The current BSC guidance issued by the FDA allows for biowaivers based on conservative criteria. Possible new criteria and class boundaries are proposed for additional biowaivers based on the ...underlying physiology of the gastrointestinal tract. The proposed changes in new class boundaries for solubility and permeability are as follows: 1. Narrow the required solubility pH range from 1.0-7.5 to 1.0-6.8. 2. Reduce the high permeability requirement from 90% to 85%. The following new criterion and potential biowaiver extension require more research: 1. Define a new intermediate permeability class boundary. 2. Allow biowaivers for highly soluble and intermediately permeable drugs in IR solid oral dosage forms with no less than 85% dissolved in 15 min in all physiologically relevant dissolution media, provided these IR products contain only known excipients that do not affect the oral drug absorption. The following areas require more extensive research: 1. Increase the dose volume for solubility classification to 500 mL. 2. Include bile salt in the solubility measurement. 3. Use the intrinsic dissolution method for solubility classification. 4. Define an intermediate solubility class for BCS Class II drugs. 5. Include surfactants in in vitro dissolution testing.
Depression and symptom severity are predictive of survival in cancer patients, but are often correlated with each other. This paper compares the physical symptom profiles of depressed and ...nondepressed cancer patients and further examines the predictive ability of multiple symptoms on depressive status. Data were collected from 121 hospitalized patients with breast, oesophageal and head and neck cancer. Patients were categorized as depressed (n =30) or nondepressed (n =91) using the Hospital Anxiety and Depression Scale. Occurrence of symptoms was evaluated with the Patient Disease Symptom/Sign Assessment Scale. The most prevalent symptom in the total sample was insomnia (occurrence rate=67%). Insomnia, pain, anorexia, fatigue, and wound or pressure sore occurred significantly more often in depressed patients, with no difference in occurrence rates of nausea/vomiting and dyspnoea. Significantly more symptoms were observed in depressed than in nondepressed patients (mean=3.77 versus 2.52). Both groups showed similar rankings of symptom occurrence rates. Patients simultaneously experiencing insomnia, pain, anorexia and fatigue had a higher risk of depression (odds ratio=5.03).
Noncancerous disease-targeting AIEgens Duo, Yanhong; Luo, Guanghong; Zhang, Wentao ...
Chemical Society reviews,
02/2023, Letnik:
52, Številka:
3
Journal Article
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Odprti dostop
Noncancerous diseases include a wide plethora of medical conditions beyond cancer and are a major cause of mortality around the world. Despite progresses in clinical research, many puzzles about ...these diseases remain unanswered, and new therapies are continuously being sought. The evolution of bio-nanomedicine has enabled huge advancements in biosensing, diagnosis, bioimaging, and therapeutics. The recent development of aggregation-induced emission luminogens (AIEgens) has provided an impetus to the field of molecular bionanomaterials. Following aggregation, AIEgens show strong emission, overcoming the problems associated with the aggregation-caused quenching (ACQ) effect. They also have other unique properties, including low background interferences, high signal-to-noise ratios, photostability, and excellent biocompatibility, along with activatable aggregation-enhanced theranostic effects, which help them achieve excellent therapeutic effects as an one-for-all multimodal theranostic platform. This review provides a comprehensive overview of the overall progresses in AIEgen-based nanoplatforms for the detection, diagnosis, bioimaging, and bioimaging-guided treatment of noncancerous diseases. In addition, it details future perspectives and the potential clinical applications of these AIEgens in noncancerous diseases are also proposed. This review hopes to motivate further interest in this topic and promote ideation for the further exploration of more advanced AIEgens in a broad range of biomedical and clinical applications in patients with noncancerous diseases.
Long segmental repair of trachea stenosis is an intractable condition in the clinic. The reconstruction of an artificial substitute by tissue engineering is a promising approach to solve this unmet ...clinical need. 3D printing technology provides an infinite possibility for engineering a trachea. Here, we 3D printed a biodegradable reticular polycaprolactone (PCL) scaffold with similar morphology to the whole segment of rabbits' native trachea. The 3D-printed scaffold was suspended in culture with chondrocytes for 2 (Group I) or 4 (Group II) weeks, respectively. This in vitro suspension produced a more successful reconstruction of a tissue-engineered trachea (TET), which enhanced the overall support function of the replaced tracheal segment. After implantation of the chondrocyte-treated scaffold into the subcutaneous tissue of nude mice, the TET presented properties of mature cartilage tissue. To further evaluate the feasibility of repairing whole segment tracheal defects, replacement surgery of rabbits' native trachea by TET was performed. Following postoperative care, mean survival time in Group I was 14.38 ± 5.42 days, and in Group II was 22.58 ± 16.10 days, with the longest survival time being 10 weeks in Group II. In conclusion, we demonstrate the feasibility of repairing whole segment tracheal defects with 3D printed TET.
Schematic diagram of the mitochondria-targeted novel black phosphorus nanosheets platform for the cascaded gas/mild photothermal/photodynamic synergistic therapy of tumor. BP: black phosphorus, Ce6: ...chlorin e6, SNP: sodium nitroprusside dihydrate, NO: nitric oxide, mPTT: mild photothermal therapy, PDT: photodynamic therapy.
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•BCS platform shows high specific capability to mitochondria of tumor.•The intelligent releasing to the tumor environment and NIR with the BCS.•The BCS blocks the function of mitochondrial and perturbs the lysosomes.•The BCS shows three-staged cascaded GT/mPTT/PDT synergistic therapeutic.
The mitochondria critically determine the cell fates and therapeutic interventions. Contrary to the conventional and prevalent nanomaterial-based antitumor strategy, this study proposed a novel synergistic solution that accomplied with a dual tumor and mitochondria-specific BP@PDA-Ce6&SNP-TPP&FA (BCS) platform. The Ce6 and SNP were released in response to the tumor microenvironment and 660 nm laser irradiation. This induced the generation of NO, mild temperature, and ROS, and a second dynamic therapy (ONOO−), destroying the mitochondrial structure and inhibiting the mitochondrial function. The blockade of the mitochondrial function would hinder the cellular respiration and ATP supply, and also perturb the communication and cellular components between the mitochondria and lysosomes. Consequently, the BCS NPs exhibited better antitumor efficacy as well as excellent biosafety than the gas therapy (GT), mild photothermal therapy (mPTT), or photodynamic therapy (PDT) nanoagents individually. This novel cascaded GT/mPTT/PDT synergistic solution offering great potential for numerous anti-cancer treatments.
Background and Purpose- There has been a recent sharp rise in opioid-related deaths in the United States. Intravenous opioid use can lead to infective endocarditis (IE) which can result in stroke. ...There are scant data on recent trends in this neurological complication of opioid abuse. We hypothesized that increasing opioid abuse has led to a higher incidence of stroke associated with IE and opioid use. Methods- We used the 1993 to 2015 releases of the National Inpatient Sample and validated International Classification of Diseases, Ninth Revision, Clinical Modification codes ( ICD-9-CM) to identify hospitalizations with the combination of opioid abuse, IE, and stroke (defined as ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage). Survey weights provided by the National Inpatient Sample were used to calculate nationally representative estimates and population estimates from the United States. Census data were used to calculate annual hospitalization rates per 10 million person-years. Joinpoint regression was used to assess trends. Results- From 1993 through 2015, there were 5283 hospitalizations with stroke associated with IE and opioid use. Across this period, the rate of such hospitalizations increased from 2.4 (95% CI, 0.5-4.3) to 18.8 (95% CI, 14.4-23.3) per 10 million US residents. Joinpoint regression detected 2 segments: no significant change in the hospitalization rate was apparent from 1993 to 2008 (annual percentage change, 1.9%; 95% CI, -2.2% to 6.1%), and then rates significantly increased from 2008 to 2015 (annual percentage change, 20.3%; 95% CI, 10.5%-30.9%), most dramatically in non-Hispanic white patients in the Northeastern and Southern United States. Conclusions- US hospitalization rates for stroke associated with IE and opioid use were stable for ≈2 decades but then sharply increased starting in 2008, coinciding with the emergence of the opioid epidemic.
Paroxysmal atrial fibrillation (PAF) can be eliminated with continuous circular lesions (CCLs) around the pulmonary veins (PVs), but it is unclear whether all PVs are completely isolated.
Forty-one ...patients with symptomatic PAF underwent 3D mapping, and all PV ostia were marked on the 3D map based on venography. Irrigated radiofrequency energy was applied at a distance from the PV ostia guided by 2 Lasso catheters placed within the ipsilateral superior and inferior PVs. The mean radiofrequency duration was 1550+/-511 seconds for left-sided PVs and 1512+/-506 seconds for right-sided PVs. After isolation, automatic activity was observed in the right-sided PVs in 87.8% and in the left-sided PVs in 80.5%. During the procedure, a spontaneous or induced PV tachycardia (PVT) with a cycle length of 189+/-29 ms was observed in 19 patients. During a mean follow-up of 6 months, atrial tachyarrhythmias recurred in 10 patients. Nine patients underwent a repeat procedure. Conduction gaps in the left CCL in 9 patients and in the right CCL in 2 patients were closed during the second procedure. A spontaneous PVT with a cycle length of 212+/-44 ms was demonstrated in 7 of 9 patients, even though no PVT had been observed in 6 of these 7 patients during the first procedure. No AF recurred in 39 patients after PV isolation during follow-up.
Automatic activity and fast tachycardia within the PVs could reflect an arrhythmogenic substrate in patients with PAF, which could be eliminated by isolating all PVs with CCLs guided by 3D mapping and the double-Lasso technique in the majority of patients.
The serine/threonine kinase Akt has been implicated in the control of cell survival and metabolism. Here we report the disruption of the most ubiquitously expressed member of the akt family of genes, ...akt1, in the mouse. Akt1(-/-) mice are viable but smaller when compared to wild-type littermates. In addition, the life span of Akt1(-/-) mice, upon exposure to genotoxic stress, is shorter. However, Akt1(-/-) mice do not display a diabetic phenotype. Increased spontaneous apoptosis in testes, and attenuation of spermatogenesis is observed in Akt1(-/-) male mice. Increased spontaneous apoptosis is also observed in the thymi of Akt1(-/-) mice, and Akt1(-/-) thymocytes are more sensitive to apoptosis induced by gamma-irradiation and dexamethasone. Finally, Akt1(-/-) mouse embryo fibroblasts (MEFs) are more susceptible to apoptosis induced by TNF, anti-Fas, UV irradiation, and serum withdrawal.
This study aims to analyze the prevalence of dyslipidemia and identify the cardiovascular disease (CVD) risk stratification among older adults living in Quanzhou, China's southeast coastal region, ...where the ancient Maritime Silk Road starts.
A population-based cross-sectional survey of 2,018 adults was conducted in 60-98-year-old residents in Quanzhou from September 2016 to March 2018 using multistage stratified cluster random sampling. The 10-year CVD risk was also estimated by applying the Chinese model recommended by the Chinese Guidelines for Prevention of Cardiovascular Diseases.
The overall prevalence of dyslipidemia among older adults was 56.8%. The prevalence of high total cholesterol (TC), high low-density lipoprotein cholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C) and high triglyceride (TG) were 8.4%, 13.9%, 23.1% and 11.4%, respectively. The mean levels of TC, LDL-C, HDL-C and TG were 5.12±1.18, 3.37±0.81, 1.03±0.27 and 1.65±0.76 mmol/L, respectively. Older adults had low risk, moderate risk and high risk for CVD, which were 49.7%, 36.8% and 13.5%, respectively. Age, body mass index and abdominal obesity were significantly associated with the risk of increasing LDL-C levels and were positively correlated to CVD risk.
The prevalence of high TC, high LDL-C, low HDL-C and high TG was relatively low among older adults in Quanzhou, but their lipid levels were high. Approximately half of the elderly adults had moderate or high CVD risk. The personalized primary prevention and control of CVD are recommended for elderly people to identify high-risk individuals.
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