Dysregulation of miR-378 has been found in diverse types of tumors as well as in leukemia. The role of miR-378 in chronic myeloid leukemia (CML) remains unclear. The aim of the study was to reveal ...the potential effects of miR-378 in the pathological process and progress in CML. Our results showed general level of miR-378 was significant higher in CML patients compared to controls. Overexpression of miR-378 dramatically promoted cell proliferation and drug-resistance. Additionally, apoptosis was inhibited in cells transfected with miR-378. More and bigger stem cell sphere formation was observed in miR-378 transfected cells. Furthermore, enhanced expression of miR-378 was associated with upregulation of stem-cell makers OCT4 and c-Myc. Further study validated that miR-378 inhibited the expression of FUS1. Our research demonstrated the oncogenic nature of miR-378 in CML, and might contribute to the progress of CML.
Background:
The standard of induction therapy for fit patients(pts) with acute myeloid leukemia (AML) has not changed much since 1973, when the 7+3 regimen of cytarabine and anthracycline was born. ...This combination of agents produces complete remission (CR) in about 60-80% of younger adults and in 40-60% of older adults (60 years) depending on genetic risk group. However, compared with AML in favorable- and intermediate-risk categories, induction therapy for fit AML pts in adverse-risk category had significantly lower CR rates and dismal outcome. Recently, combination therapy with venetoclax and azacitidine or decitabine for the treatment of older pts with de novo AML unsuitable for intensive chemotherapy, has resulted in response rates of 60-70%. Currently, the role of venetoclax in combination with azacitidine or decitabine in young adults with newly diagnosed ELN adverse-risk AML remains unclear. This study aims to evaluate the safety and efficacy of venetoclax plus decitabine as induction therapy in young adults with newly diagnosed ELN adverse-risk AML.
Methods:
This is an interim analysis of an ongoing phase 2 clinical trial (NCT04752527) of a planned 42 untreated ELN adverse-risk AML pts 18-59. The fast next-generation sequencing (NGS) for the most commonly mutated genes in AML using Oncomine TM myeloid research assay on Ion S5 and Chef platform (Thermo Fisher) was completed within 72 hours, which could screen for the ELN adverse-risk features in AML pts together with multiplex RT-PCR and fluorescence in situ hybridization (FISH). In cycle 1, pts receive decitabine 20mg/m 2 on d1-5 and venetoclax escalated from 100mg to 200mg to 400mg until 28-day cycle is finished. For pts with high FLT3-ITD allelic ratio, sorafenib was optional administered at a dose of 400mg orally twice daily. Bone marrow assessments were performed on d28 before subsequent cycle. Pts who achieve composite complete remission (defined as complete remission CR, CR with incomplete hematologic recovery CRi, CR with partial hematological recovery CRh, and morphologic leukemia free state MLFS) receive 1 or 2 cycles of consolidation with high dose of cytarabine followed by allogeneic hematopoietic stem cell transplantation. Non-responders or pts who achieve partial remission (PR) receive 1 additional cycle of combination of venetoclax plus decitabine. The primary objective is to determine the composite complete remission rate (CR+CRi+CRh+MLFS). The endpoint is to show that venetoclax plus decitabine is superior to historical control (HC) of cytarabine combined with idarubicin (12 mg/m 2) in young adults with newly diagnosed ELN adverse-risk AML.
Results:
From February 1, 2021 to July 31, 2021, a total of 104 newly-diagnosed AML pts underwent screening, and 30 pts were classified as ELN adverse-risk category by NGS (within 72 hours) together with multiplex RT-PCR and FISH. Totally, 19 pts with ELN adverse-risk were enrolled, comprising 14 males and 5 females. 2 (10%) pts had secondary AML (sAML). Median age was 38 years (range, 19-57 years). The baseline patient characteristics are summarized in Table 1. Outcome data were updated as of July 2021, for a median follow-up of 2.7 months. Among 14 evaluable pts, 4 (28.6%) achieved a CR, 5 (35.7%) achieved a CRh and 5 (35.7%) had a PR in cycle 1. Individual pts data of this study (n = 14) was compared to a HC, combining individual pts data of AML with adverse-risk from the SZ3202 registry (n = 42) and the pts treated with IA (IDA:12 mg/m 2) in the same period (n = 18). The venetoclax plus decitabine cohort demonstrated higher rates of CR than the HC cohort, with an observed CR/CRh rate of 64.3%, compared with 38.3% (Figure 1).
The regimen was well tolerated, with 4- and 8-week mortality rates of 0% and 0%, respectively. The most frequent nonhematologic adverse events of any grade were neutropenic fever (n=6) and pneumonia (n=3). With a median follow-up of 2.7 months, the median remission duration and overall survival (OS) have not been reached. Tumor lysis syndrome occurred in one patient and resolved with medical management.
Conclusions:
Preliminary results indicate that venetoclax plus decitabine is an effective, lower-intensity regimen that is well tolerated for young adults with newly diagnosed ELN adverse-risk AML, producing high rates of CR, low rates of infections, and low rates of early death. Recruitment of young adults with newly diagnosed ELN adverse-risk AML pts for this trial is ongoing.
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No relevant conflicts of interest to declare.
Objective: To survey the vaccination status, lymphoma status, characteristics and outcomes of COVID-19 infections in elderly patients with lymphoma in Jiangsu Province of China.
Methods: Elderly ...patients with lymphoma (age≥60 years) in Jiangsu Province was investigated by questionnaire and telephone follow-up during December 2022 to June 2023. Basic information, Lymphoma status, comorbidities, vaccination, severity and outcome of COVID-19 infection were collected.
Results: A total of 402 patients were followed up in this study, 364 were confirmed with COVID-19 infection during December 2022 to June 2023. Among these patients, median age was 70 years (range 60-92), Of which 50.25% (202/402) were over 70 years old. Most patients (85.9%,313/364) were symptomatic at COVID-19 diagnosis. 45.6% (166/364) and 54.4% (198/364) was defined as mild COVID-19 and severe COVID-19 infections according to Diagnosis and treatment plan for COVID -19（trial version 10）in China, all patients with severe COVID-19 infection were hospitalized. 56.0% (204 /364) of patients were aggressive lymphoma and 43.4%(158 /364) were indolent lymphoma. Only 43.9% of the patients had received two or more doses of SARS-CoV-2 vaccine at the onset of COVID-19. In univariable analysis, age >70 years(OR 1.88;95% CI 1.24-2.85,p=0.003), the presence of comorbidities (OR 1.41;95% CI 1.41-1.11,p=0.005), active hematological disease(progressive disease or relapsed/refractory disease, OR 2.02;95% CI 1.53-2.67,P<0.001), ≥2 prior treatment(OR 1.88,95% CI 1.42-2.47,p<0.001), and time from anti-lymphoma treatment to COVID-19 (OR 1.90,95% CI 1.53-2.36,p<0.001) were associated with severe COVID-19 infection in the entire cohort. For anti-lymphoma treatment, anti-CD20-based treatments within the last 6 months was associated with severe COVID-19 infection in the aggressive lymphoma patients (OR 2.17,95% CI 1.21-3.88, p=0.009) as well as in the indolent lymphoma patients (OR 5.67,95% CI 1.97-16.29, p=0.001). Of note, among the indolent lymphoma subsets, only anti-CD20-based maintenance therapy might be a risk factor for exacerbating COVID-19 infection (OR 4.42,95% CI 1.15-17.03,p=0.031), while continuous BTK inhibitors might be protective effect on the outcome when compared with other targeted drugs(OR 0.44,95% CI 0.20-0.97,p=0.043). Overall, 7.7% of patients (28/364) ceased，among them 57.4% (16/28) was due to COVID-19 infection,14.9% (4/28) was due to lymphoma deteriation, 17.9%(5/28) due to COVID-19 infection concurrent with lymphoma progression and 10.7%(3/28) with heart failure . Mortality rate increase by lymphoma status Controlled disease: 8.67%(15/173) ; Stable disease: 9.80%(5/51);Active disease:16,67%(6/36), p=0.006), prior lines of anti-lymphoma therapy 1 prior: 7.14%(13/182)；2 prior: 5.26%(3/57);≥3 prior: 25%(9/36), p<0.001 and anti-lymphoma therapy within one month of COVID-19 infection>1 months: 8.52%(11/129) ;<1 months: 16.67%(17/102); p=0.002.
Conclusions: Elderly patients with lymphoma have a low rate of COVID-19 vaccination and a high rate of severe COVID-19 infection. Patients with active disease, multiple lines of prior therapy, advanced age, multiple comorbidities, and anti-CD20-based treatments within the last 6 months was associated with severe COVID-19 infection..
This review is intended to provide the reader with an overview of the all-purpose topical insect repellent N,N-diethyl-3-methylbenzamide (deet), with emphasis on its pharmacokinetics, formulation, ...and safety aspects. N,N-diethyl-3-methylbenzamide is effective against a variety of mosquitoes, flies, fleas, and ticks, and its protection efficacy depends on factors such as type of formulation, application pattern, physical activity of the user, environment, and species and feeding behavior of the insects. It offers an inexpensive and practical means of preventing the attack of biting insects and, more importantly, the transmission of vector-borne diseases. In both humans and animals, deet skin penetration and biodistribution are rapid and extensive, and metabolism and elimination appear to be complete. As evidenced by over 4 decades of human experience and rigorous animal testing, deet is generally safe for topical use if applied as recommended, although it has occasionally been related to side effects such as toxic encephalopathy, seizure, acute manic psychosis, cardiovascular toxicity, and dermatitis, along with a few cases of death due to extensive skin absorption. N,N-diethyl-3-methylbenzamide may compete in metabolism with and alter the biodistribution properties of other compounds to which a subject is simultaneously exposed, resulting in an added risk of side effects. The appropriate use of formulation techniques and new formulation excipients not only offers a way to extend the duration of protection, but also reduces deet skin penetration. In addition to extended repellency, minimal skin penetration of deet should be an important consideration in the evaluation of a deet formulation during new product development.
Elderly patients with lymphoproliferative diseases (LPD) are vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we retrospectively described the clinical ...features and outcomes of the first time infection of Omicron SARS-CoV-2 in 364 elderly patients with lymphoma enrolled in Jiangsu Cooperative Lymphoma Group (JCLG) between November 2022 and April 2023 in China. Median age was 69 years (range 60-92). 54.4% (198/364) of patients were confirmed as severe and critical COVID-19 infection. In univariable analysis, Age > 70 years (OR 1.88, p = 0.003), with multiple comorbidities (OR 1.41, p = 0.005), aggressive lymphoma (OR 2.33, p < 0.001), active disease (progressive or relapsed/refractory, OR 2.02, p < 0.001), and active anti-lymphoma therapy (OR 1.90, p < 0.001) were associated with severe COVID-19. Multiple (three or more) lines of previous anti-lymphoma therapy (OR 3.84, p = 0.021) remained an adverse factor for severe COVID-19 in multivariable analysis. Moreover, CD20 antibody (Rituximab or Obinutuzumab)-based treatments within the last 6 months was associated with severe COVID-19 in the entire cohort (OR 3.42, p < 0.001). Continuous BTK inhibitors might be protective effect on the outcome of COVID-19 infection (OR 0.44, p = 0.043) in the indolent lymphoma cohort. Overall, 7.7% (28/364) of the patients ceased, multiple lines of previous anti-lymphoma therapy (OR 3.46, p = 0.016) remained an adverse factor for mortality.
The broad-spectrum topical insect repellent
N,
N-diethyl-
m-toluamide (DEET) is highly skin permeable, and serious adverse effects associated with the use of commercial DEET products have occurred in ...users due to extensive DEET skin permeation. In an effort to develop topical DEET formulations with reduced DEET skin permeation and extended repellency, this study investigated the effects of vehicle on DEET in vitro skin permeation from topical DEET solution and gel emulsion formulations prepared with ethanol, polyethylene glycol 400 (PEG 400), stearic acid and polyacrylic acid polymers Carbopol 940NF and Pemulen TR-2. In vitro skin permeation of DEET was evaluated in Franz diffusion cells using freshly excised abdominal cotton rat skin at 32±1°C. The receiver phase samples were analyzed by HPLC with
N,
N-diethyl-2-phenylacetamide as reference standard. Relative to technical DEET, 40 and 50% (v/v) aqueous ethanol solutions increased DEET steady-state skin flux (
J
ss) by 157 and 137%, respectively, while 75% (v/v) aqueous ethanol solution, neat ethanol and PEG 400 decreased the
J
ss by 67, 74 and 59%, respectively. The incorporation of skin humectants glycerol, dimethicone or mineral oil to DEET gel emulsions based on Carbopol 940NF and stearic acid at 15% (w/w) did not significantly reduce the
J
ss. Compared with a name-brand lotion of 7.125% (w/w) DEET, the use of 20% (w/w) PEG 400 and 1% (w/w) Tween 80, or 75% (v/v) aqueous ethanol in Carbopol 940NF and Pemulen TR-2 based formulations containing 7.5% (w/w) DEET resulted in 22.7, 18.2 and 9.1% reduction in the
J
ss, respectively. For safety concerns, the incorporation of ethanol in commercial DEET products needs to be reevaluated. The topical formulation vehicle based on PEG 400, Carbopol 940NF and Pemulen TR-2 was effective in reducing DEET skin permeation.
The common topical insect repellent N,N-diethyl-m-toluamide (DEET) has caused serious adverse effects in the users of DEET products due to its high skin permeability. This study investigated the ...pharma-cokinetics of DEET following iv and dermal routes of administration in beagle dogs. The pharmacokinetics of DEET was linear over the dose range of 2.5–6.0mg/kg. Following the iv dosing, plasma DEET concentrations declined biexponentially with an elimination half-life of 2.56h. Volume of distribution at steady-state, systematic clearance, and mean residence time were estimated as 6.21L/kg, 2.66L/h/kg, and 2.34 h, respectively, indicating that DEET underwent extensive extravascular distribution and rapid elimination. After the dermal application of a commercial lotion and a new DEET lotion at 15mg of DEET/kg, plasma DEET concentrations peaked at 1–2h postdose. The DEET transdermal bioavailability and mean absorption time were 18.3% and 2.05 h, respectively, for the commercial lotion and 14.0% and 2.66 h, respectively, for the new lotion. The difference in DEET transdermal absorption between the two lotions suggested that commercial DEET products could be optimized for reduced DEET absorption for safer use.
N,N-diethyl-m-toluamide (DEET) has been used as an all-purpose topical insect repellent for the protection of humans and livestock from the attack of biting insects. In order to reduce the extensive ...skin permeation of DEET which causes serious systemic and local adverse effects and enhance the protection time following dermal application, various DEET formulations were developed and evaluated in vitro and in vivo. Aqueous ethanol solutions promoted or retarded DEET permeation through cotton rat skin depending on the ethanol content. Compared with technical DEET, solutions of 40% and 50% ethanol enhanced the steady-state skin flux (J$\sb{\rm ss})$ of DEET by 156% and 129%, respectively, while 75% aqueous ethanol and neat ethanol decreased the J$\sb{\rm ss}$ by 67% and 80%, respectively. A new lotion based on polyacrylic acid polymers and PEG 400 of 7.5% DEET demonstrated 19.5% reduction in the J$\sb{\rm ss}$ and 23.5% reduction in the transdermal bioavailability of DEET in beagle dogs relative to a commercial lotion containing similar level of DEET. The new lotion also provided better repellency against Aedes aegypti within 6 hr following dermal application to shaved areas of dogs at 0.5 mg DEET/cm$\sp2.$ Linear pharmacokinetics of DEET was observed in dogs within the intravenous dose range of 2.5 to 6.0 mg/kg. Following the intravenous doses, volume of distribution at steady state, systemic clearance, mean residence time (MRT) and terminal elimination half-life of DEET were estimated as 6.21 L/kg, 2.66 L/hr/kg, 2.34 hr and 2.56 hr, respectively, indicating DEET underwent extensive extravascular distribution and rapid elimination. DEET transdermal absorption following dermal treatment of DEET lotions was rapid. At dermal dose of 15 mg DEET/cm$\sp2$, MRT valued from 4 to 5 hr, and plasma DEET concentration peaked at 1 to 2 hr postdose. To conduct the in vivo studies, a sensitive liquid chromatographic method which offered a limit of quantitation of 15 ng/mL was developed with the establishment of an effective solid-phase extraction procedure. Use of ethanol in end-use DEET formulations need to be reevaluated due to its enhancer properties. To obtain a formulation with reduced DEET transdermal absorption and extended protection, further optimization of the new DEET lotion based on polyacrylic acid polymers and PEG 400 would be worthwhile.
ABSTRACT
Extensive absorption of the topical insect repellent N, N-diethyl-m-toluamide (DEET) causes systemic and local toxicities. This report describes the preparation and characterization of a new ...insect repellent formulation (FA), a PEG-polyacrylic acid polymer system, for its DEET release, in vitro skin permeation, and in vivo transdermal absorption properties; and for its relative repellency against Aedss aegypti mosquitoes. DEET release and skin permeation were studied in Franz diffusion cells. DEET transdermal absorption and relative repellency of FA were assessed in beagle dogs. A commercial DEET lotion (FB) and technical DEET (FC) were used as references. FA exhibited 19.5% and 61.7% decrease in DEET steady-state skin flux compared with FB and FC, respectively. At 15 mg DEET/kg, the absolute DEET transdermal bioavailability and Cmax were 13.4% and 154.3 ng/ml, respectively, for FA; and were 17.5% and 196.5 ng/ml, respectively, for FB. DEET half-lives (t1/2) for FA (2.52 hr) and FB (2.73 hr) were similar, while MRTfor FA (4.99 hr) was significantly greater (p < 0.05) than that for FB (4.38 hr). FA showed lower mosquito biting rates at 1, 2, 3, 4, 5, and 6 hr postdose at 0.5 mg DEET/cm2. FA exhibited reduced in vitro skin permeation and in vivo transdermal absorption of DEET as well as superior repellency compared with FB. The PEG-polyacrylic acid polymer system is of value in the formulation of DEET lotions.
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