Reconfigurable DNA Nanocage for Protein Encapsulation and Regulation.

Creating nanomachines capable of precisely capturing, organizing, and regulating the activity of target biomolecules holds profound significance for advancing nanotechnology and therapeutics. Here, we develop a multistage reconfigurable DNA nanocage that can enclose and modulate proteins through multivalent interactions, activated by specific molecular signals. By strategically designing and manipulating the strut architecture of the DNA nanocages, we can achieve precise control over their reconfiguration among pyramid, square, and linear branch shapes. Additionally, we demonstrated its ability to capture thrombin and effectively inhibit its coagulation activity by incorporating two thrombin-targeting aptamers into the designed arms of the DNA nanocage. The activity of thrombin can be recovered by rearranging the conformation of the DNA nanocage and exposing the protein, thereby activating the coagulation process. This approach enriches the design toolbox for dynamic nanomachines and inspires a new strategy for protein encapsulation and regulation with potential future therapeutic applications.

Minimal residual disease assessment in transplant-eligible patients with multiple myeloma: real-world applications of multiparametric flow cytometry-DURAClone (CAREMM-2104).

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Self-assembly of DNA parallel double-crossover motifs.

DNA double-crossover motifs, including parallel and antiparallel crossovers, serve as the structural foundation for the creation of diverse nanostructures and dynamic devices in DNA nanotechnology. Parallel crossover motifs have unique advantages over the widely used antiparallel crossover design but have not developed as substantially due to the difficulties in assembly. Here we created 29 designs of parallel double-crossover motifs varying in hybridization pathways, central domain lengths, and crossover locations to investigate their assembly mechanism. Arrays were successfully formed in four distinct designs, and large tubular structures were obtained in seven designs with predefined pathways and central domains appoximately 16 nucleotides in length. The nanotubes obtained from parallel crossover design showed improved nuclease resistance than the ones from the antiparallel counterpart design. Overall, our study provides a basis for the development of generalized assembly rules of DNA parallel crossover systems and opens new opportunities for their potential use in biological systems.

DNA T-shaped crossover tiles for 2D tessellation and nanoring reconfiguration.

DNA tiles serve as the fundamental building blocks for DNA self-assembled nanostructures such as DNA arrays, origami, and designer crystals. Introducing additional binding arms to DNA crossover tiles holds the promise of unlocking diverse nano-assemblies and potential applications. Here, we present one-, two-, and three-layer T-shaped crossover tiles, by integrating T junction with antiparallel crossover tiles. These tiles carry over the orthogonal binding directions from T junction and retain the rigidity from antiparallel crossover tiles, enabling the assembly of various 2D tessellations. To demonstrate the versatility of the design rules, we create 2-state reconfigurable nanorings from both single-stranded tiles and single-unit assemblies. Moreover, four sets of 4-state reconfiguration systems are constructed, showing effective transformations between ladders and/or rings with pore sizes spanning ~20 nm to ~168 nm. These DNA tiles enrich the design tools in nucleic acid nanotechnology, offering exciting opportunities for the creation of artificial dynamic DNA nanopores.

Prospective Comparative Study of Etoposide plus G-CSF versus G-CSF Alone, Followed by Risk-Adapted Plerixafor for Peripheral Blood Stem Cell Mobilization in Patients with Newly Diagnosed Multiple Myeloma: CAtholic REsearch Network for Multiple Myeloma Study (CAREMM-2001).

To explore the optimal mobilization for multiple myeloma (MM) patients, we conducted a prospective trial comparing single-dose etoposide (375 mg/m2 for one day) plus G-CSF versus G-CSF alone, followed by risk-adapted plerixafor. After randomization, 27 patients in the etoposide group and 29 patients in the G-CSF alone group received mobilizations. Six (22.2%) patients in the etoposide group and 15 (51.7%) patients in the G-CSF alone group received plerixafor based on a peripheral blood CD34+ cell count of < 15/mm3 (p = 0.045). The median count of CD34+ cells collected was significantly higher in the etoposide group (9.5 × 106/kg vs. 7.9 × 106/kg; p = 0.018), but the optimal collection rate (CD34+ cells ≥ 6 × 106/kg) was not significantly different between the two groups (96.3% vs. 82.8%; p = 0.195). The rate of CD34+ cells collected of ≥ 8.0 × 106/kg was significantly higher in the etoposide group (77.8% vs. 44.8%; p = 0.025). Although the rates of grade II-IV thrombocytopenia (63.0% vs. 31.0%; p = 0.031) and grade I-IV nausea (14.8% vs. 0%; p = 0.048) were significantly higher in the etoposide group, the rates of adverse events were low in both groups, with no neutropenic fever or septic shock. Thus, both single-dose etoposide plus G-CSF and G-CSF alone with risk-adapted plerixafor were effective and safe, but the former may be the better option for patients who are expected to receive two or more transplantations.

Comparisons of efficacy between frontline treatment with bortezomib-melphalan-prednisone and lenalidomide-dexamethasone for transplant-ineligible multiple myeloma: a multicenter real-world based registry report, CAREMM-2102 study.

BACKGROUND: Bortezomib-melphalan-prednisone (VMP) and lenalidomide-dexamethasone (Rd) remain the standard treatments for transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). This study aimed to compare real-world benefits between the two regimens. We also were interested in exploring efficacy according to subsequent therapy following VMP or Rd. METHODS: A total of 559 NDMM patients treated with VMP (n = 443, 79.2%) or Rd (n = 116, 20.8%) was recruited retrospectively from a multicenter database. RESULTS: Rd provided more benefits than VMP-overall response rate: 92.2 vs. 81.8%, p = 0.018; median progression-free survival (PFS): 20.0 vs. 14.5 months, p <0.001; second PFS (PFS2): 43.9 vs. 36.9 months, p = 0.012; overall survival (OS): 100.1 vs. 85.0 months, p = 0.017. Multivariable analysis revealed significant benefits of Rd over VMP, with hazard ratios of 0.722, 0.627, and 0.586 for PFS, PFS2, and OS, respectively. In propensity score-matched cohorts with matched VMP (n = 201) and Rd (n = 67) arms to balance baseline characteristics, Rd still showed significantly better outcomes for PFS, PFS2, and OS than VMP. Following VMP failure, triplet therapy showed significant benefits for response and PFS2; after Rd failure, PFS2 with carfilzomib-dexamethasone was significantly better than bortezomib-based doublet treatment. CONCLUSION: These real-world findings may assist with better selection between VMP and Rd as well as subsequent therapy for NDMM.

Prognostic value of low muscle mass at the 12th thoracic vertebral level in multiple myeloma treated with transplantation: CAREMM-2101 study.

PURPOSE: Autologous hematopoietic stem cell transplantation (ASCT) has been introduced as a standard treatment for newly diagnosed multiple myeloma (NDMM) following novel agent-based induction chemotherapy. This study investigated whether pre-ASCT low muscle mass evaluated using the paraspinal muscle index (PMI) at the 12th thoracic vertebra (T12) level is a reliable prognostic marker in NDMM after chemotherapy. METHODS: A multi-center registry database was retrospectively analyzed. Between 2009 and 2020, 190 patients with chest computed tomography images underwent frontline ASCT following induction therapy. The PMI was defined as the value of the paraspinal muscle area at the T12 level divided by the square of the patient's height. The cut-off value indicating a low muscle mass was sex-specific, using the lowest quintiles. RESULTS: Of the 190 patients, 38 (20%) were in the low muscle mass group. The low muscle mass group had a lower 4-year overall survival (OS) rate than the non-low muscle mass group (68.5% vs. 81.2%; P = 0.074). The median progression-free survival (PFS) in the low muscle mass group was significantly shorter compared with the non-low muscle mass group (23.3 months vs. 29.2 months; P = 0.029). The cumulative incidence of transplant-related mortality (TRM) was significantly higher in the low muscle mass group than in the non-low muscle mass group (4-year probability of TRM incidence, 10.6% vs. 0.7%; P < 0.001). In contrast, no significant difference in the cumulative incidence of disease progression was found between the two groups. Multivariate analysis revealed that low muscle mass was associated with significant negative outcomes for OS [(hazard ratio (HR): 2.14; P = 0.047], PFS (HR: 1.78; P = 0.012), and TRM (HR: 12.05; P = 0.025). CONCLUSION: Paraspinal muscle mass may have a prognostic role in NDMM patients who undergo ASCT. Patients with low paraspinal muscle mass have lower survival outcomes compared to non-low muscle mass group.

Advantage of achieving deep response following frontline daratumumab-VTd compared to VRd in transplant-eligible multiple myeloma: multicenter study.

Background: The goal of induction therapy for multiple myeloma (MM) is to achieve adequate disease control. Current guidelines favor triplet (bortezomib-lenalidomide-dexamethasone; VRd) or quadruplet regimens (daratumumab, bortezomib-thalidomide-dexamethasone; D-VTd). In the absence of a direct comparison between two treatment regimens, we conducted this study to compare the outcomes and safety of VRd and D-VTd. Methods: Newly diagnosed MM patients aged ＞18 years who underwent induction therapy followed by autologous stem cell transplantation (ASCT) between November 2020 and December 2021 were identified. Finally, patients with VRd (N=37) and those with D-VTd (N=43) were enrolled. Results: After induction, 10.8% of the VRd group showed stringent complete remission (sCR), 21.6% showed complete response (CR), 35.1% showed very good partial response (VGPR), and 32.4% showed partial response (PR). Of the D-VTd group, 9.3% showed sCR, 34.9% CR, 48.8% VGPR, and 4.2% PR (VGPR or better: 67.6% in VRd vs. 93% in D-VTd, P=0.004). After ASCT, 68.6% of the VRd group showed CR or sCR, while 90.5% of the D-VTd group showed CR or sCR (P=0.016). VRd was associated with an increased incidence of skin rash (P=0.044). Other than rashes, there were no significant differences in terms of adverse events between the two groups. Conclusion: Our study supports the use of a front-line quadruplet induction regimen containing a CD38 monoclonal antibody for transplant-eligible patients with newly diagnosed MM.

Nucleic acid paranemic structures: a promising building block for functional nanomaterials in biomedical and bionanotechnological applications.

Over the past few decades, DNA has been recognized as a powerful self-assembling material capable of crafting supramolecular nanoarchitectures with quasi-angstrom precision, which promises various applications in the fields of materials science, nanoengineering, and biomedical science. Notable structural features include biocompatibility, biodegradability, high digital encodability by Watson-Crick base pairing, nanoscale dimension, and surface addressability. Bottom-up fabrication of complex DNA nanostructures relies on the design of fundamental DNA motifs, including parallel (PX) and antiparallel (AX) crossovers. However, paranemic or PX motifs have not been thoroughly explored for the construction of DNA-based nanostructures compared to AX motifs. In this review, we summarize the developments of PX-based DNA nanostructures, highlight the advantages as well as challenges of PX-based assemblies, and give an overview of the structural and chemical features that lend their utilization in a variety of applications. The works presented cover PX-based DNA nanostructures in biological systems, dynamic systems, and biomedical contexts. The possible future advances of PX structures and applications are also summarized, discussed, and postulated.

Functional improvement by body-powered 3D-printed prosthesis in patients with finger amputation: Two case reports.

RATIONALE: The most common upper limb amputations are finger amputations, resulting in functional limitations that lead to problems with activities of daily living or job loss. For many years, prosthetic options for finger amputations have been limited to passive prostheses. In many countries including South Korea, body-powered finger prostheses have rarely been prescribed due to high cost, lack of experience of physicians and prosthetists, low interest and no coverage by insurance benefits. We report 2 cases of work-related finger amputations in patients who received body-powered 3D-printed finger prostheses. PATIENT CONCERNS AND DIAGNOSIS: Patient 1 was a 25-year-old woman with second and third finger amputations at the proximal interphalangeal level. Patient 2 was a 26-year-old man who sustained a second finger amputation at proximal interphalangeal level. INTERVENTIONS: We created body-powered 3D-printed finger prostheses that mimicked distal interphalangeal joint motion through patient-driven metacarpophalangeal joint motion using a string connected to a wrist strap and a linkage system. The source code "Knick Finger" was downloaded from e-NABLE. OUTCOMES: After 1 month of prosthesis training, both patients were satisfied with the prostheses and showed improved performance in patient-derived goals of cooking (patient 1) and typing on a computer (patient 2). LESSONS: Over the past decade, significant advances have been made in 3D-printed prosthetics owing to their light weight, low cost, on-site fabrication, and easy customization. Although there are still several limitations in the general application of 3D-printed finger prostheses, our study suggests that for patients with finger amputations, body-powered 3D-printed finger prostheses have high potential as an additional prosthetic option to the existing passive cosmetic prostheses.

Recent Advances in Self-Assembled DNA Nanostructures for Bioimaging.

DNA nanotechnology has been proven to be a powerful platform to assist the development of imaging probes for biomedical research. The attractive features of DNA nanostructures, such as nanometer precision, controllable size, programmable functions, and biocompatibility, have enabled researchers to design and customize DNA nanoprobes for bioimaging applications. However, DNA probes with low molecular weights (e.g., 10-100 nt) generally suffer from low stability in physiological buffer environments. To improve the stability of DNA nanoprobes in such environments, DNA nanostructures can be designed with relatively larger sizes and defined shapes. In addition, the established modification methods for DNA nanostructures are also essential in enhancing their properties and performances in a physiological environment. In this review, we begin with a brief recap of the development of DNA nanostructures including DNA tiles, DNA origami, and multifunctional DNA nanostructures with modifications. Then we highlight the recent advances of DNA nanostructures for bioimaging, emphasizing the latest developments in probe modifications and DNA-PAINT imaging. Multiple imaging modules for intracellular biomolecular imaging and cell membrane biomarkers recognition are also summarized. In the end, we discuss the advantages and challenges of applying DNA nanostructures in bioimaging research and speculate on its future developments.

Prognostic role of the ratio of natural killer cells to regulatory T cells in patients with multiple myeloma treated with lenalidomide and dexamethasone.

Despite advances in treating newly diagnosed multiple myeloma (NDMM), a biomarker-driven personalized approach remains an unmet need. A combination of lenalidomide and dexamethasone (RD) is a widely available chemotherapeutic option for NDMM. We aimed to find a circulating immune cell-based biomarker to predict prognosis following RD in patients with NDMM. Clinical data and peripheral blood samples of 71 consecutive NDMM patients treated with RD were retrospectively analyzed. Peripheral blood samples were taken at the time of diagnosis. Immune cell populations, including natural killer (NK) cells, T cells, and their subpopulations, were identified by flow cytometry. In univariable analysis, four variables, including low expression (third or lower quartile) of NK cells, high expression (first or greater quartile) of regulatory T (Treg) cells, female sex, and lambda light chain type, could be plausible factors in predicting poor progression-free survival (PFS). With use of the ratio of NK cells to Treg cells (NK/Treg) as a biomarker, the median PFS of patients with low NK/Treg (less than first quartile, n = 18) was significantly inferior to that of patients with high NK/Treg (first or greater quartile, n = 53): 19.8 months versus 57.3 months, p = 0.047. In multivariable analysis, low NK/Treg was significantly associated with poor PFS (hazard ratio: 2.877, 95% confidence interval: 0.001-1.009, p = 0.048), even after adjusting for other confounding factors. NK/Treg at the time of diagnosis might be a useful immune cell biomarker for clinical decision-making for the use of RD in NDMM. Further investigations are needed to improve outcomes of NDMM patients based on the understanding of the role of NK/Treg.

Dimensionality-Dependent Mechanical Stretch Regulation of Cell Behavior.

A variety of cells are subject to mechanical stretch in vivo, which plays a critical role in the function and homeostasis of cells, tissues, and organs. Deviations from the physiologically relevant mechanical stretch are often associated with organ dysfunction and various diseases. Although mechanical stretch is provided in some in vitro cell culture models, the effects of stretch dimensionality on cells are often overlooked and it remains unclear whether and how stretch dimensionality affects cell behavior. Here we develop cell culture platforms that provide 1-D uniaxial, 2-D circumferential, or 3-D radial mechanical stretches, which recapitulate the three major types of mechanical stretches that cells experience in vivo. We investigate the behavior of human microvascular endothelial cells and human alveolar epithelial cells cultured on these platforms, showing that the mechanical stretch influences cell morphology and cell-cell and cell-substrate interactions in a stretch dimensionality-dependent manner. Furthermore, the endothelial and epithelial cells are sensitive to the physiologically relevant 2-D and 3-D stretches, respectively, which could promote the formation of endothelium and epithelium. This study underscores the importance of recreating the physiologically relevant mechanical stretch in the development of in vitro tissue/organ models.

Latent triple trajectories of substance use as predictors for the onset of antisocial personality disorder among urban African American and Puerto Rican adults: A 22-year longitudinal study.

Background: Antisocial personality disorder (ASPD) incurs a high cost to society due to the high risk of violent and nonviolent offenses associated with this personality disorder, thus making the examination of the etiology and the onset of ASPD an important public health concern. Method: The present study consisted of five waves of data collection of the Harlem Longitudinal Development Study (N = 674). In the Cox proportional hazard model, latent multiple substance use trajectories from mid-adolescence to emerging adulthood (mean age 14 to mean age 24) were used as a predictor for the onset of ASPD during emerging adulthood to the mid-thirties (mean age 24 to mean age 36). The control variables were gender, ethnicity, problem behaviors, and victimization. Results: In the multiple Cox proportional hazard model, the high (HR = 2.74, p < 0.001) and the increasing frequency of (HR = 2.55, p < 0.001) use on alcohol, cigarette, and cannabis latent trajectory groups were associated with an increased hazard of ASPD onset as compared with the no or low frequency of use on alcohol, cigarette, and cannabis latent trajectory group after controlling for demographic factors and earlier problem behaviors as well as victimization. Conclusions: The implications of this study for the prediction of adult ASPD onset time may focus on the early use of alcohol, cigarette, and cannabis from mid adolescence to emerging adulthood.

Correlates of Cannabis Use Disorders among urban women of color: childhood abuse, relationship with spouse/partner, and media exposure.

OBJECTIVES: As the rate of cannabis use increases, it is expected that more individuals will develop a Cannabis Use Disorder (CUD). Relatively little is known, however, about the psychosocial correlates of CUDs among racial/ethnic minority women. This study, therefore, examined correlates of CUDs among a cohort of adult African American and Puerto Rican women. METHODS: The sample consisted of African American and Puerto Rican female participants (N = 343), who have been followed by the Harlem Longitudinal Development Study from mean age 14 to mean age 39 years. The bivariate and multivariate associations between CUDs at age 39 and variables from 5 domains - demographics, earlier cannabis use, childhood abuse, the relationship with the spouse/partner, and media exposure - were assessed using logistic regression analyses. RESULTS: The results showed that, with the exception of demographic factors, variables from each of the domains (e.g., sexual abuse in childhood, arguments with spouse/partner, and hours of visual media exposure) were related to CUDs at age 39. CONCLUSIONS: Findings suggest that in addition to treating CUDs, couples therapy may be indicated to strengthen the spousal/partner relationship, enlist the spouse/partner's support for cannabis use cessation. Furthermore, frequency of visual media exposure may need to be reduced.

Mitochondrial antiviral signaling protein is crucial for the development of pulmonary fibrosis.

Danger signals, or damage-associated molecular patterns (DAMPs), instigate mitochondrial innate immune responses wherein mitochondrial antiviral signaling protein (MAVS) functions as a key platform molecule to mediate them. The role of MAVS in the pathogenesis of idiopathic pulmonary fibrosis (IPF), however, has not yet been identified. Whether MAVS signalling can be modulated by currently existing drugs has also not been explored.We used an established model of pulmonary fibrosis to demonstrate that MAVS is a critical mediator of multiple DAMP signalling pathways and the consequent lung fibrosis after bleomycin-induced injury in vivoAfter bleomycin injury, MAVS expression was mainly observed in macrophages. Multimeric MAVS aggregation, a key event of MAVS signalling activation, was significantly increased and persisted in bleomycin-injured lungs. A proapoptotic BH3 mimetic, ABT-263, attenuated the expression of MAVS and its signalling and, consequently, the development of experimental pulmonary fibrosis. In contrast, the therapeutic effects of nintedanib and pirfenidone, two drugs approved for IPF treatment, were not related to the modulation of MAVS or its signalling. Multimeric MAVS aggregation was significantly increased in lungs from IPF patients as well.MAVS may play an important role in the development of pulmonary fibrosis, and targeting MAVS with BH3 mimetics may provide a novel and much needed therapeutic strategy for IPF.

Longitudinal predictors of male sexual partner risk among Black and Latina women in their late thirties: ethnic/racial identity commitment as a protective factor.

This study aimed to investigate predictors of male sexual partner risk among Latinas and Black women in their late thirties. We used multiple regression analysis to examine factors associated with male sexual partner risk among 296 women who participated in two waves of the Harlem Longitudinal Development Study (New York, 2011-2013 and 2014-2016). Women who experienced childhood sexual abuse had higher risk partners than those who did not [b = 0.16, 95% confidence interval (CI) = 0.06, 0.28]. Earlier marijuana use was a risk factor for partner risk in the late thirties (b = 0.12, 95% CI = 0.04, 0.27). Higher levels of ethnic/racial identity commitment mitigated this risk (b = - 0.15, 95% CI = - 0.26, - 0.04). Ethnic/racial identity commitment can be protective against male sexual partner risk among Latina and Black women who use marijuana. Further research should explore the protective role of different dimensions of ethnic/racial identity against sexually transmitted infections, including HIV.

Adolescent risk and protective factors predicting triple trajectories of substance use from adolescence into adulthood.

OBJECTIVES: Since the number of individuals who use substances in the United States has markedly increased every year, substance use is a significant public health concern. The current study examines the possible risk and protective factors associated with triple comorbid trajectories of longitudinal alcohol, tobacco, and cannabis use from age 14 to 36. METHODS: A community sample of 674 participants (53% African Americans and 47% Puerto Ricans; 60% females) were recruited from the Harlem Longitudinal Development Study. Multinomial logistic regression analyses were conducted to examine the associations between the risk (low self-control, peer drug use) and protective (parent-child attachment, family church attendance) factors at age 14 and membership in the triple trajectory groups derived from a multivariate growth mixture model. RESULTS: Low self-control and peer drug use were associated with an increased likelihood of being a member in the triple comorbid trajectory groups compared to the reference group (i.e., low alcohol, no tobacco, and no cannabis use). On the other hand, parent-child attachment and family church attendance were associated with a decreased likelihood of being a member in the triple comorbid trajectory groups compared to the reference group. CONCLUSIONS: Treatment programs for adolescents who use substances may be more helpful if their parents and/or friends could also participate together with the adolescent, rather than only the adolescent participates in the treatment programs. Further research is needed to gain a greater understanding of the conceptual nature of the relationship between earlier risk and protective factors and later substance use patterns.