The International Association for the Study of Lung Cancer (IASLC) Staging Project for Lung Cancer: Recommendation to Introduce Spread Through Air Spaces as a Histologic Descriptor in the Ninth Edition of the TNM Classification of Lung Cancer. Analysis of 4061 Pathologic Stage I NSCLC.

INTRODUCTION: Spread through air spaces (STAS) consists of lung cancer tumor cells that are identified beyond the edge of the main tumor in the surrounding alveolar parenchyma. It has been reported by meta-analyses to be an independent prognostic factor in the major histologic types of lung cancer, but its role in lung cancer staging is not established. METHODS: To assess the clinical importance of STAS in lung cancer staging, we evaluated 4061 surgically resected pathologic stage I R0 NSCLC collected from around the world in the International Association for the Study of Lung Cancer database. We focused on whether STAS could be a useful additional histologic descriptor to supplement the existing ones of visceral pleural invasion (VPI) and lymphovascular invasion (LVI). RESULTS: STAS was found in 930 of 4061 of the pathologic stage I NSCLC (22.9%). Patients with tumors exhibiting STAS had a significantly worse recurrence-free and overall survival in both univariate and multivariable analyses involving cohorts consisting of all NSCLC, specific histologic types (adenocarcinoma and other NSCLC), and extent of resection (lobar and sublobar). Interestingly, STAS was independent of VPI in all of these analyses. CONCLUSIONS: These data support our recommendation to include STAS as a histologic descriptor for the Ninth Edition of the TNM Classification of Lung Cancer. Hopefully, gathering these data in the coming years will facilitate a thorough analysis to better understand the relative impact of STAS, LVI, and VPI on lung cancer staging for the Tenth Edition TNM Stage Classification.

First-in-human imaging with [89Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumors of the lung and prostate.

Background: Delta-like ligand 3 (DLL3) is aberrantly expressed on the cell surface in many neuroendocrine cancers including small cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC). Several therapeutic agents targeting DLL3 are in active clinical development. Molecular imaging of DLL3 would enable non-invasive diagnostic assessment to inform the use of DLL3-targeting therapeutics or to assess disease treatment response. Methods: We conducted a first-in-human immuno-positron emission tomography (immunoPET) imaging study of [89Zr]Zr-DFO-SC16.56, composed of the anti-DLL3 antibody SC16.56 conjugated to desferrioxamine (DFO) and the positron-emitting radionuclide zirconium-89, in 18 patients with neuroendocrine cancers. An initial cohort of three patients received 1-2 mCi of [89Zr]Zr-DFO-SC16.56 at a total mass dose of 2·5 mg and underwent serial PET and computed tomography (CT) imaging over the course of one week. Radiotracer clearance, tumor uptake, and radiation dosimetry were estimated. An expansion cohort of 15 additional patients were imaged using the initial activity and mass dose. Retrospectively collected tumor biopsies were assessed for DLL3 by immunohistochemistry (IHC) (n = 16). Findings: Imaging of the initial 3 SCLC patients demonstrated strong tumor-specific uptake of [89Zr]Zr-DFO-SC16.56, with similar tumor: background ratios at days 3, 4, and 7 post-injection. Serum clearance was bi-phasic with an estimated terminal clearance half-time of 119 h. The sites of highest background tracer uptake were blood pool and liver. The normal tissue receiving the highest radiation dose was liver; 1·8 mGy/MBq, and the effective dose was 0.49 mSv/MBq. Tumoral uptake varied both between and within patients, and across anatomic sites, with a wide range in SUVmax (from 3·3 to 66·7). Tumor uptake by [89Zr]Zr-DFO-SC16.56 was associated with protein expression in all cases. Two non-avid DLL3 NEPC cases by PET scanning demonstrated the lowest DLL3 expression by tumor immunohistochemistry. Only one patient had a grade 1 allergic reaction, while no grade ≥2 adverse events noted. Interpretation: DLL3 PET imaging of patients with neuroendocrine cancers is safe and feasible. These results demonstrate the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in vivo detection of DLL3-expressing malignancies. Funding: Supported by NIH R01CA213448 (JTP), R35 CA263816 (CMR), U24 CA213274 (CMR), R35 CA232130 (JSL), and a Prostate Cancer Foundation TACTICAL Award (JSL), Scannell foundation. The Radiochemistry and Molecular Imaging Probes Core Facility is supported by NIH P30 CA08748.

Doxycycline-Loaded Calcium Phosphate Nanoparticles with a Pectin Coat Can Ameliorate Lipopolysaccharide-Induced Neuroinflammation Via Enhancing AMPK.

Neuroinflammation occurs in response to different injurious triggers to limit their hazardous effects. However, failure to stop this process can end in multiple neurological diseases. Doxycycline (DX) is a tetracycline, with potential antioxidant and anti-inflammatory properties. The current study tested the effects of free DX, DX-loaded calcium phosphate (DX@CaP), and pectin-coated DX@CaP (Pec/DX@CaP) nanoparticles on the lipopolysaccharide (LPS)-induced neuroinflammation in mice and to identify the role of adenosine monophosphate-activated protein kinase (AMPK) in this effect. The present study was conducted on 48 mice, divided into 6 groups, eight mice each. Group 1 (normal control), Group 2 (blank nanoparticles-treated), Group 3 (LPS (untreated)), Groups 4, 5, and 6 received LPS, then Group 4 received free DX, Group 5 received DX-loaded calcium phosphate nanoparticles (DX@CaP), and Group 6 received DX-loaded calcium phosphate nanoparticles with a pectin coat (Pec/DX@CaP). At the end of the experimentation period, behavioral tests were carried out. Then, mice were sacrificed, and brain tissue was extracted and used for histological examination, and assessment of interleukin-6 positive cells in different brain areas, in addition to biochemical measurement of SOD activity, TLR-4, AMPK and Nrf2. LPS can induce prominent neuroinflammation. Treatment with (Pec/DX@CaP) can reverse most behavioral, histopathological, and biochemical changes caused by LPS. The findings of the current study suggest that (Pec/DX@CaP) exerts a significant reverse of LPS-induced neuroinflammation by enhancing SOD activity, AMPK, and Nrf2 expression, in addition to suppression of TLR-4.

Structure Modification Converts the Hepatotoxic Tacrine into Novel Hepatoprotective Analogs.

The liver is responsible for critical functions such as metabolism, secretion, storage, detoxification, and the excretion of various compounds. However, there is currently no approved drug treatment for liver fibrosis. Hence, this study aimed to explore the potential hepatoprotective effects of chlorinated and nonchlorinated 4-phenyl-tetrahydroquinoline derivatives. Originally developed as tacrine analogs with reduced hepatotoxicity, these compounds not only lacked hepatotoxicity but also displayed a remarkable hepatoprotective effect. Treatment with these derivatives notably prevented the chemically induced elevation of hepatic indicators associated with liver injury. Additionally, the compounds restored the activities of defense antioxidant enzymes as well as levels of inflammatory markers (TNF-α and IL-6), apoptotic proteins (Bax and Bcl2), and fibrogenic mediators (α-SMA and TGF-ß) to normal levels. Histopathologic analysis confirmed the hepatoprotective activity of tetrahydroquinolines. Furthermore, computer-assisted simulation docking results were highly consistent with those of the observed in vivo activities. In conclusion, the designed tacrine analogs exhibited a hepatoprotective role in acute liver damage, possibly through their antioxidative, anti-inflammatory, and antifibrotic effects.

Superior sulcus non-small cell lung cancers (Pancoast tumors): Current outcomes after multidisciplinary management.

OBJECTIVE: Despite neoadjuvant chemoradiotherapy, Pancoast tumors still present surgical and oncologic challenges. To optimize outcomes, we used a multidisciplinary care paradigm with medical and radiation oncology, and involvement of spine neurosurgery for most T3 and all T4 tumors. Spine neurosurgery permitted resection of transverse process for T3 and vertebral body resection for T4 tumors. METHODS: Retrospective analysis of single institution, prospective database of patients undergoing resection for cT3 4M0 Pancoast tumors. Patients were grouped as cT3 with combined resection with spine neurosurgery (T3 Neuro), cT3 without spine neurosurgery (T3 NoNeuro), and cT4. Overall survival, progression-free survival were analyzed by Kaplan-Meier and compared between groups using log-rank test. Cumulative incidence of local-regional and distant recurrence were compared using Gray test. P value <.05 was considered significant. RESULTS: From 2000 to 2021, 155 patients underwent surgery: median age was 58 years, and 81 were (52%) men. Most patients received neoadjuvant platinum-based neoadjuvant chemoradiotherapy (n = 127 [82%]). Operations were 48 cT3 Neuro, 41 cT3 NoNeuro, 66 cT4. R0 resection was achieved in 49 (94%) cT3 NoNeuro, 35 (85%) cT3 Neuro, and 57 (86%) cT4 patients (P = .4). Complete or major pathologic response occurred in 71 (55%) patients. Lower local-regional cumulative incidence was seen in cT3 Neuro versus cT3 NoNeuro (P = .05) and after major pathologic response. Overall survival and progression-free survival were associated with complete response, pathologic stage, and nodal status but not cT category. CONCLUSIONS: This treatment paradigm was associated with a high frequency of R0 resection, complete response, and major pathologic response. cT3 and cT4 tumors had similar outcomes. Novel therapies are needed to improve complete response.

Resveratrol ameliorates the behavioural and molecular changes in rats exposed to uninephrectomy: role of hippocampal SIRT1, BDNF and AChE

Subtle memory and cognitive changes may occur in uninephrectomized (Unix) patients long before the development of chronic kidney disease, such changes may be unnoticed. The dietary polyphenol, Resveratrol, displayed various neuroprotective effects, its role in chronic kidney disease is an area of intense studies. This work was designed to investigate the behavioural and molecular changes that may occur following 7 months of Unix in rats, and to determine whether Resveratrol intake can improve such pathology. Male Wistar rats were divided into three groups: sham operated, Unix and Unix group treated with Resveratrol (20 mg/kg/day). Rats were subjected to series of behavioural testing, different biochemical parameters along with RT-PCR and immunohistochemistry of the hippocampal tissue to track the development of functional or structural brain changes. Anxiety behaviour and reduced spatial memory performance were observed in rats 7 months post-nephrectomy; these deficits were remarkably reversed with Resveratrol. Among the species typical behaviour, burrowing was assessed; it showed significant impairment post-nephrectomy. Resveratrol intake was almost able to increase the burrowing behaviour. Decreased SIRT1 in immune-stained sections, oxidative stress, inflammatory changes, and increased AChE activity in hippocampal homogenates were found in Unix rats, and Resveratrol once more was capable to reverse such pathological changes. This work has investigated the occurrence of behavioural and structural brain changes 7 months following Unix and underlined the importance of Resveratrol to counterbalance the behavioural impairment, biochemical and brain pathological changes after uninephrectomy. These findings may raise the possible protective effects of Resveratrol intake in decreased kidney function. (AU)

Concurrent Tissue Engineering for Wound Healing in Diabetic Rats Utilizing Dual Actions of Green Synthesized CuO NPs Prepared from Two Plants Grown in Egypt.

Purpose: Diabetes mellitus is among the disrupting factors of orchestrated events in wound healing. This necessitates the urge for tailored medications, which are continually offered by nano-sized materials. Herein, we present greenly synthesized copper oxide nanoparticles (CuO NPs), obtained from either Punica granatum L. (PG) or Pisidium guajava L. (GV) extract, to function as potent bactericidal and fungicidal materials that promote regeneration and healing of the targeted diabetic wounded tissues. Methods: PG or GV plant extracts were compared as source of reducing agents for CuO NPs synthesis process. The yield and photocatalytic degradation potential were compared. NPs obtained from the superior extract, PG, were characterized using particles size, zeta potential, XRD, TEM, SEM, and EDX. The antimicrobial effects were evaluated on multidrug-resistant human pathogens and then the percentage biofilm inhibitory concentration was determined. The cytotoxicity and wound scratch study were conducted on a normal human skin cell line. In-vivo wound healing activity in diabetic rats was assessed along with histopathological and immunohistochemical examination of CD45 and α-SMA. Results: The greenly synthesized CuO NPs are spherical in shape having a diameter of 233nm. CuO NPs (250µg/mL) acted as promising biocontrol agent against a variety of multidrug-resistant human pathogens. They significantly exhibited 29.460±0.811% healing of the scratched wound compared to only 2.001±0.155% for the control. Wound healing experiments revealed the safety of a low CuO NPs concentration in a diabetic animal model as well as on human normal skin fibroblast cell line. The treated group with a dose of 2mg/cm2 showed superior results with a WC50 value of 7.2 days, and 92% wound contraction after 13-days. Immunohistochemical investigation of the same group demonstrated well-established fibrous tissue (5.7±3.7/HPF), and an amplified granulation tissue of recently developed blood vessels (70±1.5/HPF). Conclusion: Green synthesized CuO NPs could overcome drug resistance and promote wound healing process effectively.

Empagliflozin inhibits autophagy and mitigates airway inflammation and remodelling in mice with ovalbumin-induced allergic asthma.

Empagliflozin, a selective inhibitor of Na+-glucose cotransporter-2, has been reported to exert anti-inflammatory and anti-fibrotic effects in addition to autophagy modulation. Addressing the role of autophagy in allergic asthma revealed controversial results. The potential effect of empagliflozin treatment on airway inflammation and remodelling as well as autophagy modulation in a murine model of allergic asthma was investigated. Over a 7-week period, male BALB/c mice were sensitized and challenged by intraperitoneal injection and inhalation of ovalbumin, respectively. Animals were treated with empagliflozin (10 mg/kg; orally) and/or rapamycin (an autophagy inducer; 4 mg/kg; intraperitoneally) before every challenge. Methacholine-induced airway hyperresponsiveness was evaluated one day after the last challenge. After euthanasia, serum, bronchoalveolar lavage fluid, and lung tissues were collected for biochemical, histopathological, and immunohistochemical assessment. Results revealed that empagliflozin decreased airway hyperresponsiveness, serum ovalbumin-specific immunoglobulin E, and bronchoalveolar lavage total and differential leukocytic counts. Levels of inflammatory and profibrotic cytokines (IL-4, IL-5, IL-13, IL-17, and transforming growth factor-ß1) were all inhibited. Moreover, empagliflozin preserved pulmonary microscopic architecture and alleviated bronchiolar epithelial thickening, goblet cell hyperplasia, fibrosis and smooth muscle hypertrophy. These effects were associated with inhibition of ovalbumin-activated autophagic flux, as demonstrated by decreased LC3B expression and LC3BII/I ratio, as well as increased P62 expression. However, the therapeutic potential of empagliflozin was inhibited when rapamycin was co-administered. In conclusion, this study demonstrates that empagliflozin has immunomodulatory, anti-inflammatory, and anti-remodelling properties in ovalbumin-induced allergic asthma and suggests that autophagic flux inhibition may play a role in empagliflozin's anti-asthmatic effects.

Berberine-loaded zein/hyaluronic acid composite nanoparticles for efficient brain uptake to alleviate neuro-degeneration in the pilocarpine model of epilepsy.

Berberine hydrochloride is a plant alkaloid with versatile medicinal applications, yet it has suffered from multiple limitations in its usage. Nonetheless, the acknowledged role of berberine in controlling seizures has fuelled the need to develop a nanosystem capable of delivering it safely and efficiently to the brain. Consequently, zein and hyaluronic acid were chosen for this purpose, and about twenty formulations with different preliminary factors were screened. Afterward, three promising formulations were loaded with berberine and characterized to select an optimum formulation for further in vivo inspection. The B2 formula of particle size of 297.2 nm ± 1.86 and % entrapment efficiency of 83.75% ± 1.39 has succeeded in the increment of the brain uptake of berberine. Moreover, compared to free berberine suspension, the severity of pilocarpine-induced status epilepticus in rats was depleted after the subcutaneous administration of B2. The hippocampal tissue of rats receiving B2 showed signs of reduced neuro-degeneration, remarkably lower expression levels of COX-2 and TNF-α, and enhanced antioxidant activity. Finally, the relative safety of the developed system was determined after searching for any sign of intoxication or behavioral changes. In conclusion, the developed berberine loaded composite nanoparticles successfully delivered berberine across the BBB securely to ameliorate the deteriorating impact of pilocarpine-induced epilepsy.

Possible protective effect of zinc administration on renal and cognitive changes occurring in uninephrectomized adult male Wistar rats.

NEW FINDINGS: What is the central question of this study? Are renal changes occurring post-nephrectomy accompanied by cognitive changes, and does early administration of zinc supplements such as ZnSO4 to uninephrectomized rats ameliorate the renal and cognitive changes if present? What is the main finding and its importance? Uninephrectomy-induced renal changes were accompanied by species-atypical behaviour in rats in both Morris water maze and T maze tests, together with hypozincaemia and hippocampal inflammatory and oxidative changes. Early zinc administration to uninephrectomized rats ameliorated the renal, behavioural, hippocampal and serum zinc changes. ABSTRACT: Cognitive impairment is increasingly recognized as an important consequence of kidney disease in humans. Kidney donation is a safe procedure but is known to increase the long-term risk of cardiovascular and kidney disease. Whether kidney donation impairs cognitive function is not known. In the present study, we examined whether the renal changes occurring post-nephrectomy were accompanied by cognitive changes as well, and whether early administration of zinc supplements such as ZnSO4 to uninephrectomized (UNX) rats could ameliorate the renal and cognitive changes if present. The present study included 30 adult male Wistar rats that were randomly assigned to three groups (n = 10 per group): sham-operated rats, UNX and UNX treated with ZnSO4 for 20 weeks. Before termination, rats were subjected to 24-h urine collection and behavioural testing with the Morris water maze and T maze tests. UNX induced significant proteinuria, renal functional, fibrotic and oxidative changes, as well as increased renal desmin expression. UNX rats also showed significant behavioural changes indicating spatial learning and memory affection, together with decreased hippocampal brain derived neurotrophic factor (BDNF) and antioxidant capacity, and increased glial fibrillary acidic protein (GFAP), nitric oxide and malondialdehyde. In addition, UNX induced significant hyperglycaemia and dyslipidaemia, as well as significant reduction in serum zinc, copper and selenium. Early administration of ZnSO4 starting 1 week post-nephrectomy significantly ameliorated renal and behavioural changes, as well as hippocampal oxidative, BDNF and GFAP changes. Additionally, Zn recovered serum changes of triglycerides, cholesterol, zinc and copper. Therefore, early administration of zinc to humans undergoing nephrectomy may be of benefit and should be considered in human trials.

Development and evaluation of local regenerative biomimetic bone-extracellular matrix scaffold loaded with nano-formulated quercetin for orthopedic fractures.

The prevalence of bone injuries is greatly increasing each year and the proper healing of fractures without any complications is very challenging. Self-setting calcium phosphate cements (CPCs) have attracted great attention as bioactive synthetic bone substitutes. Quercetin (QT) is a multipurposed drug with reported bone-conserving properties. The loading of QT and QT-phospholipid complex within nanostructured lipid carriers (NLC) was proposed to overcome the poor physical properties of the drug and to introduce the use of bioactive excipients as phospholipids and olive oil. The aim of this work was to formulate a regenerative scaffold loaded with nano-formulated QT for local treatment of orthopedic fractures. For the first time, scaffolds composed of brushite CPC were prepared and loaded with quercetin lipid nano-systems. In vitro tests proved that the addition of lipid nano-systems did not deteriorate the properties of CPC where QT-NLC/CPC showed an adequate setting time, appropriate compressive strength, and porosity. The scanning electron microscope confirmed maintenance of nanoparticles integrity within the cement. Using a rat femur bone defect animal model, the histological results showed that the QT-NLC/CPC had a superior bone healing potential compared to crude unformulated QT/CPC. In conclusion, QT-NLC /CPC are promising lipid nano-composite materials that could enhance bone regeneration.

Resveratrol ameliorates the behavioural and molecular changes in rats exposed to uninephrectomy: role of hippocampal SIRT1, BDNF and AChE.

Subtle memory and cognitive changes may occur in uninephrectomized (Unix) patients long before the development of chronic kidney disease, such changes may be unnoticed. The dietary polyphenol, Resveratrol, displayed various neuroprotective effects, its role in chronic kidney disease is an area of intense studies. This work was designed to investigate the behavioural and molecular changes that may occur following 7 months of Unix in rats, and to determine whether Resveratrol intake can improve such pathology. Male Wistar rats were divided into three groups: sham operated, Unix and Unix group treated with Resveratrol (20 mg/kg/day). Rats were subjected to series of behavioural testing, different biochemical parameters along with RT-PCR and immunohistochemistry of the hippocampal tissue to track the development of functional or structural brain changes. Anxiety behaviour and reduced spatial memory performance were observed in rats 7 months post-nephrectomy; these deficits were remarkably reversed with Resveratrol. Among the species typical behaviour, burrowing was assessed; it showed significant impairment post-nephrectomy. Resveratrol intake was almost able to increase the burrowing behaviour. Decreased SIRT1 in immune-stained sections, oxidative stress, inflammatory changes, and increased AChE activity in hippocampal homogenates were found in Unix rats, and Resveratrol once more was capable to reverse such pathological changes. This work has investigated the occurrence of behavioural and structural brain changes 7 months following Unix and underlined the importance of Resveratrol to counterbalance the behavioural impairment, biochemical and brain pathological changes after uninephrectomy. These findings may raise the possible protective effects of Resveratrol intake in decreased kidney function.

Bacteriophage as a potential therapy to control antibiotic-resistant Pseudomonas aeruginosa infection through topical application onto a full-thickness wound in a rat model.

BACKGROUND: Antibiotic-resistant Pseudomonas aeruginosa (P. aeruginosa) is one of the most critical pathogens in wound infections, causing high mortality and morbidity in severe cases. However, bacteriophage therapy is a potential alternative to antibiotics against P. aeruginosa. Therefore, this study aimed to isolate a novel phage targeting P. aeruginosa and examine its efficacy in vitro and in vivo. RESULTS: The morphometric and genomic analyses revealed that ZCPA1 belongs to the Siphoviridae family and could infect 58% of the tested antibiotic-resistant P. aeruginosa clinical isolates. The phage ZCPA1 exhibited thermal stability at 37 °C, and then, it decreased gradually at 50 °C and 60 °C. At the same time, it dropped significantly at 70 °C, and the phage was undetectable at 80 °C. Moreover, the phage ZCPA1 exhibited no significant titer reduction at a wide range of pH values (4-10) with maximum activity at pH 7. In addition, it was stable for 45 min under UV light with one log reduction after 1 h. Also, it displayed significant lytic activity and biofilm elimination against P. aeruginosa by inhibiting bacterial growth in vitro in a dose-dependent pattern with a complete reduction of the bacterial growth at a multiplicity of infection (MOI) of 100. In addition, P. aeruginosa-infected wounds treated with phages displayed 100% wound closure with a high quality of regenerated skin compared to the untreated and gentamicin-treated groups due to the complete elimination of bacterial infection. CONCLUSION: The phage ZCPA1 exhibited high lytic activity against MDR P. aeruginosa planktonic and biofilms. In addition, phage ZCPA1 showed complete wound healing in the rat model. Hence, this research demonstrates the potential of phage therapy as a promising alternative in treating MDR P. aeruginosa.

Metformin, pioglitazone, dapagliflozin and their combinations ameliorate manifestations associated with NAFLD in rats via anti-inflammatory, anti-fibrotic, anti-oxidant and anti-apoptotic mechanisms.

Non-alcoholic fatty liver disease (NAFLD) is an important health threat that is strongly linked to components of metabolic syndrome, particularly the low-grade inflammatory changes. Significantly, several of the available anti-diabetic drug classes demonstrate a considerable anti-inflammatory effect, and hence might be of benefit for NAFLD patients. In this study, we used a rat model of diet-induced NAFLD to examine the potential effect of metformin, pioglitazone, dapagliflozin and their combinations on NAFLD manifestations. Rats were fed an atherogenic diet containing 1.25 % cholesterol, 0.5 % cholic acid and 60 % cocoa butter for 6 weeks causing a number of metabolic and hepatic alterations including insulin resistance, dyslipidemia, systemic inflammation, increased hepatic oxidative stress and lipid peroxidation, hepatic steatosis, lobular inflammation, as well as increased markers of liver inflammation and hepatocyte apoptosis. Drug treatment, which started at the third week of NAFLD induction and continued for three weeks, not only ameliorated the observed metabolic impairment, but also functional and structural manifestations of NAFLD. Specifically, anti-diabetic drug treatment reversed markers of systemic and hepatic inflammation, oxidative stress, hepatic fibrosis, and hepatocyte apoptosis. Our findings propose that anti-diabetic drugs with a potential anti-inflammatory effect can ameliorate the manifestations of NAFLD, and thus may provide a therapeutic option for such a condition that is closely associated with metabolic diseases. The detailed pharmacology of these classes in aspects linked to the observed impact on NAFLD requires to be further investigated and translated into clinical studies for tailored therapy specifically targeting NAFLD.

Hollow microneedle assisted intradermal delivery of hypericin lipid nanocapsules with light enabled photodynamic therapy against skin cancer.

Photodynamic therapy (PDT) to manage non-melanoma skin cancers has garnered great attention over the past few years. Hypericin (Hy) is a potent lipid-soluble photosensitiser with promising anticancer therapeutic activities. Nevertheless, its poor water-solubility, aggregation in biological systems and insufficient skin penetration restricted its effective exploitation. Herein, we report for the first-time encapsulation of Hy into lipid nanocapsules (Hy-LNCs), and then application of an AdminPen™ hollow microneedles (Ho-MNs) array and an in-house fabricated Ho-MN to enable efficient intradermal delivery. The physicochemical properties, photoactivity, ex vivo drug distribution and cellular uptake were evaluated. Results showed that Hy-LNCs were successfully formed with a particle size of 47.76 ± 0.49 nm, PDI of 0.12 ± 0.02, high encapsulation efficiency (99.67% ± 0.35), 396 fold higher photoactivity, 7 fold higher skin drug deposition, significantly greater cellular uptake and higher photocytotoxicity compared to free Hy. The therapeutic effect of Hy-LNCs was finally assessed in vivo using a nude mouse model with transplanted tumours. Interestingly, Hy-LNCs delivered by Ho-MN exhibited remarkable anti-tumour destruction (85.84%) after irradiation with 595 nm. This study showed that Ho-MNs-driven delivery of Hy-LNCs followed by irradiation could form a promising minimally invasive, effective and site-specific approach for managing non-melanoma skin cancers.

Lead acetate versus cadmium sulfate in the modulation of main physiological pathways controlling detrusor muscle contractility in rat.

Heavy metals have a deleterious effect on lower urinary tract functions. Scant data has been reported about metals' effect on altering detrusor muscle contractility. Rats were given lead acetate (3, 30 mg/kg), cadmium sulfate (0.1, 1 mg/kg) or ferrous sulfate-iron overload-(3, 30 mg/kg), in a subacute toxicity study (21 days, ip). In-vitro tension experiments were conducted using isolated rat detrusor muscle. Measurement of heavy metal concentrations in blood and tissue homogenates was performed, as well as histopathological examinations. Subacute toxicity induced by treatment with lead and cadmium was manifested as a decrease in EFS, ACh, and ATP-mediated contraction of isolated detrusor muscle. Iron overload only decreased EMAX of EFS and ACh-mediated contraction. Lead (30 mg/kg) caused an upward shift in the dose response curve of isoprenaline-induced relaxation, with a significant decrease in EMAX. Lead (30 mg/kg) or cadmium (1 mg/kg) inhibited adenosine (10-5 M)-induced relaxation. Comparisons to control tissues showed a selective accumulation of metals in the detrusor muscle. Histopathological examinations revealed edema and inflammation in the urinary bladder. Directly added lead (10 mM) inhibited detrusor muscle contraction in-vitro, and its effect was decreased in presence of atropine, and potentiated in presence of TEA, L-NAME, or MB. Cadmium's (0.1 mM) inhibitory effect was reduced in presence of nifedipine or trifluoperazine. In conclusion, lead, cadmium, or iron induce detrusor hypoactivity: The inhibitory effect of lead may be mediated by modulating muscarinic receptors but not the K+/NO/cGMP pathway, whereas cadmium inhibitory effect may be mediated by inhibiting the Ca2+/calmodulin pathway.

Tumor and Tumor-Associated Macrophage Programmed Death-Ligand 1 Expression Is Associated With Adjuvant Chemotherapy Benefit in Lung Adenocarcinoma.

INTRODUCTION: Patients with stage II to III lung adenocarcinomas are treated with adjuvant chemotherapy (ACT) to target the premetastatic niche that persists after curative-intent resection. We hypothesized that the premetastatic niche is a scion of resected lung tumor microenvironment and that analysis of tumor microenvironment can stratify survival benefit from ACT. METHODS: Using tumor and tumoral stroma from 475 treatment-naive patients with stage II to III lung adenocarcinomas, we constructed a tissue microarray and performed multiplex immunofluorescent staining for immune markers (programmed death-ligand 1 [PD-L1], tumor-associated macrophages [TAMs], and myeloid-derived suppressor cells) and derived myeloid-lymphoid ratio. The association between immune markers and survival was evaluated using Cox models adjusted for pathologic stage. RESULTS: Patients with high PD-L1 expression on TAMs or tumor cells in resected tumors had improved survival with ACT (TAMs: hazard ratio [HR] = 1.79, 95% confidence interval [CI]: 1.12-2.85; tumor cells: HR = 3.02, 95% CI: 1.69-5.40). Among patients with high PD-L1 expression on TAMs alone or TAMs and tumor cells, ACT survival benefit is pronounced with high myeloid-lymphoid ratio (TAMs: HR = 3.87, 95% CI: 1.79-8.37; TAMs and tumor cells: HR = 2.19, 95% CI: 1.02-4.71) or with high stromal myeloid-derived suppressor cell ratio (TAMs: HR = 2.53, 95% CI: 1.29-4.96; TAMs and tumor cells: HR = 3.21, 95% CI: 1.23-8.35). Patients with low or no PD-L1 expression on TAMs or tumor cells had no survival benefit from ACT. CONCLUSIONS: Our observation that PD-L1 expression on TAMs or tumor cells is associated with improved survival with ACT provides rationale for prospective investigation and developing chemoimmunotherapy strategies for patients with lung adenocarcinoma.

Topically Applied Bacteriophage to Control Multi-Drug Resistant Klebsiella pneumoniae Infected Wound in a Rat Model.

(Background): Multi-drug-resistant Klebsiella pneumoniae (MDR-KP) has steadily grown beyond antibiotic control. Wound infection kills many patients each year, due to the entry of multi-drug resistant (MDR) bacterial pathogens into the skin gaps. However, a bacteriophage (phage) is considered to be a potential antibiotic alternative for treating bacterial infections. This research aims at isolating and characterizing a specific phage and evaluate its topical activity against MDR-KP isolated from infected wounds. (Methods): A lytic phage ZCKP8 was isolated by using a clinical isolate KP/15 as a host strain then characterized. Additionally, phage was assessed for its in vitro host range, temperature, ultraviolet (UV), and pH sensitivity. The therapeutic efficiency of phage suspension and a phage-impeded gel vehicle were assessed in vivo against a K. pneumoniae infected wound on a rat model. (Result): The phage produced a clear plaque and was classified as Siphoviridae. The phage inhibited KP/15 growth in vitro in a dose-dependent pattern and it was found to resist high temperature (˂70 °C) and was primarily active at pH 5; moreover, it showed UV stability for 45 min. Phage-treated K. pneumoniae inoculated wounds showed the highest healing efficiency by lowering the infection. The quality of the regenerated skin was evidenced via histological examination compared to the untreated control group. (Conclusions): This research represents the evidence of effective phage therapy against MDR-KP.

Hybrid lipid core chitosan-TPGS shell nanocomposites as a promising integrated nanoplatform for enhanced oral delivery of sulpiride in depressive disorder therapy.

Sulpiride (SUL), a benzamide derivative, acts as a multitarget drug with extensive biological properties. However, being a P-glycoprotein efflux substrate with a limited oral bioavailability imposes a challenge to its clinical efficacy. The current research explores the impact of tailored hybrid lipid-polysaccharide nanocomposites in augmenting the biological performance of SUL. Chitosan-graft-tocopherol polyethylene glycol 1000 succinate (TPGS) copolymers were synthesized and integrated as a polysaccharide shell into a SUL-loaded lipid nanocore. The optimized nanohybrids revealed a nanocore-shell structure with 110.1 nm particle size, 23.7 mV zeta potential, 85.42% encapsulation efficiency, a pH-dependent-release profile, and an acceptable mucoadhesive tendency. Employing TPGS into the chitosan backbone alleviated the cellular internalization of nanohybrids into the Caco-2 intestinal cells and hence increased the intestinal permeation and the oral bioavailability of SUL by 3.3, and 8.7-folds, respectively. Reserpine-induced depression rat model confirmed the superior antidepressant activity of nanohybrids, compared with free SUL and a marketed product. The nanohybrids exhibited 1.87- and 1.47-folds enhancement in both serotonin and dopamine levels, respectively. Additionally, nanohybrids were shown to attenuate brain oxidative stress state and SUL irritant effect on different body tissues. Overall, the newly tailored nanohybrids pave the way for an advance in the field of oral drug delivery.

Potential Privilege of Maltodextrin-α-Tocopherol Nano-Micelles in Seizing Tacrolimus Renal Toxicity, Managing Rheumatoid Arthritis and Accelerating Bone Regeneration.

BACKGROUND: Tacrolimus (TAC) is a powerful immunosuppressive agent whose therapeutic applicability is confined owing to its systemic side effects. OBJECTIVE: Herein, we harnessed a natural polymer based bioconjugate composed of maltodextrin and α-tocopherol (MD-α-TOC) to encapsulate TAC as an attempt to overcome its biological limitations while enhancing its therapeutic anti-rheumatic efficacy. METHODS: The designed TAC loaded maltodextrin-α-tocopherol nano-micelles (TAC@MD-α-TOC) were assessed for their physical properties, safety, toxicological behavior, their ability to combat arthritis and assist bone/cartilage formation. RESULTS: In vitro cell viability assay revealed enhanced safety profile of optimized TAC@MD-α-TOC with 1.6- to 2-fold increase in Vero cells viability compared with free TAC. Subacute toxicity study demonstrated a diminished nephro- and hepato-toxicity accompanied with optimized TAC@MD-α-TOC. TAC@MD-α-TOC also showed significantly enhanced anti-arthritic activity compared with free TAC, as reflected by improved clinical scores and decreased IL-6 and TNF-α levels in serum and synovial fluids. Unique bone formation criteria were proved with TAC@MD-α-TOC by elevated serum and synovial fluid levels of osteocalcin and osteopontin mRNA and proteins expression. Chondrogenic differentiation abilities of TAC@MD-α-TOC were proved by increased serum and synovial fluid levels of SOX9 mRNA and protein expression. CONCLUSION: Overall, our designed bioconjugate micelles offered an excellent approach for improved TAC safety profile with enhanced anti-arthritic activity and unique bone formation characteristics.