

We conducted a retrospective cohort study at a primary health care clinic in Cape Town, South Africa, providing ART to HIV-infected adolescents and adults since 2002. Those aged 10 to 24 years at ART initiation, who accessed care clinic between September 2002 and April 2019. Data was retrieved from electronic information systems: ART regimens, ART changes, dates for initiation or stop of each drug/regimen, laboratory results (viral loads, haemoglobin, liver enzyme results, and creatinine to support the reason for ART switch. From written records, we abstracted reason for single drug switch or regimen change, as well as socio demographic and clinical data. We fitted cox regression models to determine factors associated with ART switch (Having a change in one or more drugs in ART combination) and the rate of occurrence.

Results

Of 2601 adolescents included, 605 (24.9%) adolescents switched ART over 5090.5 person years at risk (PYAR), a rate of 11.9 /100PYAR. Median follow-up time was 4.4 (± 3.2) years. At multivariable analysis, the older age group was protective of the risk of ART switch: adjusted Hazard Ratio [aHR] 0.78, 95% CI 0.62–0.98, transfer status [transferred out 1.42 [1.11–1.82]. The hazard of ART switch increased with more severe HIV-disease at ART start, as observed by increasing WHO clinical stage or reduced CD4 count at baseline. The primary reasons for ART switch were side effects (20.0%), virological failure (17.9%) and formulation switch (27.8%). Others reasons included pregnancy, Hepatitis B, tuberculosis and psychosis.

Conclusion

ART switches are frequent and occur at a consistent rate across 7.5 years from initiation. The main reasons for ART switch were virological failure and drug side effects.
Expanding anti-CD38 immunotherapy for lymphoid malignancies
Authors: Wang Xu , Yu Xinfang , Li Wei , Neeli Praveen , Liu Ming , Li Ling , Zhang Mingzhi , Fang Xiaosheng , Young Ken H. , Li Yong
Published: June 2022

Background

Lymphoid neoplasms, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and NK/T cell neoplasms, are a major cause of blood cancer morbidity and mortality. CD38 (cyclic ADP ribose hydrolase) is a transmembrane glycoprotein expressed on the surface of plasma cells and MM cells. The high expression of CD38 across MM and other lymphoid malignancies and its restricted expression in normal tissues make CD38 an attractive target for immunotherapy. CD38-targeting antibodies, like daratumumab, have been approved for the treatment of MM and tested against lymphoma and leukemia in multiple clinical trials.

Methods

We generated chimeric antigen receptor (CAR) T cells targeting CD38 and tested its cytotoxicity against multiple CD38high and CD38low lymphoid cancer cells. We evaluated the synergistic effects of all-trans retinoic acid (ATRA) and CAR T cells or daratumumab against cancer cells and xenograft tumors.

Results

CD38-CAR T cells dramatically inhibited the growth of CD38high MM, mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia (WM), T-cell acute lymphoblastic leukemia (T-ALL), and NK/T-cell lymphoma (NKTCL) in vitro and in mouse xenografts. ATRA elevated CD38 expression in multiple CD38low cancer cells and enhanced the anti-tumor activity of daratumumab and CD38-CAR T cells in xenograft tumors.

Conclusions

These findings may expand anti-CD38 immunotherapy to a broad spectrum of lymphoid malignancies and call for the incorporation of ATRA into daratumumab or other anti-CD38 immunological agents for cancer therapy.
Mental and psychosocial health among youth after their first psychiatric hospitalization: a feasibility study
Authors: Ferro Mark A. , Chan Christy K. Y. , Vanderkooy John D. , Horricks Laurie , Duncan Laura , Lipman Ellen L.
Published: June 2022

Objective

This pilot study investigated the feasibility of studying 12-month readmission of youth aged 10–16 years following their first psychiatric hospitalization and changes in youth mental and psychosocial health prospectively.

Results

Inpatient youth with a first psychiatric hospitalization and their parents were recruited from a regional hospital in Canada. Data were collected at recruitment, and at 3-, 6-, and 12-months post-discharge. Repeated measures ANOVA was performed to assess changes in health outcomes. Nineteen eligible youth were approached and 15 (78.9%) consented to participate (13.9 ± 2.0 years, 73.3% female). Eleven youth (73.3%) gave permission to contact their parents, all of whom participated (39.2 ± 7.6 years). Four youth dropped out of the study (26.7%) and six youth-parent dyads completed all four follow-ups. The readmission rate was 20.0% (n = 3) over 12 months. Significant changes in youth-reported symptoms of conduct disorder (F = 3.0, p = 0.06) and adverse childhood experiences (F = 3.4, p = 0.05) were found. Changes in parent-reported youth mental health symptoms (F = 3.1, p = 0.06), particularly among internalizing disorders, youth health-related quality of life (F = 11.3, p < 0.01), and youth disability (F = 2.7, p = 0.08) were significant. This preliminary work demonstrates the feasibility of, and need to, engage youth and their families to understand their mental and psychosocial health during this vulnerable period of time.
Narrative elaboration makes misinformation and corrective information regarding COVID-19 more believable
Authors: Greer Joanna , Fitzgerald Kaitlyn , Vijaykumar Santosh
Published: June 2022

Objective

People gather information about health topics from online channels oftentimes awash with misinformation. Investigating this problem during the COVID-19 pandemic is important, as the misinformation effect occurs when misleading details are embedded in narratives and questions. This pilot study investigated whether narrative elaboration increases believability in misinformation statements about COVID-19, and willingness to share these statements online.

Results

Results from our online survey (n = 80) demonstrated that narrative elaboration increased believability in both misinformation and accurate statements, with a more pronounced effect on younger adults. Future research may investigate cognitive vulnerabilities imposed by elaborate narratives embedded in online health misinformation with increased attention on developing misinformation resilience among younger adults.
Investigation of the location and secretion features of Candida albicans enolase with monoclonal antibodies
Authors: He Zhengxin , Piao Jingzi , Qiu Yanguang , Lei Daxin , Yang Yanhui , Shi Lanchun , Wang Fukun
Published: June 2022

Purpose

The glycolytic enzyme enolase plays important role in the pathogenesis of Candida albicans infection and has been also considered as a promising molecular marker for the diagnosis of invasive candidiasis. This study aimed to investigate the location and secretion features of Candida albicans enolase (CaEno) with a couple of specific monoclonal antibodies (mAbs).

Methods

Two mAbs named 9H8 and 10H8 against CaEno were generated by fusing SP2/0 myeloma cell with the spleen lymphocytes from CaEno immunized mice. The specificity of the mAbs was then validated by Western blot and liquid chromatography-mass spectrometry (LC–MS/MS). A diverse set of experiments were conducted based on the pair of mAbs which involved immunohistochemical staining analysis, whole cell enzyme-linked immunosorbent assay (ELISA), double antibody sandwich ELISA, and confocal microscopy to analyze the possible location and secretion features of CaEno.

Results

CaEno is abundantly expressed in the cytoplasm of C. albicans blastospores and is distributed in a ring-shaped pattern along the cell wall. CaEno appeared in the hyphal C. albicans as just a “mushroom” form. CaEno was found to be weakly expressed on the surface of blastospores but constantly expressed at various stages of growth. CaEno concentrations in C. albicans blastospores culture supernatant are considerably higher than in C. albicans hyphae culture supernatant. The dynamic changes of supernatant CaEno concentration in blastospores and hyphal C. albicans exhibit distinct features, although both appear to be associated with the C. albicans growth state. When cultivated under normal circumstances, however, no apparent CaEno degradation was seen in the cell-free supernatant.

Conclusion

Our results implied that CaEno was constantly expressed on the cell surface and its secretion features varied according to the growth stage of C. albicans. However, further experimental and theoretical studies are needed in future to identify the specific mechanisms by which this phenomenon can arise.
Oncostatin M receptor regulates osteoblast differentiation via extracellular signal-regulated kinase/autophagy signaling
Authors: Zhou Jie , Yang Junying , Dong Yuan , Shi Yaru , Zhu Endong , Yuan Hairui , Li Xiaoxia , Wang Baoli
Published: June 2022

Background

Oncostatin M receptor (OSMR), as one of the receptors for oncostatin M (OSM), has previously been shown to mediate the stimulatory role of OSM in osteoclastogenesis and bone resorption. However, it remains to be clarified whether and how OSMR affects the differentiation of osteoblasts.

Methods

The expression level of OSMR during osteoblast and adipocyte differentiation was examined. The role of OSMR in the differentiation was investigated using in vitro gain-of-function and loss-of-function experiments. The mechanisms by which OSMR regulates bone cell differentiation were explored. Finally, in vivo function of OSMR in cell fate determination and bone homeostasis was studied after transplantation of OSMR-silenced bone marrow stromal cells (BMSCs) to the marrow of ovariectomized mice.

Results

OSMR was regulated during osteogenic and adipogenic differentiation of marrow stromal progenitor cells and increased in the metaphysis of ovariectomized mice. OSMR suppressed osteogenic differentiation and stimulated adipogenic differentiation of progenitor cells. Mechanistic investigations showed that OSMR inhibited extracellular signal-regulated kinase (ERK) and autophagy signaling. The downregulation of autophagy, which was mediated by ERK inhibition, suppressed osteogenic differentiation of progenitor cells. Additionally, inactivation of ERK/autophagy signaling attenuated the stimulation of osteogenic differentiation induced by Osmr siRNA. Furthermore, transplantation of BMSCs in which OSMR was silenced to the marrow of mice promoted osteoblast differentiation, attenuated fat accumulation and osteoclast differentiation, and thereby relieved the osteopenic phenotype in the ovariectomized mice.

Conclusions

Our study has for the first time established the direct role of OSMR in regulating osteogenic differentiation of marrow stromal progenitor cells through ERK-mediated autophagy signaling. OSMR thus contributes to bone homeostasis through dual regulation of osteoblasts and osteoclasts. It also suggests that OSMR may be a potential target for the treatment of metabolic disorders such as osteoporosis.
Engrafted glial progenitor cells yield long-term integration and sensory improvement in aged mice
Authors: Yang Zhiqi , Gong Mingyue , Jian Tingliang , Li Jin , Yang Chuanyan , Ma Qinlong , Deng Ping , Wang Yuxia , Huang Mingzhu , Wang Haoyu , Yang Shaofan , Chen Xiaowei , Yu Zhengping , Wang Manxia , Chen Chunhai , Zhang Kuan
Published: June 2022

Aging causes astrocyte morphological degeneration and functional deficiency, which impairs neuronal functions. Until now, whether age-induced neuronal deficiency could be alleviated by engraftment of glial progenitor cell (GPC) derived astrocytes remained unknown. In the current study, GPCs were generated from embryonic cortical neural stem cells in vitro and transplanted into the brains of aged mice. Their integration and intervention effects in the aged brain were examined 12 months after transplantation. Results indicated that these in-vitro-generated GPC-derived astrocytes possessed normal functional properties. After transplantation they could migrate, differentiate, achieve long-term integration, and maintain much younger morphology in the aged brain. Additionally, these GPC-derived astrocytes established endfeet expressing aquaporin-4 (AQP4) and ameliorate AQP4 polarization in the aged neocortex. More importantly, age-dependent sensory response degeneration was reversed by GPC transplantation. This work demonstrates that rejuvenation of the astrocyte niche is a promising treatment to prevent age-induced degradation of neuronal and behavioral functions.
DNA methyltransferase 1 knockdown reverses PTEN and VDR by mediating demethylation of promoter and protects against renal injuries in hepatitis B virus-associated glomerulonephritis
Authors: Guan Haochen , Zhu Nan , Tang Gang , Du Yi , Wang Ling , Yuan Weijie
Published: June 2022

Background

Aberrant DNA methylation patterns, including hypermethylation of key genes that inhibit fibrosis and inflammation, have been described in human kidney diseases. However, the role of DNA methyltransferase 1 (DNMT1) in hepatitis B virus-associated glomerulonephritis (HBV-GN) remains unclear.

Methods

We explored the underlying mechanism by establishing HBV X protein (HBx) overexpressing renal tubular epithelial (HK-2) cells and human podocytes with DNMT1 knockdown. Using RNA-sequencing to determine the downstream targets of DNMT1 and evaluate its levels of promoter methylation. HBV transgenic mice were used to examine the effects of DNMT1 inhibitor on renal in vivo.

Results

DNMT1 was significantly upregulated in the renal tissue of HBV-GN patients, accompanied by injuries of HK-2 cells and podocytes. HBx markedly upregulated DNMT1 and induced epithelial-mesenchymal transition (EMT) and inflammation in HK-2 cells and human podocytes. This increased DNMT1 expression was attenuated after DNMT1 knockdown, accompanied by restored HK-2 cells and podocyte injuries resulting from the activation of PI3K/Akt/mTOR and nuclear factor-kappa B (NF-κB) pathways. Hypermethylation of the phosphatase and tensin homolog (PTEN) promoter and vitamin D receptor (VDR) was induced in HBx-overexpressing HK-2 cells and podocytes, respectively, whereas DNMT1 knockdown effectively corrected these alterations. Furthermore, PTEN and VDR ablation resulted in marked EMT and inflammation induction in HBx-overexpressing HK-2 cells and human podocytes even with DNMT1 knockdown. Downregulation of the PI3K/Akt/mTOR-related pathway attenuated HBx-induced EMT and inflammation in HK-2 cells. Luciferase reporter assay revealed VDR as a direct target of the Snail family transcriptional repressor 1 (SNAI1) in HBx-overexpressing podocytes. DNA methylation inhibitor 5-azacytidine alleviated urinary protein and renal inflammation in HBV transgenic mice via PTEN-PI3K/Akt signaling and VDR signaling axis.

Conclusions

Our study clarifies the potential epigenetic mechanisms underlying HBx-induced renal injuries in HBV-GN and the renoprotective effects of inhibiting DNMT1, which can provide important insights into the development of treatments for HBV-GN.
Novel insights into non-alcoholic fatty liver disease and dementia: insulin resistance, hyperammonemia, gut dysbiosis, vascular impairment, and inflammation
Authors: Cheon So Yeong , Song Juhyun
Published: June 2022

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease characterized by multiple pathologies. The progression of dementia with NAFLD may be affected by various risk factors, including brain insulin resistance, cerebrovascular dysfunction, gut dysbiosis, and neuroinflammation. Many recent studies have focused on the increasing prevalence of dementia in patients with NAFLD. Dementia is characterized by cognitive and memory deficits and has diverse subtypes, including vascular dementia, Alzheimer’s dementia, and diabetes mellitus-induced dementia. Considering the common pathological features of NAFLD and dementia, further studies on the association between them are needed to find appropriate therapeutic solutions for diseases. This review summarizes the common pathological characteristics and mechanisms of NAFLD and dementia. Additionally, it describes recent evidence on association between NAFLD and dementia progression and provides novel perspectives with regard to the treatment of patients with dementia secondary to NAFLD.
Exact recovery of sparse signals with side information
Authors: Luo Xiaohu , Feng Nianci , Guo Xuhui , Zhang Zili
Published: June 2022

Compressed sensing has captured considerable attention of researchers in the past decades. In this paper, with the aid of the powerful null space property, some deterministic recovery conditions are established for the previous $$\ell _{1}$$

ℓ
1

–$$\ell _{1}$$

ℓ
1

method and the $$\ell _{1}$$

ℓ
1

–$$\ell _{2}$$

ℓ
2

method to guarantee the exact sparse recovery when the side information of the desired signal is available. These obtained results provide a useful and necessary complement to the previous investigation of the $$\ell _{1}$$

ℓ
1

–$$\ell _{1}$$

ℓ
1

and $$\ell _{1}$$

ℓ
1

–$$\ell _{2}$$

ℓ
2

methods that are based on the statistical analysis. Moreover, one of our theoretical findings also shows that the sharp conditions previously established for the classical $$\ell _{1}$$

ℓ
1

method remain suitable for the $$\ell _{1}$$

ℓ
1

–$$\ell _{1}$$

ℓ
1

method to guarantee the exact sparse recovery. Numerical experiments on both the synthetic signals and the real-world images are also carried out to further test the recovery performance of the above two methods.
The deception effect of FDA counteracting amplitude-comparison monopulse reconnaissance
Authors: Ge Jiaang , Xie Junwei
Published: June 2022

Conventional phased array radar can direct the high-gain beam, resulting in high visibility under the reconnaissance system and even direct exposure to the enemy. As an amplitude-based direction-finding system, the amplitude monopulse system can recognize the traditional radar signals. However, there are still some issues with the countermeasures of the monopulse system, so it is necessary to find better styles of jamming. Since the beam of the frequency diverse array (FDA) signal at a certain angle varies with the range, we studied the deception effect of the FDA against the amplitude-comparison monopulse direction-finding system. By analyzing the established FDA-based direction-of-arrival location deception model against the amplitude-comparison monopulse system, we found that the introduction of the frequency increment might cause the FDA signals to deceit the monopulse system in principle. Then, to indicate the superiority of our deception method, we obtain the instantaneous signal-to-noise ratio, Cramér–Rao lower bound, root-means-square error, and variation. Numerical simulation results demonstrate that the FDA can generate deceptive signals to counteract the amplitude-comparison monopulse direction-finding system.
Blowup for semilinear wave equation with space-dependent damping and combined nonlinearities
Authors: Yao Jiangyan , Ming Sen , Fan Xiongmei
Published: June 2022

This paper is concerned with the Cauchy problem for semilinear wave equation with space-dependent scattering damping and combined nonlinearities. The blowup results of solution are established by introducing proper test functions. Moreover, upper bound lifespan estimates of a solution to the Cauchy problem with small initial values are derived. To the best of our knowledge, the results in Theorems 1.1–1.2 are new.
Towards developing innovation management framework (IMF) for ICT organizations at Pakistan
Authors: Abbasi Eram , Amin Imran , Siddiqui Shama
Published: June 2022

Various aspects of innovation management have been discussed in literature over the past few decades. Most of the innovation management frameworks have been formulated by undertaking studies in the developed world and lack the industry/culture specific focus. In this paper, we revisit the generic innovation management studies to develop an innovation management framework for highlighting the factors affecting innovation specifically at the Information Communication Technology (ICT) sector of Pakistan. A detailed literature review has been conducted to identify the factors included in the past innovation management models. To identify the factors specific for Pakistan, senior-level professionals, working at the Pakistani ICT organizations were interviewed based on a survey. A comparative analysis of the innovation management frameworks for Pakistan against those previously found in literature revealed interesting similarities and differences. Based on the study findings, an innovation management framework is developed that highlights the present factors which are important for innovation in the ICT sector for Pakistan. This framework can be used by Pakistan and other underdeveloped countries for improving their innovation in ICT sectors in particular and other sectors in general.