bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonlinear Dynamics of Cutting Process considering Higher‐Order Deformation of Composite Cutting Tool
Authors: Yao Donghui , Ren Yongsheng , Zhang Yuhuan , Ma Bole
Published: December 2021

In this paper, the nonlinear dynamic analysis of the cutting process of composite cutting tool is performed. The cutting tool is simplified to a nonplanar bending rotating shaft. The higher‐order bending deformation, structural damping, and gyroscopic effect of cutting tool are considered. It is assumed that cutting tool is subjected to a regenerative two‐dimensional cutting force containing the first and second harmonic components. Based on the Hamilton principle, the motion equation of nonlinear chatter of the cutting system is derived. The nonlinear ordinary differential equations in the generalized coordinates are obtained by Galerkin method. In order to analyze the nonlinear dynamic response of cutting process, the multiscale method is used to derive the analytical approximate solution of the forced response for the cutting system under periodic cutting forces. In the forced response analysis, four cases including primary resonance and superharmonic resonance, i.e., , , , and , are considered. The influences of ratio of length to diameter, structural damping, cutting force, and ply angle on primary resonance and superharmonic resonance are investigated. The results show that nonlinearity due to higher‐order bending deformation significantly affects the dynamic behavior of the milling process and that the effective nonlinearity of the cutting system is of hard type. Multivalued resonance curves and jump phenomenon are presented. The influences of various factors, such as ratio of length to diameter, ply angle, structural damping, cutting force, and rotating speed, are thoroughly discussed.
Frequencies of CYP2B6∗4,∗5, and ∗6 Alleles within an Iranian Population (Mazandaran)
Authors: Hashemi-Soteh Mohammad Bagher , Hosseini Elaheh , Fazelnia Shokoufeh , Ghasemian-Sorbeni Faramarz , Madahian Sara , Shiran Mohammad Reza
Published: December 2021

Background. The human CYP2B subfamily consists of one functional gene (CYP2B6) and one pseudogene (CYP2B7P). Cytochrome P450 2B6 (CYP2B6) is a highly polymorphic enzyme that shows marked interindividual and interethnic variations. Currently, 38 alleles have been described, and some of the allelic variants have been associated with low enzyme activity. The aim of this study was to investigate the frequencies of CYP2B6∗4, CYP2B6∗5, and CYP2B6∗6 alleles in the Mazani ethnic group among Iranian Population. Methods. The study was conducted in 289 unrelated healthy volunteers. DNA was extracted from peripheral blood and analyzed by the PCR-RFLP protocol. The PCR product was digested with restriction enzymes and then separated using agarose gel electrophoresis. Results. The frequency of CYP2B6∗4, CYP2B6∗5, and CYP2B6∗6 in this study was 34.60%, 7.26%, and 34.54%, respectively. Conclusion. The frequency of the CYP2B6∗4 allele in the Mazani ethnic group was much higher (34.60%) than other population. The frequency of CYP2B6∗6 (34.54%) also was higher than its frequency in other previously reported population. But the frequency of CYP2B6∗5 in this study was lower than expected. These results will be useful in understanding the ethnic diversity in Iranian population and offer a preliminary basis for more rational use of drugs that are substrates for CYP2B6 in this population.
A Satisficing Heuristic Decision-Making Model under Limited Attention and Incomplete Preferences
Authors: Wu Xinlin , Ding Daoxin
Published: December 2021

Classical choice theory assumes that a decision-maker considers all feasible alternatives. However, a decision-maker in the real world can not consider all alternatives because of limited attention. In this paper, we propose a satisficing choice model to describe the choice procedure based on the incomplete preferences under the limited attention of the decision-maker. Moreover, the existence and rationality properties of the satisficing choice model on the different domains are studied combined with some proposed rationality conditions. Further, the proposed satisficing choice model is applied to a case of quality competition. Results show that the satisficing choice model of this paper is of a certain theoretical guiding significance to a kind of emergency decisions made by decision-makers under the circumstance of time pressure and limited information. It can also be the theoretical foundation for the study on the boundedly rational decision-making.
Dual Spaces of Multiparameter Local Hardy Spaces
Authors: Ding Wei , Yu Feng
Published: December 2021

In this paper, we study the duality theory of the multiparameter local Hardy spaceshpℝn1×ℝn2, and we prove thathpℝn1×ℝn2∗=cmopℝn1×ℝn2, wherecmopℝn1×ℝn2are defined by discrete Carleson measure. Moreover, we discuss the relationship amongcmopℝn1×ℝn2,Lippℝn1×ℝn2, and rectanglecmorectpℝn1×ℝn2.
Towards Green Economics and Society: Exploring the Efficiency of New Energy Generation
Authors: Ye Guoqing , Xu Xin Long , Chen Yujie , Zhang Kai Quan
Published: December 2021

In recent years, solar and wind energy have been increasingly abandoned due to the blind expansion of the new energy industry. Due to the competitive relationships between different types of new energy, reasonable industrial development planning needs to be implemented to not only save the cost of government subsidies but also clarify the investment direction of social capital. Based on the panel data of OECD countries between 2006 and 2018, the stochastic frontier analysis (SFA) was used to measure the efficiency of new energy generation (NEG) and the influencing factors were analyzed in this paper. Results were as follows: the efficiency of NEG in OECD countries is improving; the efficiency of NEG is positively correlated with technical innovation, government policies, economic level, and education level and negatively correlated with urbanization. Based on the empirical results of this study, problems in the development of the new energy industry have been discussed and suggestions to improve the efficiency of NEG have been proposed.
Racialized Economic Segregation and Breast Cancer Mortality among Women in Maryland
Authors: Connor Avonne E. , Kaur Maneet , Dibble Kate E. , Visvanathan Kala , Dean Lorraine T. , Hayes Jennifer H.
Published: December 2021

Background:

Our objective was to determine the association between racialized economic segregation and the hazard of breast cancer mortality in Maryland.

Methods:

Among 35,066 women (24,540 White; 10,526 Black) diagnosed with incident invasive breast cancer in Maryland during 2007 to 2017, exposure to racialized economic segregation was measured at the census tract level using Index of Concentration at the Extremes metrics. HRs and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression for the association between racialized economic segregation and the hazard of breast cancer mortality, accounting for clustering at the census tract level. Models were adjusted for age and stratified by race, median age (<60 years, ≥60 years), and clinical characteristics.

Results:

Overall, the hazard of breast cancer mortality was 1.84 times as high (95% CI, 1.64–2.06) for the least privileged quintile of racialized economic segregation compared with the most privileged quintile. This association differed significantly (Pinteraction< 0.05) by race and age, with 1.20 (95% CI, 0.90–1.60) times the hazard of breast cancer mortality for Black women versus 1.66 (95% CI, 1.41–1.95) times the hazard for White women, and with greater hazards for younger women (HR, 2.17; 95% CI, 1.83–2.57) than older women (HR, 1.62; 95% CI, 1.40–1.88).

Conclusions:

Our results suggest that breast cancer survival disparities exist in Maryland among women residing in the least privileged census tracts with lower income households and higher proportions of Black residents.

Impact:

Our findings provide new insights into the breast cancer mortality disparities observed among women in Maryland.
Results from a First-in-Human Phase I Study of Siremadlin (HDM201) in Patients with Advanced Wild-Type TP53 Solid Tumors and Acute Leukemia
Authors: Stein Eytan M. , DeAngelo Daniel J. , Chromik Jörg , Chatterjee Manik , Bauer Sebastian , Lin Chia-Chi , Suarez Cristina , de Vos Filip , Steeghs Neeltje , Cassier Philippe A. , Tai David , Kiladjian Jean-Jacques , Yamamoto Noboru , Mous Rogier , Esteve Jordi , Minami Hironobu , Ferretti Stephane , Guerreiro Nelson , Meille Christophe , Radhakrishnan Rajkumar , Pereira Bernard , Mariconti Luisa , Halilovic Ensar , Fabre Claire , Carpio Cecilia
Published: December 2021

Purpose:

This phase I, dose-escalation study investigated the recommended dose for expansion (RDE) of siremadlin, a p53–MDM2 inhibitor, in patients with wild-type TP53 advanced solid or hematologic cancers.

Patients and Methods:

Initial dosing regimens were: 1A (day 1; 21-day cycle; dose 12.5–350 mg) and 2A (days 1–14; 28-day cycle; dose 1–20 mg). Alternative regimens included 1B (days 1 and 8; 28-day cycle) and 2C (days 1–7; 28-day cycle). The primary endpoint was incidence of dose-limiting toxicities (DLT) during cycle 1.

Results:

Overall, 115 patients with solid tumors and 93 with hematologic malignancies received treatment. DLTs occurred in 8/92 patients with solid tumors and 10/53 patients with hematologic malignancies. In solid tumors, an RDE of 120 mg was defined in 1B. In hematologic tumors, RDEs were defined in 1A: 250 mg, 1B: 120 mg, and 2C: 45 mg. More patients with hematologic malignancies compared with solid tumors experienced grade 3/4 treatment-related adverse events (71% vs. 45%), most commonly resulting from myelosuppression. These were more frequent and severe in patients with hematologic malignancies; 22 patients exhibited tumor lysis syndrome. Overall response rates at the RDEs were 10.3% [95% confidence interval (CI), 2.2–27.4] in solid tumors and 4.2% (95% CI, 0.1–21.1), 20% (95% CI, 4.3–48.1), and 22.2% (95% CI, 8.6–42.3) in acute myeloid leukemia (AML) in 1B, 1A, and 2C, respectively.

Conclusions:

A common safety profile was identified and preliminary activity was noted, particularly in AML. Comprehensive investigation of dosing regimens yielded recommended doses/regimens for future combination studies.
Safety and Efficacy of Pembrolizumab in Combination with Acalabrutinib in Advanced Head and Neck Squamous Cell Carcinoma: Phase 2 Proof-of-Concept Study
Authors: Taylor Matthew H. , Betts Courtney B. , Maloney Lauren , Nadler Eric , Algazi Alain , Guarino Michael J. , Nemunaitis John , Jimeno Antonio , Patel Priti , Munugalavadla Veerendra , Tao Lin , Adkins Douglas , Goldschmidt Jerome H. , Cohen Ezra E.W. , Coussens Lisa M.
Published: December 2021

Purpose:

Programmed cell death-1 (PD-1) receptor inhibitors have shown efficacy in head and neck squamous cell carcinoma (HNSCC), but treatment failure or secondary resistance occurs in most patients. In preclinical murine carcinoma models, inhibition of Bruton's tyrosine kinase (BTK) induces myeloid cell reprogramming that subsequently bolsters CD8+ T cell responses, resulting in enhanced antitumor activity. This phase 2, multicenter, open-label, randomized study evaluated pembrolizumab (anti–PD-1 monoclonal antibody) plus acalabrutinib (BTK inhibitor) in recurrent or metastatic HNSCC.

Patients and Methods:

Patients received pembrolizumab 200 mg intravenously every 3 weeks, alone or in combination with acalabrutinib 100 mg orally twice daily. Safety and overall response rate (ORR) were co-primary objectives. The secondary objectives were progression-free survival (PFS) and overall survival.

Results:

Seventy-six patients were evaluated (pembrolizumab, n = 39; pembrolizumab + acalabrutinib, n = 37). Higher frequencies of grade 3–4 treatment-emergent adverse events (AE; 65% vs. 39%) and serious AEs (68% vs. 31%) were observed with combination therapy versus monotherapy. ORR was 18% with monotherapy versus 14% with combination therapy. Median PFS was 2.7 [95% confidence interval (CI), 1.4–6.8] months in the combination arm and 1.7 (95% CI, 1.4–4.0) months in the monotherapy arm. The study was terminated due to lack of clinical benefit with combination treatment. To assess how tumor immune contexture was affected by therapy in patients with pre- and post-treatment biopsies, spatial proteomic analyses were conducted that revealed a trend toward increased CD45+ leukocyte infiltration of tumors from baseline at day 43 with pembrolizumab (monotherapy, n = 5; combination, n = 2), which appeared to be higher in combination-treated patients; however, definitive conclusions could not be drawn due to limited sample size.

Conclusions:

Despite lack of clinical efficacy, immune subset analyses suggest that there are additive effects of this combination; however, the associated toxicity limits the feasibility of combination treatment with pembrolizumab and acalabrutinib in patients with recurrent or metastatic HNSCC.
Targeting Treg-Expressed STAT3 Enhances NK-Mediated Surveillance of Metastasis and Improves Therapeutic Response in Pancreatic Adenocarcinoma
Authors: Piper Miles , Van Court Benjamin , Mueller Adam , Watanabe Shuichi , Bickett Thomas , Bhatia Shilpa , Darragh Laurel B. , Mayeda Max , Nguyen Diemmy , Gadwa Jacob , Knitz Michael , Corbo Sophia , Morgan Rustain , Lee Jung-Jae , Dent Alexander , Goodman Karyn , Messersmith Wells , Schulick Richard , Del Chiaro Marco , Zhu Yuwen , Kedl Ross M. , Lenz Laurel , Karam Sana D.
Published: December 2021

Purpose:

Metastasis remains a major hurdle in treating aggressive malignancies such as pancreatic ductal adenocarcinoma (PDAC). Improving response to treatment, therefore, requires a more detailed characterization of the cellular populations involved in controlling metastatic burden.

Experimental Design:

PDAC patient tissue samples were subjected to RNA sequencing analysis to identify changes in immune infiltration following radiotherapy. Genetically engineered mouse strains in combination with orthotopic tumor models of PDAC were used to characterize disease progression. Flow cytometry was used to analyze tumor infiltrating, circulating, and nodal immune populations.

Results:

We demonstrate that although radiotherapy increases the infiltration and activation of dendritic cells (DC), it also increases the infiltration of regulatory T cells (Treg) while failing to recruit natural killer (NK) and CD8 T cells in PDAC patient tissue samples. In murine orthotopic tumor models, we show that genetic and pharmacologic depletion of Tregs and NK cells enhances and attenuates response to radiotherapy, respectively. We further demonstrate that targeted inhibition of STAT3 on Tregs results in improved control of local and distant disease progression and enhanced NK-mediated immunosurveillance of metastasis. Moreover, combination treatment of STAT3 antisense oligonucleotide (ASO) and radiotherapy invigorated systemic immune activation and conferred a survival advantage in orthotopic and metastatic tumor models. Finally, we show the response to STAT3 ASO + radiotherapy treatment is dependent on NK and DC subsets.

Conclusions:

Our results suggest targeting Treg-mediated immunosuppression is a critical step in mediating a response to treatment, and identifying NK cells as not only a prognostic marker of improved survival, but also as an effector population that functions to combat metastasis.
Abstract P244: NVL-655 exhibits antitumor activity in lorlatinib-resistant and intracranial models of ALK-rearranged NSCLC
Authors: Tangpeerachaikul Anupong , Deshpande Amit , Kohl Nancy E. , Horan Joshua C. , Pelish Henry E.
Published: December 2021

ALK receptor tyrosine kinase can be aberrantly activated by gene rearrangement or point mutation to drive tumor cell proliferation, survival, and metastasis. ALK rearrangements are detected in up to 5% of advanced non-small cell lung cancer (NSCLC), and up to 40% of patients present with brain metastases at diagnosis. Crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are FDA-approved tyrosine kinase inhibitors for ALK-positive NSCLC. However, durability of response to these treatments is partly limited by mutations in ALK that confer resistance. The G1202R solvent front mutation is commonly observed in patients that have progressed on crizotinib, ceritinib, alectinib, or brigatinib. Patients with tumors harboring G1202R have responded to lorlatinib, but many have relapsed after acquiring compound mutations such as G1202R/L1196M and G1202R/G1269A. Another challenge with lorlatinib is central nervous system (CNS) adverse events attributed to inhibition of tropomyosin receptor kinase B (TRKB), a kinase structurally related to ALK. NVL-655 is a novel preclinical brain-penetrant ALK inhibitor with selectivity over TRKB. We previously reported that NVL-655 inhibits ALK G1202R, G1202R/L1196M, G1202R/G1269A, and G1202R/L1198F in vitro; has favorable kinome and ALK-vs-TRKB selectivity profiles; and shows antitumor activity in a Ba/F3 EML4-ALK variant 1 (v1) G1202R/L1196M xenograft model. Here we report results of a broader preclinical characterization of NVL-655 across ALK models, including an intracranial model. NVL-655 was observed to induce regression in a HIP1-ALK patient-derived xenograft model, an EML4-ALK v1 human cancer cell line-derived model (NCI-H3122), and Ba/F3 xenograft models expressing EML4-ALK v1 G1202R and G1202R/G1269A. Pharmacodynamic (PD) biomarker analyses supported in vivo ALK inhibition by NVL-655. Furthermore, NVL-655 was observed to reduce tumor size and prolong survival by more than 4-fold in a mouse intracranial tumor model of Ba/F3 EML4-ALK v1 G1202R/L1196M luciferase. In conclusion, NVL-655 has a preclinical profile that we believe supports its potential to address a medical need for patients with ALK-positive disease, including those with G1202R compound mutations. We believe the findings presented here support the evaluation of NVL-655 for the treatment of patients with ALK-driven disease.

Citation Format: Anupong Tangpeerachaikul, Amit Deshpande, Nancy E. Kohl, Joshua C. Horan, Henry E. Pelish. NVL-655 exhibits antitumor activity in lorlatinib-resistant and intracranial models of ALK-rearranged NSCLC [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P244.
Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Authors: Garciaz Sylvain , Guirguis Andrew A. , Müller Sebastian , Brown Fiona C. , Chan Yih-Chih , Motazedian Ali , Rowe Caitlin L. , Kuzich James A. , Chan Kah Lok , Tran Kevin , Smith Lorey , MacPherson Laura , Liddicoat Brian , Lam Enid Y.N. , Cañeque Tatiana , Burr Marian L. , Litalien Véronique , Pomilio Giovanna , Poplineau Mathilde , Duprez Estelle , Dawson Sarah-Jane , Ramm Georg , Cox Andrew G. , Brown Kristin K. , Huang David C.S. , Wei Andrew H. , McArthur Kate , Rodriguez Raphaël , Dawson Mark A.
Published: December 2021

Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples.

Significance:

Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia.

This article is highlighted in the In This Issue feature, p. 587
Outcomes Based on Plasma Biomarkers for the Phase 3 CELESTIAL Trial of Cabozantinib versus Placebo in Advanced Hepatocellular Carcinoma
Authors: Rimassa Lorenza , Kelley Robin Kate , Meyer Tim , Ryoo Baek-Yeol , Merle Philippe , Park Joong-Won , Blanc Jean-Frederic , Lim Ho Yeong , Tran Albert , Chan Yi-Wah , McAdam Paul , Wang Evelyn , Cheng Ann-Lii , El-Khoueiry Anthony B. , Abou-Alfa Ghassan K.
Published: December 2021

Introduction: Cabozantinib, an inhibitor of MET, AXL, and VEGF receptors, significantly improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). In this exploratory analysis, outcomes were evaluated according to plasma biomarker levels. Methods: Baseline plasma levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, EPO, ANG2, IGF-1, VEGF-C, and c-KIT for 674/707 randomized patients; and Week 4 levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, and EPO for 614 patients. OS and PFS were analyzed by baseline levels as dichotomized or continuous variables and by on-treatment changes at Week 4 as continuous variables; biomarkers were considered potentially prognostic if p < 0.05 and predictive if p < 0.05 for the interaction between treatment and the biomarker. Multivariable analyses adjusting for clinical covariates were also performed. Results: In the placebo group, high levels of MET, HGF, GAS6, IL-8, and ANG2 and low levels of IGF-1 were associated with shorter OS in univariate and multivariable analyses; these associations were also observed for MET, IL-8, and ANG2 in the cabozantinib group. Hazard ratios for OS and PFS favored cabozantinib over the placebo at low and high baseline levels for all biomarkers. No baseline biomarkers were predictive of a treatment benefit. Cabozantinib promoted pharmacodynamic changes in several biomarkers, including increases in VEGF-A, PlGF, AXL, and GAS6 levels and decreases in VEGFR2 and HGF levels; these changes were not associated with OS or PFS. Conclusion: Cabozantinib improved OS and PFS versus placebo at high and low baseline concentrations for all biomarkers analyzed. Low baseline levels of MET, HGF, GAS6, IL-8, and ANG2 and high levels of IGF-1 were identified as potential favorable prognostic biomarkers for survival in previously treated advanced HCC. Although cabozantinib promoted pharmacodynamic changes in several biomarkers, these changes were not associated with survival.
Depression, Anxiety, and Suicidal Ideation in Patients with Atopic Eczema in a Prospective Study in Leipzig, Germany
Authors: Kage Paula , Poblotzki Laura , Zeynalova Samira , Zarnowski Julia , Simon Jan-Christoph , Treudler Regina
Published: December 2021

Background: Atopic eczema (AE) is known to be associated with depression and anxiety. We aimed at investigating the occurrence of selected psychological comorbidities in patients with AE under treatment in our university dermatological department. Methods: Monocentric prospective examination of adult AE patients using PO-SCORAD (Patient-Oriented Severity Scoring of AD), EASI (Eczema Area and Severity Index), POEM (Patient-Oriented Eczema Measure), DLQI (Dermatologic Life Quality Index), LSNS-6 (Lubben Social Network Scale 6), CES-D (Center for Epidemiologic Studies Depression Scale), HADS-D and -A (Hospital Anxiety and Depression Scale), and GAD-7 (Generalized Anxiety Disorder Scale-7) was carried out. We looked for correlations between AE severity and psychosocial comorbidities. Data were compared with age- and sex-matched controls from nonatopic subjects. Statistics: Mann-Whitney U test and Spearman’s rank correlation were used. Results: Eighty-four patients (44 women, median age 35.0 years, range: 19.4–92.8 years) were included. PO-SCORAD was 40.4 [23.4–55.4] (median [interquartile range]), EASI 9.3 [3.4–18.9], POEM 16 [8–24], and DLQI 10 [4–18]. Compared with 161 from the healthy LIFE-Adult cohort controls, our patients with AE had significantly higher scores for HADS, GAD-7, and CES-D (p < 0.001, respectively), but there was no increase in the LSNS score (18 vs. 19; p = 0.067). Within the group of AE patients, there was a significant correlation of the subjective skin severity and the depression and anxiety values: POEM significantly correlated with GAD-7, CES-D, and HADS-A and -D (p < 0.001). PO-SCORAD significantly correlated with GAD-7 and CES-D (p < 0.05). EASI correlated neither with HADS-A or -D nor with CES-D. Patients with suicidal thoughts, plans, or attempts in the last 12 months had significantly more severe AE than those without (POEM 25 [15.3–26] vs. 15 [7–23]; p = 0.013, and PO-SCORAD 51.6 [40.2–63] vs. 20.5 [20.7–52]; p = 0.014). Conclusion: Patients with AE being currently under treatment in our department had significantly increased scores indicating depression and anxiety. Suicidal tendency was increased in patients with severe AE. Key Message: AE patients may develop depression, anxiety, and suicidal ideation. Patient-oriented scores may help identifying high-risk patients.
Updated Perspectives on the Management of Relapsed and Refractory Multiple Myeloma
Authors: Heimberg Linda , Knop Stefan
Published: December 2021

Background: With the availability of T-cell-directed therapy and next-generation compounds of established classes of drugs, the treatment of relapsed/refractory (r/r) myeloma is getting more complex. However, treatment options in practice are limited by availability, approval, and patient comorbidity. The aim of this article is to provide a practical approach toward the choice of treatment for r/r myeloma patients. Summary: Regarding market authorization and current guidelines, at least in Germany, most patients nowadays will have received a doublet or triplet combination as first-line therapy containing a proteasome inhibitor and an immunomodulatory drug, mostly lenalidomide. We focus on the treatment options for patients that are ineligible for (another) stem cell transplantation. We will review treatment options for relapse after first- or second-line therapy and beyond third-line. Key Messages: There is promising data supporting the efficacy and safety of triplet combinations containing anti-CD38-monoclonal antibodies (anti-CD38 mAbs) at first or second relapse in combination with next-generation compounds. For the treatment beyond third-line, comparative studies are scarce but some promising compounds are available via conditional authorization, and there is more to come in the future. We will present some early phase trials featuring promising results.
Current Treatment Approaches to Newly Diagnosed Multiple Myeloma
Authors: Ghandili Susanne , Weisel Katja C. , Bokemeyer Carsten , Leypoldt Lisa Beatrice
Published: December 2021

Background: Multiple myeloma is a so far incurable malignant plasma cell disorder. During the past 2 decades, treatment paradigms substantially changed when novel drugs were introduced initially in treatment of relapsed disease and subsequently also in first-line treatment. Summary: Up to now, first-line treatment differs between patients initially classified as transplant eligible and those who are considered as nontransplant eligible. Transplant-eligible patients receive a primary proteasome inhibitor (PI)-based induction which is being combined with an immunomodulating agent and a CD38-directed monoclonal antibody followed by high-dose melphalan therapy and autologous stem cell transplantation with subsequent maintenance treatment with lenalidomide. Patients who are considered as nontransplant eligible receive upfront treatment preferentially with a continuous combination treatment either with a CD38-directed monoclonal antibody in combination with the immunomodulating agent lenalidomide or a lenalidomide-PI combination followed by lenalidomide maintenance. Key Messages: Primary goal of the initiated treatment is to induce a rapid and deep remission which ideally leads to an eradication of the residual plasma cell clone in sense of a minimal residual disease negativity. Achievement of long-term remission with limited toxicity despite continuous treatment strategies and maintenance or improvement of life-quality is key. Despite successful treatment options, specific difficult-to-treat subgroups, especially patients with high-risk myeloma remain with inferior prognosis and a clear unmet need for novel therapeutic strategies. Future concepts will evaluate cellular treatments and other innovative immunotherapies in first-line treatment in curative intention.
The Effects of the Heat Shock Protein 90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin, Cannabinoid Agonist WIN 55,212-2, and Nitric Oxide Synthase Inhibitor Nω-Nitro-L-Arginine Methyl Ester Hydrochloride on the Serotonin and Dry Skin-Induced Itch
Authors: Todurga Seven Zeynep Gizem , Tombulturk Fatma Kubra , Gokdemir Selim , Ozyazgan Sibel
Published: December 2021

Introduction: In many types of itch, the interaction between immune system cells, keratinocytes, and sensory nerves involved in the transmission of itch is quite complex. Especially for patients with chronic itching, current treatments are insufficient, and their quality of life deteriorates significantly. Objective: In this study, we aimed to investigate the role of the heat shock protein 90 (Hsp90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), cannabinoid agonist WIN 55,212-2, and nitric oxide (NO) synthase inhibitor Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) in pruritus. Methods: We created a serotonin (5-HT)-induced (50 μg/μL/mouse, i.d.) acute and acetone-ether-water (AEW)-induced chronic itching models. 17-AAG (1, 3, and 5 mg/kg, intraperitoneally [i.p.]), WIN 55,212-2 (1 mg/kg, i.p.), and L-NAME (1 mg/kg, i.p.) were applied to Balb/c mice. Results: We found that 17-AAG suppressed the scratches of mice, depending on the dose. The itch behavior was reduced by WIN 55,212-2, but L-NAME showed no antipruritic effect at the administered dose. The combined application of these agents in both pruritus models showed synergism in terms of the antipruritic effect. Our results showed that NO did not play a role in the antipruritic effect of WIN 55,212-2 and 17-AAG. Increased plasma IgE levels with AEW treatment decreased with the administration of 17-AAG (5 mg/kg, i.p.) and WIN 55,212-2. Conclusion: These results demonstrate that Hsp90 may play a role in the peripheral pathway of pruritus, and cannabinoid agonists and Hsp90 inhibitors can be used together in the treatment of pruritus.
Amygdala in Action: Functional Connectivity during Approach and Avoidance Behaviors
Authors: Leitão Joana , Burckhardt Maya , Vuilleumier Patrik
Published: December 2021

Motivation is an important feature of emotion. By driving approach to positive events and promoting avoidance of negative stimuli, motivation drives adaptive actions and goal pursuit. The amygdala has been associated with a variety of affective processes, particularly the appraisal of stimulus valence that is assumed to play a crucial role in the generation of approach and avoidance behaviors. Here, we measured amygdala functional connectivity patterns while participants played a video game manipulating goal conduciveness through the presence of good, neutral, or bad monsters. As expected, good versus bad monsters elicited opposing motivated behaviors, whereby good monsters induced more approach and bad monsters triggered more avoidance. These opposing directional behaviors were paralleled by increased connectivity between the amygdala and medial brain areas, such as the OFC and posterior cingulate, for good relative to bad, and between amygdala and caudate for bad relative to good monsters. Moreover, in both conditions, individual connectivity strength between the amygdala and medial prefrontal regions was positively correlated with brain scores from a latent component representing efficient goal pursuit, which was identified by a partial least squares analysis determining the multivariate association between amygdala connectivity and behavioral motivation indices during gameplay. At the brain level, this latent component highlighted a widespread pattern of amygdala connectivity, including a dorsal frontoparietal network and motor areas. These results suggest that amygdala-medial prefrontal interactions captured the overall subjective relevance of ongoing events, which could consecutively drive the engagement of attentional, executive, and motor circuits necessary for implementing successful goal-pursuit, irrespective of approach or avoidance directions.
Phyllagathis chongzuoensis (Melastomataceae), a new species from Guangxi, China
Authors: ZHANG ZHE , TU XIONG-DE , YAO SHI-WEI , MA LIANG , ZENG SI-JIN
Published: December 2021

Phyllagathis chongzuoensis, a new species from Guangxi Province, China, is described here. It is similar to P. erecta in having stiffly papery leaf blades with abaxially furfuraceous indumentum, similar leaf vernation, umbellate paniculate inflorescences and cup-shaped capsules, but differs in stoloniferous stem with indistinct internodes, shorter petioles, and obovate to suborbicular leaf blades with irregularly denticulate margin. Phylogenetic analyses based on nrITS and plastid genome confirmed that it is close to P. erecta.
Beilschmiedia danhkyii (Lauraceae), a new species from Vu Quang National Park, Vietnam
Authors: QUANG BUI HONG , TAGANE SHUICHIRO , VIET HUNG NGUYEN , CANH TOAN THAI
Published: December 2021

The new species Beilschmiedia danhkyii (Lauraceae) is described from Ha Tinh Province, Central Highland of Vietnam. Beilschmiedia danhkyii is characterized by ferruginous hairy terminal buds, branchlets and abaxial surfaces of lamina, subopposite leaves, adaxially impressed midrib and secondary veins, short inflorescence 2–3(–5) cm long, and large ellipsoid fruits 5–8 cm long, by which combination it is cleary distinguished from the other species of Beilschmiedia in the region. Taxonomic description, a table comparing morphological characters of the allied species, and color photo-plate are provided.
A Comparison of Factors That Led to the Extreme Sea Ice Minima in the Twenty-First Century in the Arctic Ocean
Authors: Liang Xi , Li Xichen , Bi Haibo , Losch Martin , Gao Yongqi , Zhao Fu , Tian Zhongxiang , Liu Chengyan
Published: December 2021

The extreme Arctic sea ice minima in the twenty-first century have been attributed to multiple factors, such as anomalous atmospheric circulation, excess solar radiation absorbed by open ocean, and thinning sea ice in a warming world. Most likely it is the combination of these factors that drives the extreme sea ice minima, but how the factors rank in setting the conditions for these events has not been quantified. To address this question, the sea ice budget of an Arctic regional sea ice–ocean model forced by atmospheric reanalysis data is analyzed to assess the development of the observed sea ice minima. Results show that the ice area difference in the years 2012, 2019, and 2007 is driven to over 60% by the difference in summertime sea ice area loss due to air–ocean heat flux over open water. Other contributions are small. For the years 2012 and 2020 the situation is different and more complex. The air–ice heat flux causes more sea ice area loss in summer 2020 than in 2012 due to warmer air temperatures, but this difference in sea ice area loss is compensated by reduced advective sea ice loss out of the Arctic Ocean mainly caused by the relaxation of the Arctic dipole. The difference in open water area in early August leads to different air–ocean heat fluxes, which distinguishes the sea ice minima in 2012 and 2020. Further, sensitivity experiments indicate that both the atmospheric circulation associated with the Arctic dipole and extreme storms are essential conditions for a new low record of sea ice extent.
Video-Assisted Thoracoscopic Internal Rib Fixation
Authors: Castater Christine , Hazen Ben , Davis Carolyn , Hoppe Samuel , Butler Caroline , Grant April , Archer-Arroyo Krystal , Maceroli Michael , Todd S. Rob , Nguyen Jonathan
Published: December 2021

Rib fractures result in serious morbidity and mortality after trauma. Although there is ongoing debate about surgical rib fixation, it is increasingly important for some patients. Minimally invasive techniques for rib fixation are gaining traction within the trauma community. We present an observational experience at our level 1 trauma center with our first 10 cases of video-assisted thoracoscopic surgery (VATS) internal rib fixation. Video-assisted thoracoscopic surgery internal plates are especially helpful for rib fractures under the scapula, which are difficult to access traditionally. This technique is also excellent at reducing complex segmental fractures as the bridge can span across multiple fractures with a single post on either side. They also work well for posterior fractures where multiple screws cannot be placed. Video-assisted thoracoscopic surgery internal rib fixation is a viable and exciting option for surgical fixation. The plates work particularly well for certain fracture patterns.
Computer Science Trends and Trade-offs in California High Schools
Authors: Bruno Paul , Lewis Colleen M.
Published: December 2021

Purpose: We aim to better understand the curricular, staffing, and achievement trade-offs entailed by expansions of high-school computer science (CS) for students, schools, and school leaders. Methods: We use descriptive, correlational, and quasi-experimental methods to analyze statewide longitudinal course-, school-, and staff-level data from California, where CS course taking has expanded rapidly. Findings: We find that these rapid CS course expansions have not come at the expense of CS teachers’ observable qualifications (namely certification, education, or experience). Within-school course taking patterns over time suggest that CS enrollment growth has come at the expense of social studies, English/language arts (ELA), and arts courses, as well as from other miscellaneous electives. However, we find no evidence that increased enrollment of students in CS courses at a school has a significant effect on students’ math or ELA test scores. Implications: Flexible authorization requirements for CS teachers appear to have allowed school leaders to staff new CS courses with teachers whose observable qualifications are strong, though we do not observe teachers’ CS teaching skill. Increasing CS participation is unlikely to noticeably improve school-level student test scores, but administrators also do not need to be overly concerned that test scores will suffer. However, school leaders and policymakers should think carefully about what courses new CS courses will replace and whether such replacements are worthwhile.
The Ethics of War and War-Making: A Philosophical Interrogation of African Involvement in the World Wars and Their Exclusion From War Monuments and Memorials
Authors: Chukwuokolo Chidozie J.
Published: December 2021

Wars are cataclysmic events that inflict horrendous damage on people and society. In the case of the two World Wars whose magnitudes were global, and manners of prosecution total, this assertion pales in logic. The dangers that a future global war could pose for humanity given the tremendous leaps forward in the science and technology of warfare and weapons since the last World War are tremendous. This paper aims to use the examination of the ethics of war and warfare as backdrop on the analytical assessment of the implications of the exclusion of Africans from both the memorial and monuments that honor soldiers and their service in the two World Wars, even though their service and sundry contributions are salient and tremendous. The paper calls up the issue of racial identity in both Wars in puzzles: Do African soldiers in the Wars share a common humanity with their White counterparts? If they do, another puzzle is the following: Why then is their service still being commodified, to the extent of exclusion in memorials and monuments to soldiers that served and died in both Wars? The damning extrapolation from these puzzles is that there is still the belief albeit erroneous, in the establishment circles that regardless of the facts of history about the Wars, Africans are still viewed as lacking in contributions to the resolution of the threats that the World Wars represented to global peace. To reposition that under laying mind-set, the paper recommends the inclusion of African values of complementarity and inclusiveness in the quest for lasting global peace and the prevention of future Wars.
The Janus Face of Agricultural Policies, Kisans and Sethias: Local and Global
Authors: Alagh Yoginder K.
Published: December 2021

Indian agriculture is at a crossroads. We can plan out the phasing of reforms or force the pace and mess up the process. The Supreme Court had taken a practical stand on the Farm Trade Laws—implement them after consultation and with a well-defined framework spelt out. They had also appointed an expert amicus curiae. But this was not acceptable to the agitating farmer organisations in view of the stated views the experts had. It is possible that experts can re-examine their position as the Court said, but not highly probable. So going back to direct negotiations led to the stand the government has taken of holding the laws in abeyance for a year or a year-and-a-half. This will provide time for discussion of the details of agricultural reform which was needed since the laws were passed in a hurry on a single day. To begin with, it has to be understood that in a continental country one-size-fits-all will not work. The policy bind India is in is therefore a difficult one, even if the arguments are not ideologically anti-trade or those that lack policy interest. If a feasible alternate transitional policy set exists, a sensible approach would be to try to establish a roadmap of economic policies for, say a few major crops, and see if feasible alternatives exist.
Robust mixed H2/H∞ fuzzy tracking control of photovoltaic system subject to asymmetric actuator saturation
Authors: Boubekri Noureddine , Doudou Sofiane , Saifia Dounia , Chadli Mohammed
Published: December 2021

This paper focuses on mixed [Formula: see text] fuzzy maximum power point tracking (MPPT) of photovoltaic (PV) system under asymmetric saturation and variations in climatic conditions. To maximize the power from the PV panel array, the DC–DC boost converter is controlled by its duty ratio which is practically saturated between 0 and 1. MPPT based on conventional control presents the problems of oscillations around maximum power point (MPP) and divergence under rapid climatic changes. In order to attenuate the effect of atmospheric condition variation and take into account asymmetric saturation of the duty ratio, we propose a novel robust saturated controller based on both [Formula: see text] performances and Takagi-Sugeno (T-S) representation of PV-boost nonlinear system. Within this approach, the nonlinear PV-boost system and its reference are first described by T-S fuzzy models. Second, the saturation effect is represented by a polytopic model. Then, a fuzzy integral state feedback controller is designed to achieve stable MPPT control. Based on Lyapunov function, the mixed [Formula: see text] stabilization conditions are derived in terms of linear matrix inequalities (LMIs). The optimization of the attraction domain of closed-loop system is solved as a convex optimization problem in LMI terms. Finally, the efficiency of the proposed controller under irradiance and temperature variations is demonstrated through the simulation results. The comparison with some existing controllers shows an improvement of MPPT control performance in terms of power extraction.
Migration and Dynamics in Men’s and Women’s Domestic Work
Authors: Krieger Magdalena , Salikutluk Zerrin
Published: December 2021

International migration of couples is rising. Still, there is little evidence on men’s and women’s domestic work hours before and after migration. This is despite the fact that domestic work provides deep insights into family life and, for migrants, is directly linked to integration. Therefore, this study examines how immigrant men and women change their domestic work hours following migration, using data from the German Socio-Economic Panel (SOEP). Our results show that domestic work hours increase for both genders after immigration. However, men are more responsible for running errands than women in the first years after migration. In the long term, the gender gaps return to the pre-migration state, with women shouldering a greater load than men. Accordingly, this study shows that migration only has a short-term impact on couples’ division of domestic work.
Impact of farmers’ participation in tourism on sustainable livelihood outcomes in border tourism areas
Authors: Xu Shaogui , Zuo Yifan , Law Rob , Zhang Mu
Published: December 2021

Tourism, as a new way of industrial poverty alleviation, is of great significance to poverty reduction in border areas. This research takes the Sino–Vietnamese border tourism area as a case study and introduces a sustainable livelihood analysis framework. It collects questionnaire data from Napo County of Guangxi and uses structural equation modeling to analyze the behavioral intention of farmers still willing to participate in tourism after overcoming poverty. Results indicate that (1) participation motivation, participation opportunity, and participation ability had significant positive effects on farmers’ involvement level; (2) farmers’ economic, social, cultural, political, and environmental outcome perceptions had significant effects on their sustainable livelihood outcome perception; (3) farmers’ involvement level had a significant positive effect on their sustainable livelihood outcome perception; (4) the positive effect of the involvement level on behavioral intention failed to pass the significance test; and (5) farmers’ sustainable livelihood outcome perception had a significant positive impact on behavioral intention. Therefore, farmers’ involvement in poverty alleviation through tourism is a complex process of behavior and psychological perceptions.
Resting-state functional MRI signal fluctuation amplitudes are correlated with brain amyloid-β deposition in patients with mild cognitive impairment
Authors: Scheel Norman , Tarumi Takashi , Tomoto Tsubasa , Cullum C Munro , Zhang Rong , Zhu David C
Published: December 2021

Mounting evidence suggests that amyloid-β (Aβ) and vascular etiologies are intertwined in the pathogenesis of Alzheimer’s disease (AD). Blood-oxygen-level-dependent (BOLD) signals, measured by resting-state functional MRI (rs-fMRI), are associated with neuronal activity and cerebrovascular hemodynamics. Nevertheless, it is unclear if BOLD fluctuations are associated with Aβ deposition in individuals at high risk of AD. Thirty-three patients with amnestic mild cognitive impairment underwent rs-fMRI and AV45 PET. The AV45 standardized uptake value ratio (AV45-SUVR) was calculated using cerebral white matter as reference, to assess Aβ deposition. The whole-brain normalized amplitudes of low-frequency fluctuations (sALFF) of local BOLD signals were calculated in the frequency band of 0.01–0.08 Hz. Stepwise increasing physiological/vascular signal regressions on the rs-fMRI data examined whether sALFF-AV45 correlations were driven by vascular hemodynamics, neuronal activities, or both. We found that sALFF and AV45-SUVR were negatively correlated in regions of default-mode and visual networks (precuneus, angular, lingual and fusiform gyri). Regions with higher sALFF had less Aβ accumulation. Correlated cluster sizes in MNI space ( r ≈ −0.47) were reduced from 3018 mm3 to 1072 mm3 with stronger cardiovascular regression. These preliminary findings imply that local brain blood fluctuations due to vascular hemodynamics or neuronal activity can affect Aβ homeostasis.