bluuebunny/crossref_metadata_2025 huggingface dataset:
The Association between Polluted Neighborhoods andTP53-Mutated Non–Small Cell Lung Cancer
Authors: Erhunmwunsee Loretta , Wing Sam E. , Shen Jenny , Hu Hengrui , Sosa Ernesto , Lopez Lisa N. , Raquel Catherine , Sur Melissa , Ibarra-Noriega Pilar , Currey Madeline , Lee Janet , Kim Jae Y. , Raz Dan J. , Amini Arya , Sampath Sagus , Koczywas Marianna , Massarelli Erminia , West Howard L. , Reckamp Karen L. , Kittles Rick A. , Salgia Ravi , Seewaldt Victoria L. , Neuhausen Susan L. , Gray Stacy W.
Published: June 2021

Background:

Poor patients often reside in neighborhoods of lower socioeconomic status (SES) with high levels of airborne pollutants. They also have higher mortality from non–small cell lung cancer (NSCLC) than those living in wealthier communities. We investigated whether living in polluted neighborhoods is associated with somatic mutations linked with lower survival rates, i.e., TP53 mutations.

Methods:

In a retrospective cohort of 478 patients with NSCLC treated at a comprehensive cancer center between 2015 and 2018, we used logistic regression to assess associations between individual demographic and clinical characteristics, including somatic TP53 mutation status and environmental risk factors of annual average particulate matter (PM2.5) levels, and neighborhood SES.

Results:

277 patients (58%) had somatic TP53 mutations. Of those, 45% lived in neighborhoods with “moderate” Environmental Protection Agency–defined PM2.5 exposure, compared with 39% of patients without TP53 mutations. We found significant associations between living in neighborhoods with “moderate” versus “good” PM2.5 concentrations and minority population percentage [OR, 1.06; 95% confidence interval (CI), 1.04–1.08]. There was a significant association between presence of TP53 mutations and PM2.5 exposure (moderate versus good: OR, 1.66; 95% CI, 1.02–2.72) after adjusting for patient characteristics, other environmental factors, and neighborhood-level SES.

Conclusions:

When controlling for individual- and neighborhood-level confounders, we find that the odds of having a TP53-mutated NSCLC are increased in areas with higher PM2.5 exposure.

Impact:

The link between pollution and aggressive biology may contribute to the increased burden of adverse NSCLC outcomes in individuals living in lower SES neighborhoods.
Polyunsaturated Fatty Acid Levels and the Risk of Keratinocyte Cancer: A Mendelian Randomization Analysis
Authors: Seviiri Mathias , Law Matthew H. , Ong Jue Sheng , Gharahkhani Puya , Nyholt Dale R. , Olsen Catherine M. , Whiteman David C. , MacGregor Stuart
Published: June 2021

Background:

Keratinocyte cancer is the commonest cancer, imposing a high economic burden on the health care system. Observational studies have shown mixed associations between polyunsaturated fatty acids (PUFA) and keratinocyte cancer, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). We explored whether genetically predicted PUFA levels are associated with BCC and SCC risks.

Methods:

We conducted a two-sample Mendelian randomization study using PUFA level genome-wide association studies (GWAS) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n > 8,000), and the meta-analysis GWASs from UKB, 23andMe, and Qskin for BCC (n = 651,138) and SCC (n = 635,331) risk.

Results:

One SD increase in genetically predicted levels of linoleic acid [OR = 0.94, 95% confidence interval (CI) = 0.91–0.97, P = 1.4 × 10–4] and alpha-linolenic acid (OR = 0.91, 95% CI = 0.86–0.96, P = 5.1 × 10–4) was associated with a reduced BCC risk, while arachidonic acid (OR = 1.04, 95% CI = 1.02–1.06, P = 3.2 × 10–4) and eicosapentaenoic acid (OR = 1.10, 95% CI = 1.04–1.16, P = 1.5 × 10–3) were associated with an increased BCC risk.

Conclusions:

Higher genetically predicted levels of linoleic acid and alpha-linolenic acid were associated with a reduced BCC risk, but arachidonic acid and eicosapentaenoic acid were associated with a higher BCC risk.

Impact:

PUFA-related diet and supplementation could influence BCC etiology.
Long-term Follow-up and Correlative Analysis of Two Phase II Trials of Rituximab and Lenalidomide Followed by Continuous Lenalidomide in Untreated and Relapsed/Refractory Indolent Lymphoma
Authors: Tuscano Joseph M. , Poh Christina , Kaesberg Paul , Luxardi Guilluame , Merleev Alexander , Marusina Alina , Brunson Ann , Rosenberg Aaron , Jonas Brian , Maverakis Emanual
Published: June 2021

Purpose:

Rituximab and lenalidomide are effective for previously untreated and relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). However, long-term survival and predictive biomarkers are not well described.

Patients and Methods:

We conducted two phase II open-label trials involving 60 patients with previously untreated and R/R advanced-stage iNHL. Patients received lenalidomide and rituximab induction followed by continuous lenalidomide until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Correlative studies included plasma cytokine monitoring, flow cytometry of peripheral blood mononuclear cells (PBMC; days 0, 15, 30, and 60), and RNA sequencing (RNA-seq) of pretreatment tumor biopsies.

Results:

At a median follow-up of 63 months for previously untreated and 100 months for R/R, ORR was 82% for both. The 11 R/R patients who achieved complete remission remained in continuous remission for 16 to 141 months, thereafter. Median overall survival (OS) was not reached in the previously untreated and was 140 months (95% confidence interval, 53.4–140) in the R/R group. A mixed-effects linear regression model identified significant associations between Granzyme B+ (GranB+) CD8+ T cells and long-term complete response (LTCR; P = 5.3e-4). Furthermore, prior to start of therapy, treatment response could be predicted by B-cell and GranB+ CD8+ T-cell levels (% total lymphocytes).

Conclusions:

Rituximab plus lenalidomide followed by continuous lenalidomide is effective with manageable toxicity in patients with previously untreated and R/R iNHL. This regimen produces durable remissions, even in heavily pretreated patients, with some lasting greater than 10 years. GranB+ CD8+ T cells, B cells, and plasma IFNγ allowed prediction of LTCR but need validation in larger trials.
An Open-Source, Automated Tumor-Infiltrating Lymphocyte Algorithm for Prognosis in Triple-Negative Breast Cancer
Authors: Bai Yalai , Cole Kimberly , Martinez-Morilla Sandra , Ahmed Fahad Shabbir , Zugazagoitia Jon , Staaf Johan , Bosch Ana , Ehinger Anna , Nimeus Emma , Hartman Johan , Acs Balazs , Rimm David L.
Published: June 2021

Purpose:

Although tumor-infiltrating lymphocytes (TIL) assessment has been acknowledged to have both prognostic and predictive importance in triple-negative breast cancer (TNBC), it is subject to inter and intraobserver variability that has prevented widespread adoption. Here we constructed a machine-learning based breast cancer TIL scoring approach and validated its prognostic potential in multiple TNBC cohorts.

Experimental Design:

Using the QuPath open-source software, we built a neural-network classifier for tumor cells, lymphocytes, fibroblasts, and “other” cells on hematoxylin–eosin (H&E)–stained sections. We analyzed the classifier-derived TIL measurements with five unique constructed TIL variables. A retrospective collection of 171 TNBC cases was used as the discovery set to identify the optimal association of machine-read TIL variables with patient outcome. For validation, we evaluated a retrospective collection of 749 TNBC patients comprised of four independent validation subsets.

Results:

We found that all five machine TIL variables had significant prognostic association with outcomes (P ≤ 0.01 for all comparisons) but showed cell-specific variation in validation sets. Cox regression analysis demonstrated that all five TIL variables were independently associated with improved overall survival after adjusting for clinicopathologic factors including stage, age, and histologic grade (P ≤ 0.0003 for all analyses).

Conclusions:

Neural net-driven cell classifier-defined TIL variables were robust and independent prognostic factors in several independent validation cohorts of TNBC patients. These objective, open-source TIL variables are freely available to download and can now be considered for testing in a prospective setting to assess clinical utility.

See related commentary by Symmans, p. 5446
Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA
Authors: Chen Xiaoji , Dong Zhao , Hubbell Earl , Kurtzman Kathryn N. , Oxnard Geoffrey R. , Venn Oliver , Melton Collin , Clarke Christina A. , Shaknovich Rita , Ma Ting , Meixiong Gerry , Seiden Michael V. , Klein Eric A. , Fung Eric T. , Liu Minetta C.
Published: June 2021

Purpose:

We recently reported the development of a cell-free DNA (cfDNA) targeted methylation (TM)-based sequencing approach for a multi-cancer early detection (MCED) test that includes cancer signal origin prediction. Here, we evaluated the prognostic significance of cancer detection by the MCED test using longitudinal follow-up data.

Experimental Design:

As part of a Circulating Cell-free Genome Atlas (CCGA) substudy, plasma cfDNA samples were sequenced using a TM approach, and machine learning classifiers predicted cancer status and cancer signal origin. Overall survival (OS) of cancer participants in the first 3 years of follow-up was evaluated in relation to cancer detection by the MCED test and clinical characteristics.

Results:

Cancers not detected by the MCED test had significantly better OS (P < 0.0001) than cancers detected, even after accounting for other covariates, including clinical stage and method of clinical diagnosis (i.e., standard-of-care screening or clinical presentation with signs/symptoms). Additionally, cancers not detected by the MCED test had better OS than was expected when data were adjusted for age, stage, and cancer type from the Surveillance, Epidemiology, and End Results (SEER) program. In cancers with current screening options, the MCED test also differentiated more aggressive cancers from less aggressive cancers (P < 0.0001).

Conclusions:

Cancer detection by the MCED test was prognostic beyond clinical stage and method of diagnosis. Cancers not detected by the MCED test had better prognosis than cancers detected and SEER-based expected survival. Cancer detection and prognosis may be linked by the underlying biological factor of tumor fraction in cfDNA.
Venetoclax-based Rational Combinations are Effective in Models of MYCN-amplified Neuroblastoma
Authors: Dalton Krista M. , Krytska Kateryna , Lochmann Timothy L. , Sano Renata , Casey Colleen , D'Aulerio Alessia , Khan Qasim A. , Crowther Giovanna Stein , Coon Colin , Cai Jinyang , Jacob Sheeba , Kurupi Richard , Hu Bin , Dozmorov Mikhail , Greninger Patricia , Souers Andrew J. , Benes Cyril H. , Mossé Yael P. , Faber Anthony C.
Published: June 2021

Venetoclax is a small molecule inhibitor of the prosurvival protein BCL-2 that has gained market approval in BCL-2–dependent hematologic cancers including chronic lymphocytic leukemia and acute myeloid leukemia. Neuroblastoma is a heterogenous pediatric cancer with a 5-year survival rate of less than 50% for high-risk patients, which includes nearly all cases with amplified MYCN. We previously demonstrated that venetoclax is active in MYCN-amplified neuroblastoma but has limited single-agent activity in most models, presumably the result of other pro-survival BCL-2 family protein expression or insufficient prodeath protein mobilization. As the relative tolerability of venetoclax makes it amenable to combining with other therapies, we evaluated the sensitivity of MYCN-amplified neuroblastoma models to rational combinations of venetoclax with agents that have both mechanistic complementarity and active clinical programs. First, the MDM2 inhibitor NVP-CGM097 increases the prodeath BH3-only protein NOXA to sensitize p53-wild-type, MYCN-amplified neuroblastomas to venetoclax. Second, the MCL-1 inhibitor S63845 sensitizes MYCN-amplified neuroblastoma through neutralization of MCL-1, inducing synergistic cell killing when combined with venetoclax. Finally, the standard-of-care drug cocktail cyclophosphamide and topotecan reduces the apoptotic threshold of neuroblastoma, thus setting the stage for robust combination efficacy with venetoclax. In all cases, these rational combinations translated to in vivo tumor regressions in MYCN-amplified patient-derived xenograft models. Venetoclax is currently being evaluated in pediatric patients in the clinic, including neuroblastoma (NCT03236857). Although establishment of safety is still ongoing, the data disclosed herein indicate rational and clinically actionable combination strategies that could potentiate the activity of venetoclax in patients with amplified MYCN with neuroblastoma.
EMT-Derived Alterations in Glutamine Metabolism Sensitize Mesenchymal Breast Cells to mTOR Inhibition
Authors: Karvelsson Sigurdur Trausti , Sigurdsson Arnar , Seip Kotryna , Grinde Maria Tunset , Wang Qiong , Johannsson Freyr , Mælandsmo Gunhild Mari , Moestue Siver Andreas , Rolfsson Ottar , Halldorsson Skarphedinn
Published: June 2021

Epithelial-to-mesenchymal transition (EMT) is a fundamental developmental process with strong implications in cancer progression. Understanding the metabolic alterations associated with EMT may open new avenues of treatment and prevention. Here we used 13C carbon analogs of glucose and glutamine to examine differences in their utilization within central carbon and lipid metabolism following EMT in breast epithelial cell lines. We found that there are inherent differences in metabolic profiles before and after EMT. We observed EMT-dependent re-routing of the TCA-cycle, characterized by increased mitochondrial IDH2-mediated reductive carboxylation of glutamine to lipid biosynthesis with a concomitant lowering of glycolytic rates and glutamine-dependent glutathione (GSH) generation. Using weighted correlation network analysis, we identified cancer drugs whose efficacy against the NCI-60 Human Tumor Cell Line panel is significantly associated with GSH abundance and confirmed these in vitro. We report that EMT-linked alterations in GSH synthesis modulate the sensitivity of breast epithelial cells to mTOR inhibitors.

Implications:

EMT in breast cells causes an increased demand for glutamine for fatty acid biosynthesis, altering its contribution to glutathione biosynthesis, which sensitizes the cells to mTOR inhibitors.
Impact of Obesity and Heavy Alcohol Consumption on Hepatocellular Carcinoma Development after HCV Eradication with Antivirals
Authors: Minami Tatsuya , Tateishi Ryosuke , Fujiwara Naoto , Nakagomi Ryo , Nakatsuka Takuma , Sato Masaya , Uchino Koji , Enooku Kenichiro , Nakagawa Hayato , Fujinaga Hidetaka , Izumiya Masashi , Hanajiri Kazuyuki , Asaoka Yoshinari , Kondo Yuji , Tanaka Yasuo , Otsuka Motoyuki , Ohki Takamasa , Arai Masahiro , Tanaka Atsushi , Yasuda Kiyomi , Miura Hideaki , Ogata Itsuro , Kamoshida Toshiro , Inoue Kazuaki , Koike Yukihiro , Akamatsu Masatoshi , Mitsui Hiroshi , Fujie Hajime , Ogura Keiji , Yoshida Hideo , Wada Tomonori , Kurai Kiyohiko , Maekawa Hisato , Obi Shuntaro , Teratani Takuma , Masaki Naohiko , Nagashima Kayo , Ishikawa Takashi , Kato Naoya , Moriya Kyoji , Yotsuyanagi Hiroshi , Koike Kazuhiko ,   SMART-C Investigators
Published: June 2021

Background and Aims: It remains unclear whether obesity increases the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C who achieved a sustained virological response (SVR) with antiviral therapy. Methods: In this multicenter cohort study, we enrolled patients with chronic hepatitis C who achieved SVR with interferon (IFN)-based therapy (IFN group) or direct-acting antiviral (DAA) therapy (DAA group) between January 1, 1990, and December 31, 2018. The patients underwent regular surveillance for HCC. Cumulative incidence of and the risk factors for HCC development after SVR were assessed using the Kaplan-Meier method and Cox proportional hazard regression analysis, respectively. Results: Among 2,055 patients (840 in the IFN group and 1,215 in the DAA group), 75 developed HCC (41 in the IFN group and 34 in the DAA group) during the mean observation period of 4.1 years. The incidence rates of HCC at 1, 2, and 3 years were 1.2, 1.9, and 3.0%, respectively. Multivariate analysis revealed that in addition to older age, lower albumin level, lower platelet count, higher alpha-fetoprotein level, and absence of dyslipidemia, obesity (body mass index ≥25 kg/m2) and heavy alcohol consumption (≥60 g/day) were independent risk factors for HCC development, with adjusted hazard ratio (HR) of 2.53 (95% confidence interval [CI]: 1.51–4.25) and 2.56 (95% CI: 1.14–5.75), respectively. The adjusted HR was not significant between the 2 groups (DAA vs. IFN; HR 1.19, 95% CI: 0.61–2.33). Conclusions: Obesity and heavy alcohol consumption increased the risk of HCC development after SVR.
Nuclear Factor Erythroid 2-Related Factor 2-Histone Deacetylase 2 Pathway in the Pathogenesis of Refractory Sudden Sensorineural Hearing Loss and Glucocorticoid Resistance
Authors: Qi Hui , Gao Zi-Wen , Hou Jie , Zhou Qiongqiong , Ma Wei , Dai Yan-Hong , She Wan-Dong
Published: June 2021

Introduction: A significant number of sensorineural hearing loss (SSNHL) patients had no noticeable hearing improvement after glucocorticoid (GC) treatment. In the present study, we examined expression of the nuclear factor erythroid 2-related factor 2 (NRF2) and histone deacetylase 2 (HDAC2) in peripheral blood mononuclear cells (PBMCs) of refractory SSNHL patients to study the role of NRF2-HDAC2 pathway in GC insensitivity hearing improvement after GC treatment, which is usually referred to as refractory SSNHL or GC insensitivity. Materials and Methods: Forty-four refractory SSNHL patients were treated by intratympanic GC infusion. Hearing was tested in all patients before and after treatment by pure tone hearing test. NRF2/HDAC2 mRNA and protein levels were examined in PBMCs of refractory SSNHL patients before and after treatment. PBMCs from healthy volunteers were used as normal controls. Results: According to the hearing improvement after treatment, patients were assigned into 2 groups: the intratympanic GC sensitive (IGCS) group (hearing recovery ≥15 dB HL) and the intratympanic GC insensitive (IGCI) group (hearing recovery <15 dB HL). Before treatment, the NRF2 mRNA level was lower in all patients than the normal control group. After treatment, NRF2 and HDAC2 mRNA and protein levels were increased in the IGCS group, while no significant change was observed in the IGCI group. Conclusion: Low response of NRF2/HDAC2 proteins is associated with GC insensitivity in SSNHL. We speculate that the NRF2-HDAC2 pathway affects GC sensitivity in SSNHL patients.
Long-Term Effectiveness and Drug Survival of Apremilast in Treating Psoriasis: A Real-World Experience
Authors: Distel Julian , Cazzaniga Simone , Seyed Jafari S. Morteza , Emelianov Vladimir , Schlapbach Christoph , Yawalkar Nikhil , Heidemeyer Kristine
Published: June 2021

Background: Apremilast is an oral phosphodiesterase 4 (PDE4) inhibitor used for the treatment of moderate to severe psoriasis. Long-term data on the effectiveness and drug survival of patients treated with apremilast are limited. Objective: The aim of this study was to analyze the characteristics, effectiveness, and drug survival of patients treated with apremilast in a real-world setting. Methods: We conducted a retrospective cohort study of patients with psoriasis who received at least 1 dose of apremilast between 2015 and 2018. We documented sex; age; type, duration, and severity (using Psoriasis Area Severity Index [PASI] and Dermatology Life Quality Index [DLQI]) of psoriasis; comorbidities; previous treatment modalities; adverse events; and reasons for therapy discontinuation. For drug survival, estimates and efficacy analysis with Kaplan-Meier statistics were used. Results: The drug survival rate of the 93 reviewed patients was 69.5% at 6 months, 34.7% at 12 months, and 25.8% at 24 months after initiating therapy. The median survival duration was 8.0 months. Therapy was discontinued in 66.6 and 27.8% due to loss of efficacy and adverse events, respectively. At 24 months, 35.9% had achieved PASI75 response and 23.7% had achieved PASI90 response. Most observed adverse events were gastrointestinal issues, weight loss, and headache. Conclusions: Apremilast is an effective and well-tolerated therapy for patients with moderate to severe psoriasis, especially for patients with difficult-to-treat locations and/or contraindications to other biologics. Furthermore, apremilast was used for patients with a history of nonresponse to biologics and was favored for patients with relatively low PASI (<10) and a high DLQI.
Sex-Specific Long-Term Trends in Length of Hospital Stay, Postmenstrual Age at Discharge, and Survival in Very Low Birth Weight Infants
Authors: Fröhlich Matthias , Tissen-Diabaté Tatjana , Bührer Christoph , Roll Stephanie
Published: June 2021

Introduction: In very low birth weight (<1,500 g, VLBW) infants, morbidity and mortality have decreased substantially during the past decades, and both are known to be lower in girls than in boys. In this study, we assessed sex-specific changes over time in length of hospital stay (LOHS) and postmenstrual age at discharge (PAD), in addition to survival in VLBW infants. Methods: This is a single-center retrospective cohort analysis based on quality assurance data of VLBW infants born from 1978 to 2018. Estimation of sex-specific LOHS over time was based on infants discharged home from neonatal care or deceased. Estimation of sex-specific PAD over time was based on infants discharged home exclusively. Analysis of in-hospital survival was performed for all VLBW infants. Results: In 4,336 of 4,499 VLBW infants admitted from 1978 to 2018 with complete data (96.4%), survival rates improved between 1978–1982 and 1993–1997 (70.8 vs. 88.3%; hazard ratio (HR) 0.20, 95% confidence interval 0.14, 0.30) and remained stable thereafter. Boys had consistently higher mortality rates than girls (15 vs. 12%, HR 1.23 [1.05, 1.45]). Nonsurviving boys died later compared to nonsurviving girls (adjusted mean survival time 23.0 [18.0, 27.9] vs. 20.7 [15.0, 26.3] days). LOHS and PAD assessed in 3,166 survivors displayed a continuous decrease over time (1978–1982 vs. 2013–2018: LOHS days 82.9 [79.3, 86.5] vs. 60.3 [58.4, 62.1] days); PAD 40.4 (39.9, 40.9) vs. 37.4 [37.1, 37.6] weeks). Girls had shorter LOHS than boys (69.4 [68.0, 70.8] vs. 73.0 [71.6, 74.4] days) and were discharged with lower PAD (38.6 [38.4, 38.8] vs. 39.2 [39.0, 39.4] weeks). Discussion/Conclusions: LOHS and PAD decreased over the last 40 years, while survival rates improved. Male sex was associated with longer LOHS, higher PAD, and higher mortality rates.
Sex Differences in the Temporalis Tendon-Aponeurotic Complex: An in vivo MRI Macroscopic Analysis in Children and Adolescents
Authors: Isidro Rachelle , Cioffi Iacopo
Published: June 2021

The tendon-aponeurosis complex (TAC) of the temporalis dissipates forces produced during function. Abnormally reduced temporalis TACs have been found in individuals with chronic muscular temporomandibular disorders – a painful musculoskeletal condition that is more frequent in women than men. Whether there are sex differences in the temporalis TAC in healthy individuals is currently unknown. Here, we characterized and measured the temporalis TAC in healthy male and female young individuals between 5 and 15 years old to determine whether the volume of the temporalis TAC and the TAC-to-muscle ratio are different between males and females. We collected MRI studies from 90 healthy individuals, including equal numbers (15 M and 15 F) of young children (ages 5–7), children (9–11), and adolescents (13–15) and segmented the right temporalis and its TAC using software. Using general linear models, we tested the effect of sex, age, and their interaction on the volumes of the temporalis and its TAC, and the TAC-to-muscle ratio. The volumes of the temporalis and its TAC increased with age (both p < 0.001) and were not affected by sex (p = 0.252 and p = 0.179) or by the interaction sex-by-age (p = 0.079 and p = 0.095, respectively). The TAC-to-muscle ratio did not change significantly with age (p = 0.655) and was not affected by sex (0.438) or by the interaction sex-by-age (0.524). We provide, for the first time, volumetric data of the temporalis TAC in children and adolescents. The volumes of the temporalis TAC and the TAC-to-muscle ratio are not different between male and female individuals until the age of 15.
Congenital Fibrinogen Deficiency in India and Role of Human Fibrinogen Concentrate
Authors: John M. Joseph , Byreddy Poojitha , Modak Ketan , Makkar Mridul
Published: June 2021

Congenital fibrinogen deficiency is an inherited disorder due to genetic mutations with diverse presentations arising from reduced fibrinogen levels (hypofibrinogenemia), absence of fibrinogen in circulation (afibrinogenemia), abnormal functioning (dysfibrinogenemia) or both reduced levels and abnormal functioning (hypodysfibrinogenemia) of fibrinogen. The decreased fibrinogen concentration in congenital fibrinogen deficiency necessitates fibrinogen replacement therapy with fresh frozen plasma, cryoprecipitate, or human fibrinogen concentrate. However, the use of fresh frozen plasma and cryoprecipitate is limited owing to their longer transfusion time, requirement of high doses, volume overload, risk of viral transmission, and other safety concerns. The availability of human fibrinogen concentrate has made it the preferred replacement alternative due to its reduced risk of viral transmission, smaller infusion volume, and accurate dosing. The hemostatic efficacy and safety of human fibrinogen concentrate in congenital fibrinogen deficiency is well established in the literature. We review the prevalence of congenital fibrinogen deficiency in India and the current role of human fibrinogen concentrate in its management.
Ultrasonographic Assessment of Extravascular Lung Water in Hospitalized Patients Requiring Hemodialysis: A Prospective Observational Study
Authors: Miao Jing , Sy-Go Janina Paula T. , Issa Meltiady , Jenad Hussam , Manohar Sandhya , Zoghby Ziad , Kashani Kianoush B. , Gregoire James R.
Published: June 2021

Introduction: Sonographic technologies can estimate extravascular lung water (EVLW) in hemodialysis (HD) patients. This study investigated the suitability of a handheld scanner in contrast to a portable scanner for quantifying EVLW in hospitalized patients requiring HD. Methods: In this prospective study, 54 hospitalized HD patients were enrolled. Bedside lung ultrasound was performed within 30 min before and after dialysis using handheld (phased array transducer, 1.7–3.8 MHz) and portable (curved probe, 5–2 MHz) ultrasound devices. Eight lung zones were scanned for total B-lines number (TBLN). The maximum diameter of inferior vena cava (IVC) was measured. We performed Passing-Bablok regression, Deming regression, Bland-Altman, and logistic regression analysis. Results: The 2 devices did not differ in measuring TBLN and IVC (p > 0.05), showing a high correlation (r = 0.92 and r = 0.51, respectively). Passing-Bablok regression had a slope of 1.11 and an intercept of 0 for TBLN, and the slope of Deming regression was 1.02 within the CI bands of 0.94 and 1.11 in the full cohort. TBLN was logarithmically transformed for Bland-Altman analysis, showing a bias of 0.06 (TBLN = 1.2) between devices. The slope and intercept of the Deming regression in IVC measurements were 0.77 and 0.46, respectively; Bland-Altman plot showed a bias of −0.07. Compared with predialysis, TBLN significantly (p < 0.001) decreased after dialysis, while IVC was unchanged (p = 0.16). Univariate analysis showed that cardiovascular disease (odds ratio [OR] 8.94 [2.13–61.96], p = 0.002), smoking history (OR 5.75 [1.8–20.46], p = 0.003), and right pleural effusion (OR 5.0 [1.2–25.99], p = 0.03) were strong predictors of EVLW indicated by TBLN ≥ 4. Conclusion: The lung and IVC findings obtained from handheld and portable ultrasound scanners are comparable and concordant. Cardiovascular disease and smoking history were strong predictors of EVLW. The use of TBLN to assess EVLW in hospitalized HD patients is feasible. Further studies are needed to determine if TBLN can help guide volume removal in HD patients.
MLH1 Exon 12 Gene Deletion Leading to Lynch Syndrome: A Case Report
Authors: Cui Shiyun , Zhang Xiao , Zou Ruihan , Ye Fan , Wang Yutong , Sun Jing
Published: June 2021

Introduction: Deleterious heterozygous mutation of the MLH1 gene is an important cause of Lynch syndrome (LS), an autosomal dominant cancer caused by functional defects in the DNA mismatch repair (MMR) complex. Case Report: The proband was a 35-year-old patient with confirmed colorectal cancer (CRC). Immunohistochemical (IHC) staining revealed the absence of MLH1 and PMS2 expression in the colorectal tissue specimens of the patient. Genetic counselling and tumor gene testing were performed using next-generation sequencing technology. The genetic tumor verification report showed the deletion of 4 bases in exon 12 of the tested MLH1 gene and a transcoding mutation. To our knowledge, this germline splice site mutation of MLH1 has not been reported before. The proband accepted several therapeutic regimens including PD-1 inhibitor and ultimately died of multiple organ failure. Conclusion: Nonsense mutations and frameshift mutations of MMR genes are the most common causes of LS. Common mutations include those in MSH2, MLH1, MSH6, and PMS2. We report a mutation of MLH1 that has never been reported before. We recommend that patients with a history of colon or rectal cancer receive universal MMR or MSI testing and checkpoint inhibitor therapy for the first-line treatment of deficient MMR CRC.
Anatomic glossary of mesopleural structures in Bethylidae (Hymenoptera: Chrysidoidea)
Authors: Brito Chirlei Dias de , Lanes Geane de Oliveira , Azevedo Celso Oliveira
Published: June 2021

The mesopleuron of Bethylidae has many structures that are used in taxonomic and phylogenetic studies. The lack of understanding of these structures has generated independent terminologies and a series of confusing terms, hampering effective scientific communication. A morphological study and literature review were made in order to solve these problems. Our study resulted in an anatomic glossary with 49 terms that presented a large number of synonyms and polysemies. The glossary standardizes the terms used in the Bethylidae mesopleuron and in other Hymenoptera groups, which will facilitate hypotheses of primary homology in comparative biology.
New species of Paraodontomma from mid-Cretaceous Burmese amber with muscle tissue preservation (Coleoptera: Archostemata: Ommatidae)
Authors: Li Yan-Da , Yamamoto Shûhei , Huang Di-Ying , Cai Chen-Yang
Published: June 2021

The third member of the extinct ommatid genus Paraodontomma is reported from mid-Cretaceous Burmese amber. Our observation confirms the transverse ridges on elytra as a diagnostic character for the genus. Paraodontomma leptocristatum sp. nov. differs from previously reported congeners mainly in head subquadrate and without prominent protuberances, pronotal disc without prominent ridges, elytral ridges indistinct, and teeth along elytral margins not forming a wavy pattern. Musculature is preserved in the newly discovered specimen of P. leptocristatum, which further demonstrates the preservation potential and irreplaceable value of amber fossils.
Sagitta otolith of three demersal species in a tropical environment
Authors: Oliveira Crismen Santana de , Freire Kátia de Meirelles Felizola , Rosa Leonardo Cruz da , Carvalho Barbara Maichak de
Published: June 2021

The objective of this study was to describe the morphology and morphometry of saggitta otoliths of Polydactylus virginicus, Menticirrhus cuiaranensis and Conodon nobilis in a tropical environment. Fishes were caught with rod and reel in competitive fishing events promoted in 2014-2015 along the coast of Sergipe. A total of 174 pairs of sagitta otoliths of P. virginicus, 181 of M. cuiaranensis and 77 of C. nobilis was extracted. In general, the sagitta otoliths of all three species analyzed here presented different morphology and shape indices. The permutational multivariate analysis of variance (PERMANOVA) demonstrated significant differences among species and ontogenetic phases within each species using morphometry and shape indices. The linear discriminant analysis (LDA) presented a 98.3% correct reclassification of the otoliths by species.
Two new, remarkably colored species of the Neotropical catfish genus Cetopsorhamdia Eigenmann & Fisher, 1916 (Siluriformes, Heptapteridae) from Chapada dos Parecis, western Brazil, with an assessment of the morphological characters bearing on their phylogenetic relationships
Authors: Bockmann Flávio A. , Reis Roberto E.
Published: June 2021

Two new species of heptapterid catfish genus Cetopsorhamdia are described from close localities in western Brazil, at Chapada dos Parecis, an area with extremely high level of endemism. One species is from the upper Rio Madeira system, Rondônia State, and the other from the upper Rio Tapajós system, Mato Grosso State. The two species are diagnosed, among several other features, by their markedly distinctive color patterns, with the former having well-defined quadrangular marks in trunk flanks while the latter bearing irregular, vertical bars along the trunk. The monophyly of Cetopsorhamdia is discussed, with two putative synapomorphies being proposed to support the genus. Potentially informative morphological characters to resolve the internal relationships of the genus are presented and discussed. Despite the striking external differences between the two species herein described, they are found to likely form a clade.
Morphology, Pandemic, and 3D
Authors: Lobo Leonardo Souza , Grillo Orlando Nelson , Azevedo Sergio Alex Kugland de
Published: June 2021

The COVID‑19 pandemic imposes the biggest restrictions on access to morphological information housed in scientific collections, compromising the progress of scientific research. Even though it is not the first event to impose restrictions on access, it is undoubtedly the most global in range. Based on this, we discuss the barriers to access information and we show 3D technology as an important tool to create routes to mitigate the effects of future restrictions. In a global sphere, there are initiatives of inter-institutional integration and international networks focused on facilitating and disseminate the implementation of digitization tools and techniques to facilitate access to diverse biological information. Notwithstanding, when we speak in 3D technology in Latin American countries, as is well noted in Brazil, this type of progress is lacking, with only isolated initiatives from some laboratories and research centers that implement 3D digitization tools, but often as experimental uses. Moreover, recent events, such as the Museu Naciona fire and the mobility restriction imposed by the COVID‑19 pandemic, reinforce the need and urgency to discuss the virtualization of natural history collections in the national territory. In this sense, we recommend photogrammetry as a more accessible and versatile technology, which could be quickly implemented in curatorial procedures. We, also, have defined criteria to establish priorities for virtualizing the collection. The virtualization of the type specimens is an inevitable and necessary task to ensure their access and expansion of their safe preservation, as established by the ICZN, and should therefore be considered as a high priority, followed by reference specimens, which are frequently accessed. Finally, to ensure Latin America advances to levels similar to those observed in other continents, it is important to establish a collaborative network of museums and other research institutions.
Antimicrobial susceptibility profile of Streptococcus agalactiae strains isolated from bovine mastitis
Authors: Costa Geraldo Márcio da , Ribeiro Núbia Aparecida , Gonçalves Maysa Serpa , Silva Juliana Rosa da , Custódio Dircéia Aparecida da Costa , Mian Gláucia Frasnelli
Published: June 2021

Bovine mastitis is the most important disease of dairy herds worldwide. Its main etiologic agents are bacteria, including Streptococcus agalactiae. The importance of this agent in bovine mastitis is because it is highly contagious and has a high impact on the occurrence of clinical mastitis cases and in the increase of the bulk milk somatic cell counts. The dry cow therapy and the treatment of the clinical mastitis cases stand out among the measures to control intramammary infections in cows. However, these strategies require knowledge about the antimicrobial susceptibility of the causal microorganisms. Thus, this study aimed to evaluate the antimicrobial susceptibility of 89 S. agalactiae strains isolated from bovine mastitis between the years 2004 and 2008 in dairy herds from Campo das Vertentes region, Minas Gerais State, Brazil. The disc diffusion technique was used and the antimicrobials currently used in mastitis therapy were tested. The isolates tested showed 100% susceptibility to chloramphenicol, ceftiofur, cefotaxime, enrofloxacin, and cefquinome. High frequencies of susceptibility (>95%) were also observed for the beta-lactams (penicillin G, ampicillin, and oxacillin), cephalosporins (cephalotin, ceftiofur, cefotaxime, cefoperazone, and cefquinome), florfenicol, gentamicin, lincomycin, nitrofurantoin, and sulfamethoprim. The strains showed high frequencies of resistance to neomycin (15.74%), and tetracycline (21.35%). Multidrug resistance was detected in 2.25% of the tested isolates. The results pointed to variations in the antimicrobial susceptibility profiles of the studied strains and the importance of the use of the susceptibility tests to determine the correct antimicrobial to be applied in the treatment of bovine mastitis caused by S. agalactiae. The high frequencies of resistance observed to some antimicrobials, such as neomycin and tetracycline, commonly used in the treatment of mastitis and other pathologies, highlighted the need for more judicious use of antimicrobials on dairy farms.
Modern Slavery and the Law of the Sea
Authors: Kojima Chie
Published: June 2021

Practices of modern slavery across maritime borders, such as human trafficking and forced labour in the maritime and fishing industries, are often unregulated and uncontrolled due to legal uncertainties and the lack of political will. This article discusses possibilities to re-interpret the United Nations Convention on the Law of the Sea to give a complementary role to non-flag States in controlling modern slavery practices at sea. In particular, it analyses the question as to whether a non-flag State may take prescriptive and enforcement measures against a foreign vessel suspected of modern slavery on the high seas.
What Use Is Customary International Law?
Authors: Carty Anthony
Published: June 2021

Customary international law as a source of general law is given a primary place in Article 38 of the ICJ Statute. However, it is historically a concept created by legal doctrine. The very idea of custom supposes legal persons are natural persons living in a dynamic, evolving community. This was the assumption of the historical school of law in the 19th century when the concept of custom was developed. Now the dominant notion of legal personality is the State as an impersonal corporation and international legal theory (Brierly and D’Amato) can see well that the death of the historical school of law has to mean the death of the concept of custom. What should replace it? Two steps need to be taken in sequence. Firstly, following the Swedish realist philosopher Haegerstrom, we have to ascertain the precise constellations of the conflictual attitudes the populations of States have to the patterns of normativity which they project onto international society. Secondly, we should follow the virtue ethics jurisprudence of Paul Ricoeur and others, who develop a theory of critical legal doctrinal judgement, along the classical lines of Aristotle and Confucius, to challenge and sort out the prejudices of peoples into some reasonable shape, whereby these can be encouraged to understand and respect one another.

Then one will not have to endure so many silly interpretations of international law such as the one declaring that there are only rocks in the South China Sea and not islands. Such interpretations have nothing to do with the supposedly ordinary legal language analysis of a convention and the State practice surrounding it. They have to do entirely with a continued lack of respect by Western jurists for non-Western societies and nations.
The Development of International Law of the Sea by International Courts and Tribunals
Authors: Zhang Hua
Published: June 2021

The development of international law of the sea by international courts and tribunals is generally acknowledged among international lawyers. In retrospect, the creative jurisprudence of international judicial bodies was incorporated into the mainstream of international law-making process in many cases, while the experience of failure cannot be ignored. In the past decade, the strengthening of marine environmental protection has become a tendency in international adjudication. Accordingly, the content and scope of due diligence obligation has been discovered, consolidated and extended. In light of the evolution of due diligence obligation, the methodology of law-making by international judicial bodies includes: inter alia, interpretation, cross-reference of precedents, analogy, and assertion. However, from the perspective of legitimacy, law-making should not become the normal function of international judicial bodies. Bearing in mind international rule of law and good administration of justice, the lawmaking activities of international courts and tribunals should be curtailed in certain degree.
Chuanicosmetura gen. nov. of the tribe Meconematini (Orthoptera: Tettigoniidae) from southwest China and Chuanicosmetura emarginata (Liu, 2000) comb. nov.
Authors: GUO QI , WANG TAO , SHI FU-MING
Published: June 2021

Chuanicosmetura gen. nov. (Orthoptera: Tettigoniidae: Meconematinae) is established based on Chuanicosmetura emarginata (Liu, 2000) comb. nov. In this paper, this species was redescribed, and the male is firstly reported. Illustrations of important morphological characters are provided.
A new Entomolepididae genus and a new species of Spongiopsyllus Johnsson, 2000 (Copepoda, Siphonostomatoida) and their association with Aplysina Nardo, 1834 (Porifera, Demospongiae) in Todos-os-Santos Bay, Bahia, Brazil
Authors: BORGES CAMILA , FARIAS AMILCAR , MÁCOLA ROSA , NEVES ELIZABETH G. , JOHNSSON RODRIGO
Published: June 2021

The Entomolepididae family is a small taxon with a very characteristic body morphology and is represented, in the Atlantic Ocean, by three genera and five species. A recent study in Todos-os-Santos Bay, in Bahia State, has revealed a new species of Spongiopsyllus and a new species and genus belonging to the Entomolepididae. The new species of Spongiopsyllus is found in association with the sponge Aplysina cauliformis (Carter, 1882) sampled at the Porto da Barra beach. It is distinguished from its congeners mainly by differences in the segmentation pattern of the antennule, endopod of antenna, and the setation of the maxillule, maxilla and maxilliped. The new genus and species from Parmulodinae Eiselt, 1959 is found in association with the sponge Aplysina solangeae Pinheiro, Hajdu & Custódio, 2007, sampled at the Yacht Club Beach. The genus differs from others Parmulodinae mainly due to segmentation pattern of the antennule, endopod of antenna, maxilliped and swimming legs.
Macrophage-Derived Exosomal miR-31-5p Promotes Oral Squamous Cell Carcinoma Tumourigenesis Through the Large Tumor Suppressor 2-Mediated Hippo Signalling Pathway
Authors: Yuan Yi , Wang Zeyu , Chen Mengqi , Jing Yang , Shu Wei , Xie Zhuoying , Li Zhiyang , Xu Juanyong , He Feng , Jiao Pengfei , Wang Jiaqing , Xu Jiamin , Xia Yan , Liu Siyu , Du Hongming , Li Hongwei , Dai Lu , Dai Youjin , Zhang Yaqin
Published: June 2021

Tumour-associated macrophages (TAMs) are thought to contribute to oral squamous cell carcinoma (OSCC) initiation and progression. However, the underlying mechanism through which TAMs foster OSCC progression is still unclear. This study intended to determine whether there are exclusively
exosomal miRNAs-derived macrophages that are functionally necessary for OSCC progression. The phenotype of TAM recruitment in OSCC tissue samples was assessed, subsequently identifying the influence of M2 macrophages and exosomes derived from M2 macrophages on OSCC proliferation and tumorigenesis
in vitro and in vivo. CD68 and CD163, the specific markers of M2 type macrophages, were upregulated in TAMs presented in intra-cancer tissues. M2 macrophages and M2 macrophage-derived exosomes (M2 exos) both can promote OSCC growth and tumorigenicity. An exosomal RNA-seq analysis
was conducted to predict regulatory exosomal miRNAs related to OSCC growth, which determined miR-31-5p and LATS2 for subsequent experiments. Mechanistically, miR-31-5p was delivered to recipient OSCC cells through M2 exos and complementary pairing with the large tumor suppressor 2 (LATS2)
coding sequence, thus suppressing the expression of LATS2 and inactivation the Hippo signaling pathway to support OSCC growth. Collectively, our findings demonstrate that M2 macrophage-derived exosomal miR- 31-5p can make tumor suppressor LATS2 gene inhibited and facilitate the progression
of OSCC via inhibiting the Hippo signaling pathway, which possibly provides new targets for the molecular therapy of OSCC.
Applications of Nanoparticles for Herpes Simplex Virus (HSV) and Human Immunodeficiency Virus (HIV) Treatment
Authors: Obisesan Oluwafemi , Katata-Seru Lebogang , Mufamadi Steven , Mufhandu Hazel
Published: June 2021

Human Immunodeficiency Virus (HIV) is a global pandemic that has contributed to the burden of disease, and the synergistic interaction between Herpes Simplex Virus (HSV) and HIV has assisted further in the spread of the HIV disease. Moreover, several chemotherapeutic treatment options from antiviral monotherapy to highly active antiretroviral therapy (HAART) have been adopted to manage the infection; however, HIV has developed new mechanisms against these active pharmaceutical agents (APAs), limiting the effect of the drugs. In this article, we reviewed different nanoparticles and their antiviral potency against HSV and HIV infection as well as the effect of drug encapsulated nanoparticles using different drug delivery systems as they palliate to some flaws or deficiencies that the stand-alone drugs present. Drug encapsulated nanoparticles show better treatment outcomes of HSV and HIV infection. The nanoparticles can transverse the anatomic privilege sites to exert their therapeutic effect, and a prolonged and higher dose of the encapsulated therapeutic agent can ease the dosage frequency, thus palliating low drug compliance which the stand-alone drugs fail to perform. Therefore, it is clear that nanoparticles prevent antiviral drug resistance by maintaining sustained drug release over an extended period, improving the therapeutic effect of the entrapped drug.