Initial Progress Research Articles

Evolution over time of cardiac biomarkers, electrocardiographic and echocardiographic features in a large cohort of patients with wild-type transthyretin cardiac amyloidosis treated with tafamidis

Abstract Introduction Data on evolution of transthyretin wild-type cardiac amyloidosis (ATTRwt) during treatment with tafamidis is scarce. This hinders the quest for parameters of response and a priori treatment eligibility. Purpose To study the evolution of biomarkers, ECG, and echocardiographic features during early tafamidis treatment. Methods We prospectively collected data after 12-18 months of treatment in a single-centre database. Changes of NT-proBNP and high-sensitivity Troponin I (hs-cTnI) between baseline and follow-up evaluations (at 12 and 18 months) were tested for significance. For ECG and echocardiographic features, we considered baseline and the last available follow-up (median interval 11.1 months). Results We included 253 patients (median age 77[71-82]years; 90% males). Median (IQR) baseline NT-proBNP was 2472(1355-4749)ng/L, hs-cTnI 47(30-82)ng/L. Furosemide was administered in 58% of cases (median dose 25[25-50]mg/day). Compared to baseline, NT-proBNP was 2342(1316-4148)ng/L at 12 (p=0.886), and 2633(1393-6063)ng/L at 18 months (p=0.285), with 4% and 30% of patients showing ≥30% and ≥300ng/L increase at 12 and 18 months, respectively; hs-cTnI was 46(29-70)ng/L at 12 (p=0.947), and 44(25-68)ng/L at 18 months (p=0.866), with 35% and 7% showing a ≥20% increase at 12 and 18 months, respectively, and 21 (11.5% over 183 analyzable) with increase at 12 and reduction at 18 months. Patients on furosemide were 69% and 70% at 12 and 18 months, respectively; the dose increased to 37.5(25-75)mg/day at 18 months (p=0.009). At baseline, 117(47%) patients had history/permanent atrial fibrillation (AF). Forty-one(16%) had an implantable electronic device, 16(6%) underwent subsequent implantation. Median PR interval was 210(185-240)msec, trending toward prolongation (p=0.054). QRS duration increased (100[86-130]vs120[90-140]msec, p=0.004), together with conduction disturbances (left anterior fascicular block 30[21%]vs43[29%], p=0.036; right bundle branch block 14[10%]vs27[18%], p=0.002). AF prevalence raised from 19% to 25%. There were no significant changes in left ventricular (LV) geometry (septum thickness 18[16-20]vs18[16-20]mm, p=0.666; end-diastolic diameter 45±7vs45±8mm, p=0.434), systolic function (ejection fraction 51±10%vs49±11%, p=0.070), filling pressures (E/e’ 17[11-20]vs14.9[13-19], p=0.086) and left atrial size (mean volume 46±15vs48±13ml/m2, p=0.649). Tricuspid annular plane systolic excursion (18±4vs17±4mm) and pulmonary artery systolic pressure (40[33-45]vs36[30-45]mmHg) remained stable. Conclusions We did not observe neither improvement nor worsening of laboratory/instrumental variables within the first 12-18 months of tafamidis. There was a progression of electrical disorders. After initial progression hs-cTnI tended to improve. Extended follow-up and a matched case-control series will help identify possible later changes useful to monitor treatment response and effects of supporting heart failure treatments.

Emerging strategies to investigate the biology of early cancer.

Early detection and intervention of cancer or precancerous lesions hold great promise to improve patient survival. However, the processes of cancer initiation and the normal-precancer-cancer progression within a non-cancerous tissue context remain poorly understood. This is, in part, due to the scarcity of early-stage clinical samples or suitable models to study early cancer. In this Review, we introduce clinical samples and model systems, such as autochthonous mice and organoid-derived or stem cell-derived models that allow longitudinal analysis of early cancer development. We also present the emerging techniques and computational tools that enhance our understanding of cancer initiation and early progression, including direct imaging, lineage tracing, single-cell and spatial multi-omics, and artificial intelligence models. Together, these models and techniques facilitate a more comprehensive understanding of the poorly characterized early malignant transformation cascade, holding great potential to unveil key drivers and early biomarkers for cancer development. Finally, we discuss how these new insights can potentially be translated into mechanism-based strategies for early cancer detection and prevention.

Recent Progress on Organic Electron Donors (OEDs) Enabled Radical Reactions

Over the past few decades, organic transformations facilitated by small organic molecules have witnessed considerable advancements. Small organic molecules have been widely applied to the construction of various skeletons. However, reduction as one of the fundamental reactions is generally initiated by metal‐containing reducing agents, although the initial progress of organic electron donors (OEDs) enabled reductive cleavage of some chemical bonds had been achieved in 1990s. Due to their structural diversity and tunability, OEDs can overcome the limitations of metal‐based reducing agents, such as low selectivity and poor functional group tolerance as well as the environmental problems caused by substantial inorganic waste after reactions. Building on a brief historical overview of OED research, this review focuses on the rencent advancements of the OEDs promoted radical reactions. It covers the reduction of C‐X (X =C, O, N etc.) single bonds, radical cyclization, intermolecular radical addition to unsaturated bonds, radical coupling, functionalization of aromatics, and C‐H bond activation. Additionally, the mechanistic insights of the typical reactions are highlighted for well understanding of the reaction mode involving OEDs.

Efficacy in myopia control-The impact of rebound.

When myopia control treatment is discontinued, progression will increase, but does it revert to expected values based on the age and race of the child or does it accelerate further? The latter scenario is considered a rebound. A PubMed search was conducted with the words 'rebound' and 'myopia control', identifying further papers from reviews. Inclusion was limited to prospective studies with ≥6 months of treatment, ≥3 months of data following cessation and with axial length data, which allowed calculation of rebound. Nineteen studies were identified, comprising 24 treatment groups. In 10 studies, untreated control children were followed both throughout the treatment and cessation periods, allowing for a concurrent comparison group. In three studies, a control group was followed for 1 or 2 years and thereafter received the treatment under evaluation. Later, treatment ceased in the originally treated children. Finally, six studies were cross-over designs. For these latter two study designs, initial axial elongation and myopia progression in the control group were extrapolated to the cessation period, accounting for annual slowing. Values from durations of <1 year were annualised. The mean annualised rebound was +0.05 ± 0.10 mm and -0.09 ± 0.24 D for axial length and myopia progression, respectively, and these were correlated (r2 = 0.59, p < 0.001). Rebound was associated with 1-year treatment efficacy (r2 = 0.43, p < 0.001). The mean annualised rebound with optical corrections was -0.01 ± 0.03 mm. Five of the six highest rebound values (≥0.14 mm) were from red light therapy and atropine studies. Rebound ranged from +0.03 to +0.14 mm for overnight orthokeratology. Consistent with previous statements, no evidence for rebound was found for myopia control spectacles and soft contact lenses. Future research should explore the influence of age and magnitude of treatment efficacy on rebound.

Pancreatic STAT5 activation promotes KrasG12D-induced and inflammation-induced acinar-to-ductal metaplasia and pancreatic cancer

ObjectivePancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy because it is often diagnosed at a late-stage. Signal transducer and activator of transcription 5 (STAT5) is a transcription factor implicated...

Observing the SO2 and Sulfate Aerosol Plumes From the 2022 Hunga Eruption With the Infrared Atmospheric Sounding Interferometer (IASI)

AbstractThe Hunga volcano violently erupted on 15 January 2022, producing the largest perturbation of the stratospheric aerosol layer since Pinatubo 1991, despite the initially estimated modest injection of SO2. This study presents novel SO2 and sulfate aerosol (SA) co‐retrievals from the Infrared Atmospheric Sounding Interferometer, and uses them to quantify the initial progression of the Hunga plume. These observations are consistent with rapid conversion of SO2 (e‐folding time: 17.1 ± 4.3 days) to SA, with an injected burden of &gt;1.0 Tg SO2. This points at larger SO2 injections than previously thought. A long‐lasting SA plume was observed, with two separate build‐up phases, and with a meridional dispersion of marked anomalies from the tropics to the higher southern hemispheric latitudes. A limited (∼20%) SA removal was observed after 1‐year dispersion. The total injected SA mass burden was estimated at 1.6 ± 0.5 Tg in the total atmospheric column, with a build‐up e‐folding time of about 2 months.

Female-specific mechanisms of meiotic initiation and progression in mammalian oocyte development.

Meiosis is regulated in sexually dimorphic manners in mammals. In females, the commitment to and entry into meiosis are coordinated with the developmental program of oocytes. Female germ cells initiate meiosis within a short time window during the fetal period and then undergo meiotic arrest until puberty. However, the genetic mechanisms underlying the orchestration of oocyte development and meiosis to maximize the reproductive lifespan of mammalian females remain largely elusive. While meiotic initiation is regulated by a sexually common mechanism, where meiosis initiator and Stimulated by Retinoic Acid Gene 8 (STRA8) activate the meiotic genes, the female-specific mode of meiotic initiation is mediated by the interaction between retinoblastoma (RB) and STRA8. This review highlights the female-specific mechanisms of meiotic initiation and meiotic prophase progression in the context of oocyte development. Furthermore, the downstream pathway of the RB-STRA8 interaction that may regulate meiotic arrest will be discussed in the context of oocyte development, highlighting a potential genetic link between the female-specific mode of meiotic entry and meiotic arrest.

Determining Long-term Prostate Cancer Outcomes for Active Surveillance Patients Without Early Disease Progression: Implications for Slowing or Stopping Surveillance

Background and objectiveActive surveillance (AS) of prostate cancer (PCa) is the standard of care for low-grade disease, but there is limited guidance on tailoring protocols for stable patients. We investigated long-term outcomes for patients without initial progression and risk factors for upgrade. MethodsMen on AS with Gleason grade group (GG) 1 PCa on three serial biopsies, ≥5 yr without progression, and ≥10 yr of follow-up were included. Outcomes were upgrade (GG ≥2), major upgrade (GG ≥3), progression to treatment, metastasis, PCa-specific survival, and overall survival. Cox proportional hazards regression models were used to estimate the associations between patient characteristics and risk of upgrade. Key findings and limitationsA total of 774 men met the inclusion criteria. At 10, 12, and 15 yr, upgrade-free survival rates were 56%, 45%, and 21%; major upgrade–free survival rates were 88%, 83%, and 61%; treatment-free survival rates were 86%, 83%, and 73%; metastasis-free survival rates were 99%, 99%, and 98%; and overall survival rates were 98%, 96%, and 95%, respectively. PCa-specific survival was 100% at 15 yr. On a multivariable analysis, year of diagnosis, age, body mass index (BMI), and biopsy core positivity were associated with upgrade (all p < 0.01), whereas age and prostate-specific antigen (PSA) density were associated with major upgrade. Conclusions and clinical implicationsPatients without progression for 5 yr on AS had modest rates of upgrade and low rates of metastasis, and mortality at 15 yr of follow-up. Year of diagnosis, older age, increased BMI, and increased biopsy core positivity were associated with upgrade, whereas older age and greater PSA density were associated with an increased risk of major upgrade. A subset of these patients may benefit from deintensification of AS protocols. Patient summaryThere are little reported data or clinical guidelines for patients with prostate cancer (PCa) who are stable for many years on active surveillance (AS). We show, in a large cohort, that PCa patients without progression for 5 yr on AS have modest rates of upgrade and very low rates of metastasis, and mortality rates at 15 yr of follow-up, and that older age, increased body mass index, and increased PCa volume are associated with an increased likelihood of future upgrade. This study supports continued AS in this patient population and deintensification in select patients.

Evaluation of Sugarcane Crop Growth Monitoring Using Vegetation Indices Derived from RGB-Based UAV Images and Machine Learning Models

Crop monitoring with unmanned aerial vehicles (UAVs) has the potential to reduce field monitoring costs while increasing monitoring frequency and improving efficiency. However, the utilization of RGB-based UAV imagery for crop-specific monitoring, especially for sugarcane, remains limited. This work proposes a UAV platform with an RGB camera as a low-cost solution to monitor sugarcane fields, complementing the commonly used multi-spectral methods. This new approach optimizes the RGB vegetation indices for accurate prediction of sugarcane growth, providing many improvements in scalable crop-management methods. The images were captured by a DJI Mavic Pro drone. Four RGB vegetation indices (VIs) (GLI, VARI, GRVI, and MGRVI) and the crop surface model plant height (CSM_PH) were derived from the images. The fractional vegetation cover (FVC) values were compared by image classification. Sugarcane plant height predictions were generated using two machine learning (ML) algorithms—multiple linear regression (MLR) and random forest (RF)—which were compared across five predictor combinations (CSM_PH and four VIs). At the early stage, all VIs showed significantly lower values than later stages (p &lt; 0.05), indicating an initial slow progression of crop growth. MGRVI achieved a classification accuracy of over 94% across all growth phases, outperforming traditional indices. Based on the feature rankings, VARI was the least sensitive parameter, showing the lowest correlation (r &lt; 0.5) and mutual information (MI &lt; 0.4). The results showed that the RF and MLR models provided better predictions for plant height. The best estimation results were observed withthe combination of CSM_PH and GLI utilizing RF model (R2 = 0.90, RMSE = 0.37 m, MAE = 0.27 m, and AIC = 21.93). This study revealed that VIs and the CSM_PH derived from RGB images captured by UAVs could be useful in monitoring sugarcane growth to boost crop productivity.

Synchronous Oligometastasis and Oligoprogression as a Prognostic Marker in Patients With Extensive-Stage SCLC Treated With a Combination of Immune-Checkpoint Inhibitor and Chemotherapy (HOT2301)

IntroductionOligometastasis and oligoprogression (OP) has not been adequately defined in extensive-stage SCLC (ES-SCLC) and may be a good indication for adding local treatment. Therefore, this multicenter study aimed to investigate the prognostic impact of oligometastasis and OP in ES-SCLC. MethodsWe enrolled patients who received chemoimmunotherapy between September 2019 and June 2022. Patients were classified into oligometastasis and non-oligometastasis groups by determining the number of original tumor lesions and distant metastases (worsening or newly appearing lesions) at the time of initial diagnosis and disease progression after first-line treatment. ResultsWe retrospectively analyzed 265 consecutive patients with ES-SCLC. Synchronous oligometastasis (SOM) and OP was defined as less than or equal to five lesions in less than or equal to two organs, including lungs; 21.0% and 53.2% of patients had SOM and OP, respectively. Median progression-free survival was 5.8 months and 4.9 months in patients with and without SOM, respectively (hazard ratio [HR] = 0.72, 95% confidence interval [CI]: 0.51–1.02, p = 0.065). Median overall survival was 20.5 months and 15.0 months in patients with and without SOM (HR = 0.58, 95% CI: 0.37–0.95, p = 0.027) from the initiation of first-line treatment. The OP group revealed a better progression-free survival of 5.2 months (versus 3.2 mo, HR = 0.69, 95% CI: 0.50–0.96, p = 0.026) and overall survival of 15.1 months (versus 7.5 mo, HR = 0.44, 95% CI: 0.29–0.66, p = 0.027) from the initiation of second-line treatment compared with the non-OP group. The Lung Immune Prognostic Index score was significantly lower in the SOM and OP group. ConclusionsES-SCLC in patients with SOM and OP may be more indolent than that of the nonoligometastasis group, therefore, new treatment strategies, including the addition of local treatment, should be explored. Clinical trial registrationThis study was registered at UMIN-CTR (UMIN000053402).

Breakdown and Repair of Peripheral Immune Tolerance in Type 1 Diabetes.

Failures in peripheral immune tolerance mechanisms create a permissive environment for autoimmune diabetes initiation and disease progression. Biomarker analyses provide tools that allow recognition of this loss of tolerance, reflecting a serial acquisition of pathogenic characteristics causally linked to islet β-cell dysfunction and death. Autoimmune effector cell activation and expansion, ineffective immune regulation, and tissue response to injury during active disease each represent challenges to homeostasis; however, they also represent targets for therapeutic intervention, with the potential for restoration of tolerance. Limited success in recent clinical trials demonstrates that tolerance in type 1 diabetes (T1D) is achievable, but currently occurs in few subjects and is not durable in most. Combining therapeutic agents to rebuild multiple immune components to restore tolerance, particularly addressing both effector and regulatory T-cell dysfunction, is needed.

Measurement of Stark-split beam and carbon charge exchange emissions for simultaneous B-field and temperature/rotation analysis at DIII-D.

A set of two newly designed, single-channel Czerny-Turner spectrometers has been deployed at the DIII-D tokamak for measurements of the motional Stark effect (MSE) split beam emission and the C6+ (CVI) carbon charge exchange recombination (CER) emission at high spectral (δλ = 0.13nm) and temporal (1-5kHz) resolution. High throughput optics (f/# = 2.8) allow for good signal-to-noise at high time resolution using fast EMCCD detectors. The MSE emission allows for spectral fitting of the magnitude and direction of the local B-field, while the carbon emission yields local ion temperature and toroidal rotation information. To reduce so-called Doppler broadening of the MSE emission, a new channel-specific variable lens-masking approach has been developed. Experimental data collected from the 2023 DIII-D experimental campaign demonstrate the signal quality and instrument fidelity for both diagnostic measurements. Moreover, initial CER data analysis shows a clear evolution of the toroidal rotation during edge localized modes. Initial progress on the advanced MSE model, including a new validated ray-trace model of the DIII-D collection optics, is shown via sensitivity analysis.

The role of autophagy dysregulation in low and high-grade nonmuscle invasive bladder cancer: A survival analysis and clinicopathological association

IntroductionBladder cancer disproportionately affects men and often presents as nonmuscle-invasive bladder cancer (NMIBC). Despite initial treatments, the recurrence and progression of NMIBC are linked to autophagy. This study investigates the expression of autophagy genes (mTOR, ULK1, Beclin1, and LC3) in low and high-grade NMIBC, providing insights into potential prognostic markers and therapeutic targets. Material and methodsA total of 115 tissue samples (n = 85 NMIBC (pTa, pT1, and CIS) and n = 30 control from BPH patients) were collected. The expression level of autophagy genes (mTOR, ULK1, Beclin1, and LC3) and their proteins were assessed in low and high-grade NMIBC, along with control tissue samples using quantitative real-time polymerase chain reaction and western blotting. Association with clinicopathological characteristics and autophagy gene expression was analyzed by multivariate and univariate survival analysis using SPSS. ResultIn high-grade NMIBC, ULK1, P = 0.0150, Beclin1, P = 0.0041, and LC3, P = 0.0014, were substantially downregulated, whereas mTOR, P = 0.0006, was significantly upregulated. The KM plots show significant survival outcomes with autophagy genes. The clinicopathological characters, high grade (P = 0.019), tumor stage (CIS P = 0.039, pT1 P = 0.018, P = 0.045), male (P = 0.010), lymphovascular invasion (P = 0.028) and autophagy genes (ULK1 P = 0.002, beclin1 (P = 0.010, P = 0.022) were associated as risk factors for survival outcome in NMIBC patients. ConclusionThe upregulated mTOR, downregulated ULK1, and beclin1 expression is linked to a high-grade, CIS and pT1 stage, resulting in poor recurrence-free survival and progression-free survival and highlights the prognostic significance of autophagy gene in nonmuscle-invasive bladder cancer.

The disaggregation of the oswestry disability index in patients undergoing lumbar surgery for degenerative lumbar spondylolisthesis

BACKGROUND CONTEXTThe Oswestry Disability Index (ODI), is a widely used patient-reported outcome measure (PROM) for assessing functional status in individuals with lumbar spine pathology. The ODI is used by surgeons to determine the initial status and monitor progress after surgery. Compiled ODI data enables comparisons between different surgical techniques. Degenerative lumbar spondylolisthesis (DLS) often causes symptoms such as back pain and neurogenic claudication affecting quality of life and activities of daily living captured by the ODI. Despite extensive studies on ODI changes after spinal surgery, little is known about the characteristics and changes in the different ODI subsections. PURPOSETo analyze the baseline characteristics and changes in total ODI and ODI subsections 2 years after elective lumbar surgery. STUDY DESIGNRetrospective analysis on patients prospectively enrolled who underwent spinal surgery for degenerative lumbar spondylolisthesis from 2016 to 2018. The ODI was assessed preoperatively and 2 years postoperatively. PATIENT SAMPLEA total of 265 patients were included in the study, 60% were female. The mean age of the patients was 67±8 years, and the mean BMI was 30±6 kg/m2. OUTCOME MEASURESThe analysis considered the differences in ODI scores before and after surgery, as well as the changes in all ODI subsections 2 years after elective lumbar surgery for DLS. METHODSThe analysis evaluated differences in ODI scores and variations in different subsections. Patients without an ODI follow-up at 2 years were excluded from the study. The study utilized the Wilcoxon Signed Rank Test for all prepost paired samples. The Wilcoxon rank sum test was used for sex and procedure comparisons for overall ODI and ODI subsection analysis. Univariate linear regression was applied for overall and subsection specific ODI outcomes with age and BMI as independent variables, respectively. The statistical significance level was set at p<.05. RESULTSImprovement in ODI was observed in 242 patients (91%). The highest baseline disability values were found for the questions regarding pain intensity (3.4±1.3), lifting (3.2±1.9), and standing (3.4±1.3). The lowest preoperative functional limitations were observed in sleeping (1.6±1.3), personal care (1.6±1.4), traveling (1.6±1.2) and sitting (1.5±1.4). At the 2-year follow-up, there was significant improvement in all questions and the overall ODI (all p<.001). The ODI subsections that showed the greatest absolute improvements were changing degree of pain (−2.6), with 89% of patients experiencing improvement, standing (−2.4) with 87% of patients experiencing improvement, and pain intensity (−2.1) with 81% of patients experiencing improvement. The subsections with the least improvement were personal care (−0.6), sitting (−0.7), and sleeping (−0.9). The study found that female patients had a significantly higher preoperative disability in various subsections but showed greater improvement in total ODI compared to male patients (p=.001). Additionally, improvement in sitting (p<.001), traveling (p<.001), social life (p<.001) and sleeping (p=.018) were significantly higher in female patients. Older patients showed significantly less improvement in sitting (p=.005) and sleeping (p=.002). A higher BMI was significantly associated with less improvement in changing degree of pain (p=.025) and higher baseline disability in various subsections. Patients who underwent decompression and fusion had significantly higher baseline disability in several subsections compared to those who underwent decompression alone. There was no significant difference between decompression alone and decompression with fusion in terms of overall improvement in the ODI and improvement in the subsections. CONCLUSIONThese results offer a more comprehensive understanding of ODI and its changes across different subsections. This insight is invaluable for improving preoperative education and effectively managing patient expectations regarding potential postsurgery disability in specific areas.

LA INCLUSIÓN, LA EDUCACIÓN INCLUSIVA Y LA CULTURA DE PAZ EN DOS INSTITUCIONES DE EDUCACIÓN SUPERIOR MEXICANAS

Inclusion, inclusive education, and the promotion of a culture of peace in secondary and higher education represent significant challenges for higher education institutions. In Mexico, experiences have been identified that reflect both the achievements made and the obstacles that remain on the path to ensuring equitable and quality education for all. This document highlights, on the one hand, the trajectory of the Metropolitan Autonomous University, which, in the Academic Unit of Iztapalapa, developed the Academic Model for Collaborative Construction of Learning taking into account important references from the UAM-Iztapalapa Inclusive Project; on the other hand, it reflects and shows the progress of the advanced initiatives and activities that were launched at the Autonomous University of the State of Morelos through the Inclusive Education Unit. What was done in both higher education institutions is framed in the context of what was the beginning of the health contingency caused by the SARS-Cov-2 virus and its subsequent effects that still remain unfinished.

Despite the haters: The immense promise and progress of diversity, equity, and inclusion initiatives

Despite the haters: The immense promise and progress of diversity, equity, and inclusion initiatives

CD47-SIRPα signaling-inspired engineered monocytes for preventing the progression of atherosclerotic plaques

The accumulation of foam cells in the subendothelial space of the vascular wall to form plaques is the real cause of atherosclerotic lesions. Conventional interventions, such as statins and anti-cytokine or anti-inflammatory therapies, suffer problems in terms of their short therapeutic outcomes and potential disruption of the immune system. The development of more efficient therapeutics to restrict the initial progression of plaques appears to be crucial for treating and preventing atherosclerosis. Decreasing foam cell formation by reversing the excessive phagocytosis of modified low-density lipoprotein (LDL) in macrophages is highly desirable. Here, we developed a strategy based on engineered monocytes to dynamically regulate lipid uptake by macrophages inspired by a CD47–SIRPα signaling-induced defect in the phagocytosis of lesional macrophages at the advanced stage of AS. Briefly, a complex called CD47p-GQDs-miR223, which is designed to interact with SIRPα, was synthesized to remodel monocytes by decreasing the uptake of oxidized LDL through the activation of CD47-SIRPα signaling. After injection, these monocytes compete for recruitment to atherosclerotic plaques, release gene drugs and mediate anti-inflammatory phenotypic remodeling of the aboriginal macrophages, effectively inhibiting the development of foam cells. Our strategy provides a new therapeutic for preventing the progression of atherosclerosis.

Bone mineral density: Comparison between women under hormone replacement therapy with Turner syndrome or idiopathic premature ovarian insufficiency

ContextTurner syndrome (TS) is characterized by short stature and premature ovarian insufficiency (POI). The main long-term complication of POI is osteoporosis, which can be prevented by hormone replacement therapy (HRT). ObjectiveThe objective of our study was to compare initial bone mineral density (BMD) and progression between TS and idiopathic POI patients under HRT. MethodsA single-center retrospective study was conducted between 1998 and 2018. All women had undergone at least two bone densitometry assessments at least 2 years apart. ResultsSixty-eight TS patients and 67 idiopathic POI patients were included. Mean age at initial assessment was 27 years (IQR, 21–35.5 years) in TS patients and 31.5 years (IQR, 23–37 years) in idiopathic POI patients (P=0.1). Lumbar and femoral neck BMD were lower in the TS group than in the idiopathic POI group (respectively 0.89g/cm2 versus 0.95g/cm2, P=0.03; 0.70g/cm2 versus 0.77g/cm2, P<0.0001). Mosaic karyotype was associated with better BMD in TS patients while history of growth hormone treatment had no impact on BMD. Over time, a significant gain in vertebral BMD was observed in TS patients versus a loss of BMD in idiopathic POI patients (P=0.0009). ConclusionTS patients had a lower BMD at baseline than idiopathic POI patients, at both spinal and femoral levels. Over time, on HRT, a significant gain in vertebral BMD was observed in patients with TS, compared with a loss of BMD in patients with idiopathic POI. We hypothesized that earlier initiation and longer duration of HRT played an important role in this finding. Long-term prospective follow-up to assess the incidence of fractures in TS would be useful.

Solution structures and effects of a platinum compound successively bound MYC G-quadruplex.

G-quadruplex (G4) structures play integral roles in modulating biological functions and can be regulated by small molecules. The MYC gene is critical during tumor initiation and malignant progression, in which G4 acts as an important modulation motif. Herein, we reported the MYC promoter G4 recognized by a platinum(II) compound Pt-phen. Two Pt-phen-MYC G4 complex structures in 5 mM K+were determined by NMR. The Pt-phen first strongly binds the 3'-end of MYC G4 to form a 1:1 3'-end binding complex and then binds 5'-end to form a 2:1 complex with more Pt-phen. In the complexes, the Pt-phen molecules are well-defined and stack over four bases at the G-tetrad for a highly extensive π-π interaction, with the Pt atom aligning with the center of the G-tetrad. The flanking residues were observed to rearrange and cover on top of Pt-phen to stabilize the whole complex. We further demonstrated that Pt-phen targets G4 DNA in living cells and represses MYC gene expression in cancer cells. Our work elucidated the structural basis of ligand binding to MYC promoter G4. The platinum compound bound G4 includes multiple complexes formation, providing insights into the design of metal ligands targeting oncogene G4 DNA.

Clinical impact of a dose-escalation strategy for lenvatinib in differentiated thyroid cancer.

Treatment options for patients with differentiated thyroid cancer (DTC) who experience disease progression on lenvatinib treatment are limited. Although dose escalation of treatment with tyrosine kinase inhibitors at disease progression has been reported across cancer types, clinical significance in patients with DTC has not been investigated. We retrospectively reviewed patients with DTC who experienced disease progression on lenvatinib treatment from September 2011 to June 2022. We compared subjects who received dose-escalation treatment with standard treatment of termination at the time of initial disease progression. The escalated dose was decided by referencing to the previous effective and tolerated dose. Thirty-three patients were identified, 15 with dose escalation and 18 with lenvatinib termination. In both groups, the starting dose of lenvatinib was 24mg/day, and the median dose at initial disease progression was 10mg/day. In the former, the median dose escalation was 6mg/day (range: 4-12). Objective response rate, clinical benefit rate by escalation, and median treatment duration of the dose-escalation phase were 13.3%, 73.3%, and 9.9months (95% confidence interval [CI] 5.71-27.6), respectively. Median overall survival from initial disease progression was significantly longer in the dose-escalation group (median OS: 20.4months [95% CI 7.0-NA] vs. 3.9months [95% CI 1.7-7.9], log-rank p-value; 0.0004, hazard ratio; 0.22 [95% CI 0.09-0.55]). There were no grade 5 adverse events, and one patient discontinued due to a grade 3 lung abscess. The dose-escalation strategy appears to be a safe and effective treatment option after disease progression in patients treated with lenvatinib for DTC.