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1.
Bioact Mater ; 9: 168-182, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34820564

RESUMEN

Myocardial infarction (MI), as one of the leading causes of global death, urgently needs effective therapies. Recently, hydrogen sulfide (H2S) has been regarded as a promising therapeutic agent for MI, while its spatiotemporally controlled delivery remains a major issue limiting clinical translation. To address this limitation, we designed and synthesized a novel H2S donor (HSD-R) that can produce H2S and emit fluorescence in response to reactive oxygen species (ROS) highly expressed at diseased sites. HSD-R can specifically target mitochondria and provide red fluorescence to visualize and quantify H2S release in vitro and in vivo. Therapeutically, HSD-R significantly promoted the reconstruction of cardiac structure and function in a rat MI model. Mechanistically, myocardial protection is achieved by reducing cardiomyocyte apoptosis, attenuating local inflammation, and promoting angiogenesis. Furthermore, inhibition of typical pro-apoptotic genes (Bid, Apaf-1, and p53) played an important role in the anti-apoptotic effect of HSD-R to achieve cardioprotection, which were identified as new therapeutic targets of H2S against myocardial ischemia injury. This ROS-responsive, self-immolative, and fluorescent H2S donor can serve as a new theranostic agent for MI and other ischemic diseases.

2.
Clin Transl Radiat Oncol ; 32: 15-23, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34816022

RESUMEN

Purpose: Brachytherapy (BT) boost after radio-chemotherapy (RCT) is a standard of care in the management of locally advanced cervical cancer (LACC). As there is no consensus on high-dose-rate (HDR) BT fractionation schemes, our aim was to report the oncological outcome and toxicity profile of four different schemes using twice-a-day (BID) HDR-BT. Patients and methods: This was an observational, retrospective, single institution study for patients with LACC receiving a HDR-BT boost. The latter was performed with a single implant and single imaging done on day 1. The different fractionation schemes were: 7 Gy + 4x3.5 Gy (group 1); 7 Gy + 4x4.5 Gy (group 2); 3x7Gy (group 3) and 3x8Gy (group 4). Local (LFS), nodal (NFS) and metastatic (MFS) recurrence-free survival as well as progression-free survival (PFS) and overall survival (OS) were analyzed. Acute (≤6 months) and late toxicities (>6 months) were reported. Results: From 2007 to 2018, 191 patients were included. Median follow-up was 57 months [45-132] and median EQD210D90CTVHR was 84, 82 and 90 Gy for groups 2, 3 and 4 respectively (dosimetric data missing for group 1). The 5-year LFS, NFS, MFS, PFS and OS were 85% [81-90], 83% [79-86], 70% [67-73], 61% [57-64] and 75% [69-78] respectively, with no significant difference between the groups. EQD210D90CTVHR < 85 Gy was a prognostic factor for local recurrence in univariate analysis (p = 0.045). The rates of acute/late grade ≥ 2 urinary, digestive and gynecological toxicities were 9%/15%, 3%/15% and 9%/25% respectively. Conclusion: Bi-fractionated HDR-BT boost seems feasible with good oncological outcome and slightly more toxicity after dose escalation.

3.
EClinicalMedicine ; 41: 101152, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34723163

RESUMEN

Background: COVID-19 morbidity and mortality remains high and the need for safe and effective drugs continues despite vaccines. Methods: Double-blind, placebo-controlled, multi-centre, randomised, parallel group phase 2 trial to evaluate safety and efficacy of oral angiotensin II type 2 receptor agonist C21 in hospitalized patients with COVID-19 and CRP ≥ 50-150 mg/L conducted at eight sites in India (NCT04452435). Patients were randomly assigned 100 mg C21 bid or placebo for 7 days in addition to standard of care. Primary endpoint: reduction in CRP. The study period was 21 July to 13 October 2020. Findings: 106 patients were randomised and included in the analysis (51 C21, 55 placebo). There was no significant group difference in reduction of CRP, 81% and 78% in the C21 and placebo groups, respectively, with a treatment effect ratio of 0.85 [90% CI 0.57, 1.26]. In a secondary analysis in patients requiring supplemental oxygen at randomisation, CRP was reduced in the C21 group compared to placebo. At the end of the 7-day treatment, 37 (72.5%) and 30 (54.5%) of the patients did not require supplemental oxygen in the C21 and placebo group, respectively (OR 2.20 [90% CI 1.12, 4.41]). A post hoc analysis showed that at day 14, the proportion of patients not requiring supplemental oxygen was 98% and 80% in the C21 group compared to placebo (OR 12.5 [90% CI 2.9, 126]). Fewer patients required mechanical ventilation (one C21 patient; four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one vs three in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated. Interpretation: Among hospitalised patients with COVID-19 receiving C21 for 7 days there was no reduction in CRP compared to placebo. However, a post-hoc analysis indicated a marked reduction of requirement for oxygen at day 14. The day 14 results from this study justify further evaluation in a Phase 3 study and such a trial is currently underway. Funding: Vicore Pharma AB and LifeArc, UK.

4.
Ann Thorac Med ; 16(4): 337-346, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34820021

RESUMEN

BACKGROUND: Acute mountain sickness (AMS) is a benign and self-limiting syndrome, but can progress to life-threatening conditions if leave untreated. This study aimed to assess the efficacy of acetazolamide for the prophylaxis of AMS, and disclose factors that affect the treatment effect of acetazolamide. METHODS: Randomized controlled trials comparing the use of acetazolamide versus placebo for the prevention of AMS were included. The incidence of AMS was our primary endpoint. Meta-regression analysis was conducted to explore factors that associated with acetazolamide efficacy. Trial sequential analyses were conducted to estimate the statistical power of the available data. RESULTS: A total of 22 trials were included. Acetazolamide at 125, 250, and 375 mg/bid significantly reduced incidence of AMS compared to placebo. TAS indicated that the current evidence was adequate confirming the efficacy of acetazolamide at 125, 250, and 375 mg/bid in lowering incidence of AMS. There was no evidence of an association between efficacy and dose of acetazolamide, timing at start of acetazolamide treatment, mode of ascent, AMS assessment score, timing of AMS assessment, baseline altitude, and endpoint altitude. CONCLUSION: Acetazolamide is effective prophylaxis for the prevention of AMS at 125, 250, and 375 mg/bid. Future investigation should focus on personal characteristics, disclosing the correlation between acetazolamide efficacy and body mass, height, degree of prior acclimatization, individual inborn susceptibility, and history of AMS.

5.
World Neurosurg ; 2021 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-34823040

RESUMEN

BACKGROUND: Radiomics is a powerful tool for automatic extraction of morphologic features, but when applied to cerebral aneurysms is inferior to established descriptors in classifying rupture status. We sought a strategy to recover neck orientation and parent vessel caliber in a bid to enhance Radiomics performance and facilitate its adoption for aneurysm risk stratification. METHODS: 135 sidewall (32 ruptured) and 216 bifurcation (90 ruptured) aneurysms from 3-dimensional rotational catheter angiography (3DRA) datasets were analyzed. Clinical 3DRA defined in arbitrary orientation underwent affine transformations enabling aneurysm neck alignment to XY plane prior to analysis in PyRadiomics, thus facilitating automatic extraction of aneurysm height and width, previously not possible with random alignment. Additionally, parent vessel size was estimated from aneurysm location, and incorporated into enhanced Radiomics (height, width, height/width, size ratio). Rupture status classification was compared across methodologies, for 31 automatically computed conventional Radiomics, enhanced Radiomics, and established size/shape descriptors using univariate, multivariate, and area under the curve (AUC) statistics. RESULTS: Enhanced Radiomics derived Height/Width and Size Ratio were significantly higher in both ruptured subsets. Using multivariate analysis in sidewall lesions, enhanced Radiomics (AUC=0.85) matched established features (AUC=0.86) and outperformed conventional Radiomics (AUC=0.82); in bifurcation lesions enhanced Radiomics (AUC=0.78) outperformed both established features (AUC = 0.76) and conventional Radiomics (AUC=0.74). CONCLUSION: Enhanced Radiomics incorporating neck orientation and parent vessel estimate is an efficient operator-independent methodology which offers superior rupture status classification for both sidewall and bifurcation aneurysms and should be considered a strong candidate for larger scale multi-center and multi-modality validation.

6.
BMC Health Serv Res ; 21(1): 1275, 2021 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-34823516

RESUMEN

BACKGROUND: In 2019, Chinese government launched a nationwide volume-based drug procurement aiming at reducing drug prices and saving drug costs through economies of scale, which aroused widespread attention. The first round of the policy pilot was implemented in 4 municipalities and 7 sub-provincial cities, referred to as "4 + 7" policy. In the "4 + 7" policy, 7 antihypertensive drugs were included. This study was conducted to evaluate the impact of "4 + 7" policy on the use of policy-related antihypertensive drugs. METHOD: This study applied single-group Interrupted Time Series (ITS) design. We used drug purchasing data from the Centralized Drug Procurement Survey in Shenzhen 2019, covering 24 months from January 2018 to December 2019. Antihypertensive drugs related to "4 + 7" policy were selected as study samples, including 7 drugs in the "4 + 7" List and 17 alternative drugs. Alternative drugs refer to antihypertensive drugs that have an alternative relationship with "4 + 7" List drugs in clinical use and have not yet been covered by the policy. "4 + 7" List drugs were then divided into bid-winning and bid-non-winning products according to the bidding results. Purchase volume, expenditures, and daily costs were selected as outcome variables, and were measured using Defined Daily Doses (DDDs), Chinese Yuan (CNY), and Defined Daily Drug cost (DDDc). RESULTS: After "4 + 7" policy intervention, the procurement volume of bid-winning antihypertensive drugs significantly increased (3.12 million DDD, 95 % CI = 2.14 to 4.10, p < 0.001), while the volume of non-winning drugs decreased (-2.33 million DDD, 95 % CI= -2.83 to -1.82, p < 0.01). The use proportion of bid-winning antihypertensive drugs increased from 12.31 to 87.74 % after policy intervention. The overall costs of the seven "4 + 7" List antihypertensive drugs significantly declined (-5.96 million CNY, 95 % CI= -7.87 to -4.04, p < 0.001) after policy intervention, with an absolute reduction of 36.37 million CNY compared with the pre-"4 + 7" period. The DDDc of bid-winning antihypertensive drugs significantly decreased (-1.30 CNY, 95 % CI= -1.43 to -1.18, p < 0.001), while the DDDc of non-winning (0.28 CNY, 95 % CI = 0.11 to 0.46, p < 0.01) and alternative (0.14 CNY, 95 % CI = 0.03 to 0.25, p < 0.05) antihypertensive drugs increased markedly. CONCLUSIONS: The implementation of "4 + 7" policy promoted the drug use hypertensive patients gradually concentrated on the quality-guaranteed bid-winning drugs, which might be conducive to improve the overall quality level of drug use of Chinese hypertensive patients. Besides, a preliminary positive policy effect of price cut and cost-saving was observed in the antihypertensive drug category. In the future, price monitoring and drug use management regarding policy-related drugs should also be strengthened.

7.
Vaccines (Basel) ; 9(11)2021 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-34835182

RESUMEN

With the rapid development of various coronavirus disease 2019 (COVID-19) vaccines in a bid to counter and contain the COVID-19 pandemic, unusual and uncommon side effects of COVID-19 vaccination have been increasingly reported in the literature. Ipsilateral lymphadenopathy is a fairly common side effect of vaccination of any kind, with its etiology most commonly related to reactive lymphadenopathy. However, Kikuchi-Fujimoto Disease (KFD) or necrotizing histiocytic lymphadenitis is rarely observed post-vaccination, with only one other case of KFD post COVID-19 vaccination reported to date. We report two more cases of KFD post COVID-19 vaccination in the Asian population, highlighting the clinical course and salient clinical, radiological and histologic findings. In addition, we provide a literature review of the existing cases of lymphadenopathy post COVID-19 vaccination with cytologic and/or histologic correlation.

8.
Artículo en Inglés | MEDLINE | ID: mdl-34836835

RESUMEN

INTRODUCTION: Magnetic Resonance Imaging (MRI) can be a challenging examination, particularly for children. The aim of this Clinical Perspective is to outline early experiences, based upon a service evaluation (defined as an assessment of how well the intended aims are achieved), of the Playful Magnetic Resonance Imaging Simulator (PMRIS) (Domed, Lyon, France) in reducing the number of children requiring general anaesthetic (GA) in order to undergo Magnetic Resonance Imaging (MRI). METHODS: Baseline data from an audit of children undergoing MRI under GA in 2017 had previously been captured as part of the funding bid for the PMRIS. Estimation of costs associated with anaesthesia were made, then combined with the overall numbers of MRI under GA to estimate projected anaesthetic related cost-savings based on the reported effectiveness of the PMRIS. Once the PMRIS was in place, data were collected for children attending a Play Specialist supervised session. The number and age of children proceeding directly to MRI without requiring a GA was determined. The associated cost benefit was calculated and compared with the projections made in the initial funding bid. RESULTS: Over a 7 month period 36 children, average age 6 years, age range 4 to 11 years, who had initially been triaged for MRI under GA, attended a Play Specialist led session on the PMRIS. Of these, 30, average age 6 years, age range 4 to 11 years proceeded directly to MRI without a GA. Based on the costings used for the initial funding bid, this equates to a gross cost-saving of £9,000 over 7 months. DISCUSSION: This service evaluation shows a positive impact of Play Specialist sessions using the PMRIS with 30 out of 36 children having a successful awake MRI as a result. There are limitations to this evaluation, particularly that whilst all these children had been triaged for MRI under GA it cannot be known how many might have had an awake MRI with different preparation. Nevertheless, according to the local referral pathways these children would otherwise have had MRI under GA. CONCLUSION: This service evaluation has shown that the number of GAs required for children having MRI has reduced for this particular service through the use of the PMRIS, with Play Specialist support, with associated reduction in risk and cost savings.

9.
Preprint en Inglés | medRxiv | ID: ppmedrxiv-21266690

RESUMEN

Background: Favipiravir is an oral, RNA-dependent RNA polymerase inhibitor with in vitro activity against SARS-CoV2. Despite limited data, favipiravir is administered to patients with COVID-19 in several countries. Methods: We conducted a phase 2 double-blind randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV2 RT-PCR within 72 hours of enrollment. Participants were randomized 1:1 to receive placebo or favipiravir (1800 mg BID Day 1, 800mg BID Days 2-10). The primary outcome was SARS-CoV2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV2 deep sequencing, we assessed the impact of favipiravir on mutagenesis. Results: From July 8, 2020 to March 23, 2021, we randomized 149 participants with 116 included in the mITT cohort. The mean age was 43 years (SD 12.5) and 57 (49%) were women. We found no difference in time to shedding cessation by treatment arm overall (HR 0.76 favoring placebo, 95% confidence interval [CI] 0.48 - 1.20) or in sub-group analyses (age, sex, high-risk comorbidities, seropositivity or symptom duration at enrollment). We observed no difference in time to symptom resolution (initial: HR 0.84, 95% CI 0.54 - 1.29; sustained: HR 0.87, 95% CI 0.52 - 1.45). We detected no difference in accumulation of transition mutations in the viral genome during treatment. Conclusions: Our data do not support favipiravir use at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher doses of favipiravir are effective and safe for patients with COVID-19.

10.
Preprint en Inglés | medRxiv | ID: ppmedrxiv-21266330

RESUMEN

IntroductionDuring March-December 2020, Zambia recorded 20,725 confirmed COVID-19 cases, with the first wave peaking between July and August. Of the 388 COVID-19-related deaths occurring nationwide, most occurred in the community. We report findings from COVID-19 mortality surveillance among community deaths brought to the University Teaching Hospital (UTH) mortuary in Lusaka. MethodsIn Zambia, when a person dies in the community, and is brought into a health facility mortuary, they are recorded as brought in dead (BID). The UTH mortuary accepts persons BID for Lusaka District, the most populated district in Zambia. We analyzed data for persons BID at UTH during 2020. We analyzed two data sources: weekly SARS-CoV-2 test results for persons BID and monthly all-cause mortality numbers among persons BID. For all-cause mortality among persons BID, monthly deaths during 2020 that were above the upper bound of the 95% confidence interval for the historic mean (2017-2019) were considered significant. Spearmans rank test was used to correlate the overall percent positivity in Zambia with all-cause mortality and SARS-CoV-2 testing among persons BID at UTH mortuary. ResultsDuring 2020, 7,756 persons were BID at UTH (monthly range 556-810). SARS-CoV-2 testing began in April 2020, and through December 3,131 (51.9%) of 6,022 persons BID were tested. Of these, 212 (6.8%) were SARS-CoV-2 positive with weekly percent test positivity ranging from 0-32%, with the highest positivity occurring during July 2020. There were 1,139 excess persons BID from all causes at UTH mortuary in 2020 compared to the 2017-2019 mean. The monthly number of persons BID from all causes was above the upper bound of the 95% confidence interval during June-September and December. ConclusionIncreases in all-cause mortality and SARS-CoV-2 test positivity among persons BID at UTH mortuary corresponded with the first peak of the COVID-19 epidemic in June and August 2020, indicating possible increased mortality related to the COVID-19 epidemic in Zambia. Combining all-cause mortality and SARS-CoV-2 testing for persons BID provides useful information about the severity of the epidemic in Lusaka and should be implemented throughout Zambia.

11.
Preprint en Inglés | medRxiv | ID: ppmedrxiv-21265884

RESUMEN

AimTo assess the efficacy and safety of favipiravir in adults with moderate to severe coronavirus disease 2019 (COVID-19). MethodsIn this randomized, double-blind, multicenter, phase 3 trial, adults (21-80 years) with real-time reverse transcriptase polymerase chain reaction (rRT-PCR) confirmed SARS-CoV-2 infection and presenting with moderate to severe COVID-19 and requiring hospitalization were randomized 1:1 to oral favipiravir (day 1: 1800 mg BID and days 2-10: 800 mg BID) (FPV) plus standard supportive care (SoC) versus placebo plus SoC (placebo). The primary endpoint was time to resolution of hypoxia. ResultsIn total, 353 patients were randomized to receive either FPV or placebo (175 and 178 in the FPV and placebo groups, respectively). Overall, 76% of the patients (240/315, 78% in FPV vs. 75% in placebo group) reached resolution of hypoxia on or before day 28. The median time to resolution of hypoxia was 7 days in the FPV group and 8 days in the placebo group. Treatment effect was not significant [Hazard ratio (HR) (95% CI): 0.991 (0.767, 1.280) (p=0.94)]. Patients in the lower NEWS-2 clinical risk subgroup were more likely to achieve shorter time to resolution of hypoxia with the median time to resolution of hypoxia of 6 days in FPV and 7 days in placebo group [HR (95% CI): 1.21 (0.847, 1.731) (p=0.29)]; shorter time to hospital discharge with a median time to discharge of 8 and 10 days in the FPV and placebo group, respectively [HR (95% CI): 1.47 (1.081, 1.997) (p=0.014)]; and shorter time to improvement by 1-point improvement over baseline in WHO 10-point clinical status score with the median time to improvement by 1-point from baseline of 6 and 7 days in the FPV and placebo group, respectively [HR (95% CI): 1.16 (0.830, 1.624) (p=0.38)] than higher NEWS-2 clinical risk subgroup. Treatment emergent adverse event (TEAEs) were experienced by 62/334 (19%) patients [35/168 (21%) patients in FPV and 27/166 (16%) in placebo group]. Hyperuricaemia/increased blood uric acid was reported in 9 (3%)/2 (1%) patients [8 (5%)/1(1%) patients in FPV and 1 (1%)/1(1%) in placebo group], which were of mild intensity and transient. Overall, 36 serious adverse events (SAEs) were reported, 20 in FPV and 16 in placebo group. ConclusionThe trial did not find favipiravir to be effective in moderate to severe, hospitalized COVID-19 patients; favourable clinical trends were observed in patients with lower NEWS-2 risk when early administration of favipiravir could be achieved.

12.
Cancer Med ; 2021 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-34799992

RESUMEN

BACKGROUND: Dcf1 has been demonstrated to play vital roles in many CNS diseases, it also has a destructive role on cell mitochondria in glioma cells and promotes the autophagy. Hitherto, it is unclear whether the viability of glioblastoma cells is affected by Dcf1, in particular Dcf1 possesses broad localization on different organelles, and the organelles interaction frequently implicated in cancer cells survival. METHODS: Surgically excised WHO grade IV human glioblastoma tissues were collected and cells isolated for culturing. RT-PCR and DNA sequencing assay to estimate the abundance and mutation of Dcf1. iTRAQ sequencing and bioinformatic analysis were performed. Subsequently, immunoprecipitation assay to evaluate the degradation of HistoneH2A isomers by UBA52 ubiquitylation. Transmission electron microscopy (TEM) was applied to observe the structure change of mitochondria and autophagosome. Organelle isolated assay to determine the distribution of protein. Cell cycle and apoptosis were evaluated by flow cytometric assays. RESULTS: Dcf1 was downregulated in WHO grade IV tumor without mutation, and overexpression of Dcf1 was found to significantly regulate glioblastoma cells. One hundred and seventy-six differentially expressed proteins were identified by iTRAQ sequencing. Furthermore, we confirmed that overexpression of Dcf1 destabilized the structure of the nucleosome via UBA52 ubiquitination to downregulate HistoneH2A.X but not macroH2A or HistoneH2A.Z, decreased the mitochondrial DNA copy number and inhibited the mitochondrial biogenesis, thus causing mitochondrial destruction and dysfunction in order to supply cellular energy and induce mitophagy preferentially but not apoptosis. Dcf1 also has disrupted the integrity of lysosomes to block autolysosome degradation and autophagy and to increase the release of Cathepsin B and D from lysosomes into cytosol. These proteins cleaved and activated BID to induce glioblastoma cells apoptosis. CONCLUSIONS: In this study, we demonstrated that unmutated Dcf1 expression is negatively related to the malignancy of glioblastoma, Dcf1 overexpression causes nucleosomes destabilization, mitochondria destruction and dysfunction to induce mitophagy preferentially, and block autophagy by impairing lysosomes to induce apoptosis in glioblastoma.

13.
Clin Breast Cancer ; 2021 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-34824002

RESUMEN

BACKGROUND: AR is a targetable pathway with AR modulation inhibiting estrogen- and androgen-mediated cell proliferation. Orteronel is an oral, selective, nonsteroidal inhibitor of 17, 20-lyase, a key enzyme in androgen biosynthesis. This study evaluated single-agent orteronel in AR+ metastatic breast cancer (MBC). METHODS: Male/female patients with AR+ MBC were grouped in Cohort 1: AR+ TNBC with l-3 prior chemotherapy regimens or Cohort 2: AR+ HR+ (estrogen [ER+]/ progesterone receptor [PR+] positive) HER2+/- with 1 to 3 prior hormonal and at least 1 prior chemotherapy regimen. Patients with HER2+ MBC must have received at least 2 lines of HER2-targeted therapy. Orteronel was administered at 300 mg BID; response rate was the primary endpoint. RESULTS: Seventy patients were enrolled (Cohort 1, n = 26 and Cohort 2, n = 44). Median treatment duration was 7.1 weeks. Seven patients were on treatment for ≥6 months. One of the 21 evaluated patients in Cohort 1 (4.8%) had an objective response. In Cohort 2, none of the first 23 patients to be evaluated had a response and accrual was stopped. Median progression-free and overall survival were 1.8 and 8.3 months, respectively. Toxicities were predominantly Grade 1 or 2 nausea/vomiting (36%) and fatigue (31%). Grade 3 or 4 events in ≥5% of patients included increased amylase/lipase (10%) and hypertension (6%). CONCLUSIONS: Orteronel demonstrated limited clinical activity in heavily pre-treated AR+ MBC. Further development of orteronel in MBC is not recommended. Further efforts to validate the AR as a therapeutic target should focus on identifying new markers predictive of sensitivity to AR-targeted agents.

14.
Cancers (Basel) ; 13(21)2021 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-34771668

RESUMEN

Uveal melanoma (UM) is a rare subset of melanoma characterized by the presence of early initiating GNAQ/11 mutations, with downstream activation of the PKC, MAPK, and PI3Kα pathways. Activity has been observed with the PKC inhibitors sotrastaurin (AEB071) and darovasertib (IDE196) in patients with UM. Inhibition of the PI3K pathway enhances PKC inhibition in in vivo models. We therefore conducted a phase Ib study of sotrastaurin in combination with the PI3Kα inhibitor alpelisib to identify a tolerable regimen that may enhance the activity of PKC inhibition alone. Patients with metastatic uveal melanoma (n = 24) or GNAQ/11 mutant cutaneous melanoma (n = 1) were enrolled on escalating dose levels of sotrastaurin (100-400 mg BID) and alpelisib (200-350 mg QD). The primary objective was to identify the maximum tolerated dose (MTD) of these agents when administered in combination. Treatment-related adverse events (AE) occurred in 86% (any grade) and 29% (Grade 3). No Grade 4-5-related AEs occurred. Dose Level 4 (sotrastaurin 200 mg BID and alpelisib 350 mg QD) was identified as the maximum tolerated dose. Pharmacokinetic analysis demonstrated increasing concentration levels with increasing doses of sotrastaurin and alpelisib, without evidence of interaction between agents. Pharmacodynamic assessment of pMARCKS and pAKT protein expression with drug exposure suggested modest target inhibition that did not correlate with clinical response. No objective responses were observed, and median progression-free survival was 8 weeks (range, 3-51 weeks). Although a tolerable dose of sotrastaurin and alpelisib was identified with pharmacodynamic evidence of target inhibition and without evidence of a corresponding immunosuppressive effect, limited clinical activity was observed.

15.
Cureus ; 13(10): e18600, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34786219

RESUMEN

A wide range of acute neurological disorders may present with symptoms similar to a stroke, so-called 'stroke mimics'. Migraine aura and seizures account for the most extensive stroke mimics population. A large number of patients with a definite stroke mimics diagnosis (most commonly those with psychiatric disorders or seizures) had been treated with IV alteplase without adverse related events. We report a case of a man aged 70 years admitted to the emergency room because of acute onset of delirium and a loss of strength in the left arm (National Institutes of Health Stroke Scale {NIHSS}: 10), severe hyponatremia (127 mEq/L), and no evidence of intracranial arterial occlusion at CT scan. He was eligible for intravenous thrombolysis and, after treatment, neurological symptoms improved (NIHSS: 2). The subsequent appearance of "clonus" in the left lower limb, the persistence of hyponatremia, and the presence of electroencephalogram (EEG) abnormalities led to the clinical suspicion of focal motor-onset seizure with impaired awareness. The patient was treated successfully with anti-seizure medications (ASMs): lacosamide 200 mg IV during the acute setting care, followed by oral lacosamide 200 mg bis in die (BID). Since two other focal seizures occurred, brivaracetam 25 mg BID has been added in therapy with subsequent clinical discontinuance and EEG normalization. Two consecutive magnetic resonance imaging (MRI) examinations showed several cortical lesions restricted in high signal in diffusion-weighted imaging (DWI) which corresponding to T2-weighted and fluid-attenuated inversion recovery (FLAIR) hyperintensities, but without lesions evidence in apparent diffusion coefficient (ADC) map. These radiological changes disappeared at a follow-up MRI performed 20 days after the symptoms' onset. The patient fully recovered was discharged home without developing pharmacological adverse events. In this case, MRI provided an opportunity for early identification of seizure-related alterations. Hence, we discuss how prospective MRI studies during seizures and interictal period would contribute to defining the relationship between the electroclinical characteristics and MRI alteration patterns, and therefore, the potential role of MRI in the differential diagnosis between seizures and stroke mimic.

16.
Diabetes Metab Syndr ; 15(6): 102328, 2021 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-34752935

RESUMEN

BACKGROUND AND AIMS: Cardiometabolic disease may confer increased risk of adverse outcomes in COVID-19 patients by activation of the aldose reductase pathway. We hypothesized that aldose reductase inhibition with AT-001 might reduce viral inflammation and risk of adverse outcomes in diabetic patients with COVID-19. METHODS: We conducted an open-label prospective phase 2 clinical trial to assess safety, tolerability and efficacy of AT-001 in patients hospitalized with COVID-19 infection, history of diabetes mellitus and chronic heart disease. Eligible participants were prospectively enrolled and treated with AT-001 1500 mg BID for up to 14 days. Safety, tolerability, survival and length of hospital stay (LOS) were collected from the electronic medical record and compared with data from two matched control groups (MC1 and MC2) selected from a deidentified registry of COVID-19 patients at the same institution. RESULTS: AT-001 was safe and well tolerated in the 10 participants who received the study drug. In-hospital mortality observed in the AT-001 group was 20% vs. 31% in MC1 and 27% in MC2. Mean LOS observed in the AT-001 group was 5 days vs. 10 days in MC1 and 25 days in MC2. CONCLUSIONS: In hospitalized patients with COVID-19 and co-morbid diabetes mellitus and heart disease, treatment with AT-001 was safe and well tolerated. Exposure to AT-001 was associated with a trend of reduced mortality and shortened LOS. While the observed trend did not reach statistical significance, the present study provides the rationale for investigating potential benefit of AT-001 in COVID 19 affected patients in future studies.

17.
Artículo en Inglés | MEDLINE | ID: mdl-34791372

RESUMEN

Dermatomyositis (DM) is an inflammatory myopathy characterized by proximal muscle weakness and pathognomonic skin lesions. A 69-year-old woman with a recent diagnosis of DM one month prior, treated with corticosteroids and immunomodulators, presented to our inpatient rehabilitation with worsening dysphagia and constipation. At the time of our evaluation, physical examination was notable for erythematous papules over the MCPs, PIPs, elbows, and knees as well as a violaceous rash on the face. Muscle strength was diminished bilaterally with proximal distribution being affected greater than distal. Laboratory studies were notable for CK level 31 IU/ L, ANA by immunofluorescence of 1:80, and aldolase 4 u/L. The eleven-antibody myositis panel was negative. Skeletal muscle biopsy of the left thigh showed partially treated acquired inflammatory myopathy with perifascicular atrophy. During hospitalization, she was found to have pulmonary embolism. She received enoxaparin 1 mg/kg subcutaneous BID. Soon after, she developed rectal bleeding. Colonoscopy showed a stercoral ulcer caused by chronic constipation. While dysphagia is common, being present in 25-50% of patients with DM, lower gastrointestinal problems involving the small and large intestine are rare and typically present as a late manifestation of the disease. Decreased peristalsis in the large colon can lead to constipation, impaction, and subsequent mucosal ulceration, and pressure necrosis induced by fecaloma formation. Although rare, our case highlights the importance of recognizing gastrointestinal complications that dermatomyositis can cause and the effects that those complications have on morbidity and mortality.

18.
Cancer Med ; 2021 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-34791813

RESUMEN

Preclinical observations that killing of chronic lymphocytic leukemia (CLL) cells was dexamethasone (DEX) were enhanced by concomitant inhibition of Bruton's tyrosine kinase and janus kinases (JAKs) motivated a phase II trial to determine if clinical responses to ibrutinib could be deepened by DEX and the JAK inhibitor ruxolitinib. Patients on ibrutinib at 420 mg daily for 2 months or with abnormal serum ß2M levels after 6 months or with persistent lymphadenopathy or splenomegaly after 12 months were randomized to receive DEX 40 mg on days 1-4 of a 4-week cycle for six cycles alone (three patients) or with ruxolitinib 15 mg BID on days 1-21 of each cycle (five patients). Ruxolitinib dosing was based on a previous phase I trial. Steroid withdrawal symptoms and significantly decreased serum IgG levels occurred in all patients regardless of their exposure to ruxolitinib. A fatal invasive fungal infection was seen in a patient taking DEX without ruxolitinib. Complete responses anticipated with addition of ruxolitinib were not seen. Gene expression studies suggested ruxolitinib had turned off interferon signaling in CLL cells and turned on genes associated with the activation of NFκB by TNF-α. Ruxolitinib increased blood levels of TNF-α by cycle 3 and decreased the inhibitory cytokine IL-10. These results suggest ruxolitinib releases activating signals for CLL cells that persist in patients on ibrutinib. This inhibitory JAK signaling may contribute to the therapeutic activity of ibrutinib. Thus JAK inhibitors provide no added value with ibrutinib for disease control and should be used with caution in CLL patients. Combining glucocorticoids with ibrutinib may increase the risk of serious infects.

19.
Int J Nanomedicine ; 16: 7557-7574, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34803379

RESUMEN

Introduction: The use of environmentally benign resources for nanoparticles synthesis is consistently pushed to the front burner in a bid to ensure and enhance environmental protection and beneficiation. In this light, application of different plant parts for the reduction and stabilization of nanoparticles is gaining popularity. Materials and Methods: In this contribution, we have exploited Securidaca inappendiculata stem extract (SISE), as the reducing and stabilizing agent for room temperature synthesis of highly stable and dispersed AgNPs. The major bioactive compounds in SISE were profiled using an ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UHPLC-MS-QTOF-MS). Results and Discussion: SISE could reduce silver salts to its nanoparticles almost instantaneously with a maximum absorption spectrum at 423 nm, under the optimal conditions. The fabricated SISE AgNPs was extensively characterized using FTIR, TEM, SEM, XRD, EDS, Zeta analysis/DLS and TGA/DTG analysis. SISE AgNPs with average particles size between 10-15 nm and a zeta potential value of -19.5 ± 1.8 mV was obtained. It was investigated for in-vitro biological applications by carrying out, antimicrobial, antioxidant, hemolytic, cytotoxicity and antidiabetic assays. It was found that SISE AgNPs exhibited potent antimicrobial capacity against some food borne microbes, good antioxidant property, while also demonstrating high biocompatibility. Moreover, with a view to extending further the applications SISE AgNPs, it was tested as a colorimetric nanoprobe for Hg2+ detection in aqueous environment, where good linearity between 0.10 and 10.0 µM, with a detection limit of 26.5 nM, were obtained. The practicality of the probe was investigated by carrying out Hg2+ detection in water sample, with good accuracy and precision. Discussion: Overall, this work introduced a new stabilizer for biocompatible AgNPs with far-reaching applications.


Asunto(s)
Mercurio , Nanopartículas del Metal , Securidaca , Extractos Vegetales , Plata
20.
Malar J ; 20(1): 442, 2021 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-34801056

RESUMEN

Malaria is a complex parasitic disease, caused by Plasmodium spp. More than a century after the discovery of malaria parasites, this disease continues to pose a global public health problem and the pathogenesis of the severe forms of malaria remains incompletely understood. Extracellular vesicles (EVs), including exosomes and microvesicles, have been increasingly researched in the field of malaria in a bid to fill these knowledge gaps. EVs released from Plasmodium-infected red blood cells and other host cells during malaria infection are now believed to play key roles in disease pathogenesis and are suggested as vital components of the biology of Plasmodium spp. Malaria-derived EVs have been identified as potential disease biomarkers and therapeutic tools. In this review, key findings of malaria EV studies over the last 20 years are summarized and critically analysed. Outstanding areas of research into EV biology are identified. Unexplored EV research foci for the future that will contribute to consolidating the potential for EVs as agents in malaria prevention and control are proposed.

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