Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition.

Cancer is influenced by its microenvironment, yet broader, environmental effects also play a role but remain poorly defined. We report here that mice living in an enriched housing environment show reduced tumor growth and increased remission. We found this effect in melanoma and colon cancer models, and that it was not caused by physical activity alone. Serum from animals held in an enriched environment (EE) inhibited cancer proliferation in vitro and was markedly lower in leptin. Hypothalamic brain-derived neurotrophic factor (BDNF) was selectively upregulated by EE, and its genetic overexpression reduced tumor burden, whereas BDNF knockdown blocked the effect of EE. Mechanistically, we show that hypothalamic BDNF downregulated leptin production in adipocytes via sympathoneural beta-adrenergic signaling. These results suggest that genetic or environmental activation of this BDNF/leptin axis may have therapeutic significance for cancer.

Genome Editing Using CRISPR-Cas9 and Autoimmune Diseases: A Comprehensive Review.

Autoimmune diseases are disorders that destruct or disrupt the body's own tissues by its own immune system. Several studies have revealed that polymorphisms of multiple genes are involved in autoimmune diseases. Meanwhile, gene therapy has become a promising approach in autoimmune diseases, and clustered regularly interspaced palindromic repeats and CRISPR-associated protein 9 (CRISPR-Cas9) has become one of the most prominent methods. It has been shown that CRISPR-Cas9 can be applied to knock out proprotein convertase subtilisin/kexin type 9 (PCSK9) or block PCSK9, resulting in lowering low-density lipoprotein cholesterol. In other studies, it can be used to treat rare diseases such as ornithine transcarbamylase (OTC) deficiency and hereditary tyrosinemia. However, few studies on the treatment of autoimmune disease using CRISPR-Cas9 have been reported so far. In this review, we highlight the current and potential use of CRISPR-Cas9 in the management of autoimmune diseases. We summarize the potential target genes for immunomodulation using CRISPR-Cas9 in autoimmune diseases including rheumatoid arthritis (RA), inflammatory bowel diseases (IBD), systemic lupus erythematosus (SLE), multiple sclerosis (MS), type 1 diabetes mellitus (DM), psoriasis, and type 1 coeliac disease. This article will give a new perspective on understanding the use of CRISPR-Cas9 in autoimmune diseases not only through animal models but also in human models. Emerging approaches to investigate the potential target genes for CRISPR-Cas9 treatment may be promising for the tailored immunomodulation of some autoimmune diseases in the near future.

Factors determining the oral absorption and systemic disposition of zeaxanthin in rats: in vitro, in situ, and in vivo evaluations.

CONTEXT: Zeaxanthin is a yellow­coloured dietary carotenoid widely recognized as an essential component of the macula. It exerts blue light filtering and antioxidant activities, offering eye health and vision benefits. OBJECTIVE: This study explores the oral absorption and systemic disposition of zeaxanthin from biopharmaceutical and pharmacokinetic perspectives. MATERIALS AND METHODS: In vivo intravenous (5 and 10 mg/kg) and intraportal (5 mg/kg) pharmacokinetic studies were performed to determine intrinsic tissue­blood partition coefficient, elimination pathway, and hepatic clearance, of zeaxanthin in rats. Moreover, in vitro physicochemical property test, in situ closed loop study, in vivo oral pharmacokinetic study (20 and 100 mg/kg), and in vivo lymphatic absorption study (100 mg/kg) were conducted to investigate the gut absorption properties of zeaxanthin and assess the effects of several lipids on the lymphatic absorption of zeaxanthin in rats. RESULTS: Zeaxanthin exhibited poor solubility (≤144 ng/mL) and stability (6.0-76.9% of the initial amount remained at 24 h) in simulated gut luminal fluids. Gut absorption of zeaxanthin occurred primarily in the duodenum, but the major fraction (≥84.7%) of the dose remained unabsorbed across the entire gut tract. Considerable fractions of intravenous zeaxanthin accumulated in the liver, lung, and spleen (21.3, 11.7, and 2.0%, respectively). It was found that the liver is the major eliminating organ of zeaxanthin, accounting for 53.5-90.1% of the total clearance process (hepatic extraction ratio of 0.623). DISCUSSION AND CONCLUSIONS: To our knowledge, this is the first systematic study to report factors that determine the oral bioavailability and systemic clearance of zeaxanthin.

Synthetic lethality of cytolytic HSV-1 in cancer cells with ATRX and PML deficiency.

Cancers that utilize the alternative lengthening of telomeres (ALT) mechanism for telomere maintenance are often difficult to treat and have a poor prognosis. They are also commonly deficient for expression of ATRX protein, a repressor of ALT activity, and a component of promyelocytic leukemia nuclear bodies (PML NBs) that are required for intrinsic immunity to various viruses. Here, we asked whether ATRX deficiency creates a vulnerability in ALT cancer cells that could be exploited for therapeutic purposes. We showed in a range of cell types that a mutant herpes simplex virus type 1 (HSV-1) lacking ICP0, a protein that degrades PML NB components including ATRX, was ten- to one thousand-fold more effective in infecting ATRX-deficient cells than wild-type ATRX-expressing cells. Infection of co-cultured primary and ATRX-deficient cancer cells revealed that mutant HSV-1 selectively killed ATRX-deficient cells. Sensitivity to mutant HSV-1 infection also correlated inversely with PML protein levels, and we showed that ATRX upregulates PML expression at both the transcriptional and post-transcriptional levels. These data provide a basis for predicting, based on ATRX or PML levels, which tumors will respond to a selective oncolytic herpesvirus.

The GNAQ T96S Mutation Affects Cell Signaling and Enhances the Oncogenic Properties of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC), the most common malignant tumor in the liver, grows and metastasizes rapidly. Despite advances in treatment modalities, the five-year survival rate of HCC remains less than 30%. We sought genetic mutations that may affect the oncogenic properties of HCC, using The Cancer Genome Atlas (TCGA) data analysis. We found that the GNAQ T96S mutation (threonine 96 to serine alteration of the Gαq protein) was present in 12 out of 373 HCC patients (3.2%). To examine the effect of the GNAQ T96S mutation on HCC, we transfected the SK-Hep-1 cell line with the wild-type or the mutant GNAQ T96S expression vector. Transfection with the wild-type GNAQ expression vector enhanced anchorage-independent growth, migration, and the MAPK pathways in the SK-Hep-1 cells compared to control vector transfection. Moreover, cell proliferation, anchorage-independent growth, migration, and the MAPK pathways were further enhanced in the SK-Hep-1 cells transfected with the GNAQ T96S expression vector compared to the wild-type GNAQ-transfected cells. In silico structural analysis shows that the substitution of the GNAQ amino acid threonine 96 with a serine may destabilize the interaction between the regulator of G protein signaling (RGS) protein and GNAQ. This may reduce the inhibitory effect of RGS on GNAQ signaling, enhancing the GNAQ signaling pathway. Single nucleotide polymorphism (SNP) genotyping analysis for Korean HCC patients shows that the GNAQ T96S mutation was found in only one of the 456 patients (0.22%). Our data suggest that the GNAQ T96S hotspot mutation may play an oncogenic role in HCC by potentiating the GNAQ signal transduction pathway.

How Solutes Modify the Thermodynamics and Dynamics of Filling and Emptying in Extreme Ink-Bottle Pores.

We investigate the filling and emptying of extreme ink-bottle porous media-micrometer-scale pores connected by nanometer-scale pores-when changing the pressure of the external vapor, in a case where the pore liquid contains solutes. These phenomena are relevant in diverse contexts, such as the weathering of building materials and artwork, aerosol formation in the atmosphere, and the hydration of soils and plants. Using model systems made of vein-shaped microcavities interconnected by a mesoporous matrix, we show experimentally that the presence of a nonvolatile solute shifts the condensation and evaporation transitions and in a way that is consistent with a modified Kelvin-Laplace equation that takes into account the osmotic pressure of the solution. Emptying occurs far below saturation, when the Kelvin stress, mediated by the large curvature of the liquid-vapor interfaces in the nanopores, is negative enough to induce spontaneous bubble nucleation in the microveins. Filling, on the other hand, occurs close to equilibrium (i.e., at saturation, psat for pure water and ps < psat for a solution), driven by the weak capillary pressure of the liquid-vapor interface in the microveins. Interestingly, solutes allow the system to reach situations where the vapor is supersaturated with respect to the solution ( ps < p < psat). We show that in that latter situation, a condensation layer covers the outer surface of the porous system, preventing the generation of Kelvin stresses but inducing osmotic stresses and flows that are vapor pressure-dependent. The timescales and dynamics reflect these different driving forces: emptying proceeds through discrete, stochastic nucleation events with very fast, unsteady bubble growth associated with a poroelastic relaxation process, while filling occurs collectively in all veins of the sample through a slower steady-state process driven by a combination of osmosis and capillarity. The dynamics can however be rendered symmetrical between filling and emptying if bubbles pre-exist during emptying, a case that we explore using cycling of the vapor pressure around equilibrium.

Thymus and activation-regulated chemokine (TARC)/CCL17 and IgE are associated with elderly asthmatics.

BACKGROUND: The pathogenesis of asthma, which is an allergic lung disease, is associated with a variety of allergens such as house dust mite, pollen, and mould, IgE containing serum IgE and allergen-specific-IgE, and inflammatory cytokines including thymus and activation-regulated chemokine (TARC)/CCL17. Because aging is an essential factor in the pathogenesis of asthma, we examined biomarkers related to asthmatic subjects depending on age. RESULTS: Physiological indices such as FEV1(forced expiratory capacity in 1 s), FEV1 (% predicted), and FEV1/FVC(forced vital capacity) (%) in asthmatic subjects were lower than those in normal subjects. Total IgE, Der p1 specific IgE, and Der f1 specific IgE were elevated in serum of asthmatics relative to normal individuals. Regulated on activation, normal T cell expressed and secreted (RANTES)/CCL5 in serum and interleukin 6 (IL-6), interleukin 8 (IL-8), monocyte chemoattractant protein (MCP)-1/CCL2, RANTES, and macrophage inflammatory protein (MIP)-1α/CCL3 in bronchoalveolar lavage fluid (BALF) of asthmatic subjects were higher than in normal individuals. Upon classification of experimental groups depending on age, physiological indices and Der p1-specific IgE (class) were decreased in middle aged adult and elderly adult groups relative to the young adult group. TARC levels in serum were strongly elevated in the elderly adult group relative to the young adult and the middle aged adult groups. TARC in serum was related to total IgE in serum in the elderly adult group. CONCLUSIONS: Taken together, although TARC in serum and BALF is not different between normal and asthmatic individuals, TARC increases in serum of elderly asthmatic subjects. The level of TARC has a positive effect on the level of IgE in the elderly adult group. These findings may help us better understand the relationship of pathogenesis of allergic diseases and aging.

Treatment sequencing strategy for hepatic epithelioid haemangioendothelioma.

BACKGROUND: The biology of hepatic epithelial haemangioendothelioma (HEHE) is variable, lying intermediate to haemangioma and angiosarcoma. Treatments vary owing to the rarity of the disease and frequent misdiagnosis. METHODS: Between 1989 and 2013, patients retrospectively identified with HEHE from a single academic cancer centre were analysed to evaluate clinicopathological factors and initial treatment regimens associated with survival. RESULTS: Fifty patients with confirmed HEHE had a median follow-up of 51 months (range 1-322). There was no difference in 5-year survival between patients presenting with unilateral compared with bilateral hepatic disease (51.4% versus 80.7%, respectively; P = 0.1), localized compared with metastatic disease (69% versus 78.3%, respectively; P = 0.7) or an initial treatment regimen of Surgery, Chemotherapy/Embolization or Observation alone (83.3% versus 71.3% versus 72.4%, respectively; P = 0.9). However, 5-year survival for patients treated with chemotherapy at any point during their disease course was decreased compared with those who did not receive any chemotherapy (43.6% versus 82.9%, respectively; P = 0.02) and was predictive of a decreased overall survival on univariate analysis [HR 3.1 (CI 0.9-10.7), P = 0.02]. CONCLUSIONS: HEHE frequently follows an indolent course, suggesting that immediate treatment may not be the optimal strategy. Initial observation to assess disease behaviour may better stratify treatment options, reserving surgery for those who remain resectable/transplantable. Prospective cooperative trials or registries may confirm this strategy.

Doppler US for suspicion of hepatic arterial ischemia in orthotopically transplanted livers: role of central versus intrahepatic waveform analysis.

PURPOSE: To compare the diagnostic performance of combinations of parameters derived from main hepatic artery (MHA) and intrahepatic artery (IHA) waveforms at Doppler ultrasonography (US), with the aim of developing a systematic approach to the evaluation of the hepatic arteries in orthotopic liver transplants in patients suspected of having hepatic arterial ischemia. MATERIALS AND METHODS: This HIPAA-compliant retrospective study was approved by an institutional review board, with waiver of informed consent. From January 1, 2002, to November 1, 2011, 195 transplanted livers in 189 adults (129 men, 60 women; mean age, 53 years; age range, 18-73 years) who underwent Doppler US and follow-up (computed tomographic, magnetic resonance, or conventional) angiographic study within a 2-week interval were included. Diagnostic performance of the standard IHA and MHA criteria (resistive index [RI] < 0.5 and classic parvus tardus waveforms) with and without peak systolic velocity (PSV) thresholds (determined with receiver operating characteristic curve analysis) was assessed. The results of no-flow analysis and the most optimal MHA and IHA criteria were combined to create an algorithm, which was then applied to all liver transplants. RESULTS: The standard criteria (RI < 0.5 and classic parvus tardus) demonstrated greater sensitivity (80% vs 55%, P = .008) when applied to IHA waveforms compared with MHA waveforms. Optimal PSV cutoff values were less than 67 cm/sec and 39 cm/sec for MHA and IHA, respectively. The addition of a PSV threshold resulted in significant decrease in overall accuracy when applied to IHA (87% vs 73%, P < .001) and MHA (82% vs 66%, P = .002) criteria. Application of an algorithm reflecting a combination of the most optimal MHA and IHA criteria and the results of no-flow analysis resulted in 96% sensitivity and 83% specificity. CONCLUSION: An algorithmic approach involving a tailored evaluation of the geographic distribution of absent flow and the quantitative parameters and waveform morphology of the MHA and IHAs allows for improved diagnostic performance in the detection of hepatic arterial complications in at-risk patients with orthotopic liver transplants. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120557/-/DC1.

Pulmonary actinomycosis during the first decade of 21st century: cases of 94 patients.

BACKGROUND: Pulmonary actinomycosis is a chronic pulmonary infection caused by Actinomyces. Both improving oral hygiene and early application of antibiotics to the case of suspicious pulmonary infections result in changes in incidences and presentations of pulmonary actinomycosis. However, there are little reports dealt with the recent clinical characteristics of pulmonary actinomycosis. This study aimed to review the characteristics of pulmonary actinomycosis occurred during the first decade of 21st century. METHODS: This retrospective study was performed on 94 subjects with pulmonary actinomycosis diagnosed pathologically from January 2000 to December 2010 in 13 hospitals in Korea. RESULTS: The data of the study showed that pulmonary actinomycosis occurs frequently in middle to old-aged males (mean age; 57.7 years old) and that the most common symptoms are cough, hemoptysis, and sputum production. Various radiologic features such as the consolidation with central low attenuation (74.5%) and no regional predominance were also observed. Most of patients recovered completely with medical and/or surgical treatment, reaching approximately 98% cure rate. CONCLUSIONS: The results demonstrate that pulmonary actinomycosis is one of the cautious pulmonary diseases. More importantly, in cases of persistent hemoptysis or for differential diagnosis from lung malignancy, our data have revealed that surgical resection appears to be a useful intervention and that radiologic diagnosis may not provide decisive information. These findings indicate that it is important for the clinicians to include pulmonary actinomycosis as one of differential diagnoses for refractory pulmonary abnormal lesions to the current usual management.

Different anti-apoptotic effects of normal and asthmatic serum on normal eosinophil apoptosis depending on house dust mite-specific IgE.

We investigated the effect of asthmatic serum on constitutive eosinophil apoptosis in normal subjects. Eosinophil apoptosis in normal subjects was inhibited by asthmatic serum but not normal serum. In a detailed analysis based on the presence of house dust mite (HDM) IgE, HDM IgE-positive (+) asthmatic serum was more effective for eosinophil apoptosis than that of HDM IgE-negative (-) asthmatic serum. HDM IgE+ asthmatic serum inhibited both HDM IgE- and HDM IgE+ normal eosinophil apoptosis, and HDM IgE- asthmatic serum suppressed eosinophil apoptosis of HDM IgE+ normal. HDM IgE- normal serum did not inhibit either HDM IgE- or HDM IgE+ normal eosinophil apoptosis, and HDM IgE+ normal serum inhibited HDM IgE+ normal eosinophil apoptosis. The kind of HDM IgE (Dermatophagoides pteronissinus-specific IgE and Dermatophagoides farinae-specific IgE) was not related to the effect of asthmatic serum on eosinophil apoptosis. Extracts of DP and DF, Der p1, and Der p2, were not effective for eosinophil apoptosis. HDM IgE+ asthmatic serum inhibited cleavage of procaspase 9 and procaspase 3. Asthmatic serum induced Akt and ERK phosphorylation, and ERK activation was suppressed by AKTi. Taken together, asthmatic serum inhibited normal eosinophil apoptosis via PI3K/Akt/ERK cascade. The novel approach taken in this study provided better insight into HDM-associated anti-apoptotic mechanism of eosinophils in patients with asthma.

Solitary Peutz-Jeghers type harmartomatous polyp in duodenum with gastric foveolar epithelium: a case report.

Peutz-Jeghers type hamartomatous polyp is known to be associated with Peutz-Jeghers syndrome, which shows characteristic multiple hamartomatous polyp involvement in the gastrointestinal tract, combined with mucocutaneous symptom, familial history of Peutz- Jeghers syndrome or STK11/LTB1 mutation. However, some cases showing histologic appearance of the polyps discovered in Peutz- Jeghers syndrome while lacking other diagnostic criteria of the syndrome have been reported, and these are called solitary Peutz- Jeghers type polyps. Herein, we report a case of solitary Peutz-Jeghers type polyp covered with heterotopic epithelium. The patient was 47-year-old female without any mucocutaneous symptoms nor familial history of Peutz-Jeghers syndrome. Microscopic examination revealed Peutz-Jeghers type hamartomatous polyp in duodenum covered with gastric type foveolar epithelium. Considering the definition of hamartomatous polyp, which is, the abnormal overgrowth of the indigenous epithelial component, the histological feature of current case is noteworthy in a point that it shows proliferation of heterotopic component, rather than the indigenous component.

Pleurectomy and decortication are associated with better survival for bicavitary cytoreductive surgery for mesothelioma compared with extrapleural pneumonectomy.

OBJECTIVES: Mesothelioma is a nearly uniformly fatal tumor. Multimodality therapy including cytoreductive surgery and chemotherapy is associated with long-term survival in some patients. Cytoreductive surgery for thoracic disease includes a lung-sparing operation called an "extended pleurectomy/decortication" or a lung-sacrificing surgery called an "extrapleural pneumonectomy." The benefit of cytoreductive surgery for bicavitary disease (chest and abdomen) is poorly understood. Our objective was to evaluate the long-term survivals for patients undergoing cytoreductive surgery for bicavitary disease and to determine whether any prognostic factors were associated with outcome. METHODS: We reviewed our Institutional Review Board-approved, institutional, International Association for the Study of Lung Cancer Mesothelioma Staging Project database. Inclusion criteria were all patients who underwent cytoreductive surgery for bicavitary disease. Overall survival was calculated by Kaplan-Meier methodology. All International Association for the Study of Lung Cancer database elements were evaluated by univariable analysis. RESULTS: From February 2014 to August 2021, 440 patients with mesothelioma were evaluated. Fourteen patients (3%) underwent cytoreductive surgery of both chest and abdomen as a planned 2-stage operation. Most patients (13/14; 93%) underwent chest surgery before abdomen surgery. For the entire cohort, the median overall survival was 33.6 months with a 5-year survival of 20%. Extended pleurectomy/decortication was associated with a better outcome compared with extrapleural pneumonectomy, with median overall survivals of 58.2 versus 13.5 months, respectively. CONCLUSIONS: For a highly selected group of patients with bicavitary mesothelioma, long-term survival can be achieved with an aggressive, staged surgical approach. The patients who undergo extended pleurectomy/decortication with preservation of the lung appear to have more favorable outcomes compared with patients undergoing extrapleural pneumonectomy.

Clinicopathologic features and prognostic value of claudin 18.2 overexpression in patients with resectable gastric cancer.

Claudin 18.2 has emerged as a promising therapeutic target in gastric cancer based on phase 3 studies. However, clinicopathologic features associated with claudin 18.2 overexpression have not been comprehensively studied specifically for patients with resectable gastric cancer. This retrospective study included 299 patients with stage I-III resectable gastric cancer who underwent curative surgical resection. Possible associations between claudin 18.2 overexpression (moderate-to-strong expression in ≥ 75% by the 43-14A clone) and clinicopathologic features and survival outcomes were analyzed. There were 90 (30.1%), 96 (32.1%), and 113 (37.8%) patients with stage I, II, and III disease, respectively. Claudin 18.2 overexpression was noted in 139 out of 299 patients (46.5%). Claudin 18.2 overexpression was associated with a younger age, a lower invasion depth limited to the mucosa/submucosa, and less frequent lymphovascular invasion. Claudin 18.2 overexpression was also associated with Borrmann type 4 among patients with advanced gastric cancer and the diffuse histological type. Claudin 18.2 overexpression was not an independent factor for survival outcomes. In conclusion, claudin 18.2 was overexpressed in almost half of resectable gastric cancer patients. Claudin 18.2 overexpression was associated with some clinicopathological characteristics, but was not an independent prognostic factor in a localized setting.

Review of Hematology-Oncology Emergencies for Internal Medicine Residents.

The prevalence of cancer continues to grow globally every year. With therapeutic advances over the recent decades, the prevalence of individuals living with cancer continues to increase. Internal medicine residents can see patients admitted to the hospital for cancer-related emergencies. Early identification and appropriate management of these emergencies have been shown to improve mortality and morbidity. In this article, we aim to review the recent updates in the management of commonly encountered oncologic emergencies in the practice of internal medicine residents. This review will cover spinal cord compression, superior vena cava syndrome, tumor lysis syndrome, hypercalcemia, pericardial tamponade, hypoglycemia, hyponatremia, bowel obstruction, increased intracranial pressure, leukostasis, hyperviscosity syndrome, neutropenic fever, and hypersensitivity reactions.

Physicochemical characterization and phase II metabolic profiling of echinochrome A, a bioactive constituent from sea urchin, and its physiologically based pharmacokinetic modeling in rats and humans.

Echinochrome A, a natural naphthoquinone pigment found in sea urchins, is increasingly being investigated for its nutritional and therapeutic value associated with antioxidant, anticancer, antiviral, antidiabetic, and cardioprotective activities. Although several studies have demonstrated the biological effects and therapeutic potential of echinochrome A, little is known regarding its biopharmaceutical behaviors. Here, we aimed to investigate the physicochemical properties and metabolic profiles of echinochrome A and establish a physiologically-based pharmacokinetic (PBPK) model as a useful tool to support its clinical applications. We found that the lipophilicity, color variability, ultraviolet/visible spectrometry, and stability of echinochrome A were markedly affected by pH conditions. Moreover, metabolic and pharmacokinetic profiling studies demonstrated that echinochrome A is eliminated primarily by hepatic metabolism and that four possible metabolites, i.e., two glucuronidated and two methylated conjugates, are formed in rat and human liver preparations. A whole-body PBPK model incorporating the newly identified hepatic phase II metabolic process was constructed and optimized with respect to chemical-specific parameters. Furthermore, model simulations suggested that echinochrome A could exhibit linear disposition profiles without systemic and local tissue accumulation in clinical settings. Our proposed PBPK model of echinochrome A could be a valuable tool for predicting drug interactions in previously unexplored scenarios and for optimizing dosage regimens and drug formulations.

Differential effect of CCL2 on constitutive neutrophil apoptosis between normal and asthmatic subjects.

In this study, we investigated the effects of CCL2 on constitutive apoptosis of normal and asthmatic neutrophils. CCL2 blocked the constitutive apoptosis of normal neutrophils through CCR2. CCL2 also induced elevation of the cytosolic Ca(2+) concentration but had no effect on normal neutrophil chemotaxis. Constitutive apoptosis, calcium influx, and cell migration of asthmatic neutrophils were not affected by CCL2 stimulation. Supernatant collected from CCL2-treated normal neutrophils inhibited the constitutive apoptosis of normal neutrophils. Anti-apoptotic signaling mediated by CCL2 was found to be associated with the PI3K/Akt/ERK/NF-κB cascade in normal neutrophils. Both the cleavage of procaspase 3 and procaspase 9 and the decrease of in Mcl-1 expression were delayed by CCL2 stimulation. Inhibition of NF-κB blocked constitutive apoptosis of neutrophils from asthmatic patients via inhibition of the cleavage of procaspase 3 and procaspase 9, in contrast to normal neutrophils. NF-κB was involved in CCL2-induced anti-apoptotic signaling in normal neutrophils, whereas NF-κB functioned as a basal pro-apoptotic factor in asthmatic neutrophils. A better understanding of the difference in the regulation of neutrophil apoptosis due to CCL2 between normal individuals and asthmatics will enable elucidation of the role of CC chemokine in neutrophils and a framework for understanding the pathogenesis of asthma.

Synchronous development of prostate sarcoma and squamous cell carcinoma following radiotherapy.

With the development of more sensitive screening tools, malignancies are being diagnosed at an earlier stage, resulting in earlier intervention and longer survival times. As a consequence, the long-term complications of cancer therapy are increasing in incidence, particularly second primary cancers from radiation therapy. Bladder and colorectal cancers are the most commonly reported malignancies secondary to radiation therapy for prostate cancer. We present the case of a 78-year-old patient with a remote history of prostate adenocarcinoma, status post brachytherapy, who subsequently developed both prostate sarcoma and prostate squamous cell carcinoma secondary to the prior treatment. Because his cancer was metastatic, he was not a candidate for surgery and was treated with chemotherapy and palliative radiation.

Observation of curcumin-loaded hydroxypropyl methylcellulose (HPMC) oleogels under in vitro lipid digestion and in situ intestinal absorption in rats.

Curcumin-loaded nanostructured lipid carriers (Cur-NLCs)-based hydroxypropyl methylcellulose (HPMC) oleogels (Cur-NLCs-HPMC-OGs) were fabricated using a cryogel template. The effect of the HPMC viscosity grade on the oleogel characteristics and in situ intestinal absorption were examined. Highly stable Cur-NLCs were prepared with a mean particle size of 314 nm and polydispersity index of 0.275. Cur-NLCs affected the creamy texture of self-standing Cur-NLCs-HPMC-OGs. The Cur-NLCs were tightly packed as oil droplets in the network of HPMC. However, a high viscosity of HPMC-4000 led to a greater ability to entrap and prevent droplet coalescence compared to a low viscosity of HPMC-400. NLCs promoted the release of free fatty acids during in vitro lipid digestion, whereas HPMC-4000 maintained the strength and durability of oleogels against mechanical and enzymatic breakdown. The in situ loop results revealed higher curcumin absorption by Cur-NLCs-HPMC-OGs than by Cur-HPMC-OGs. HMPC-4000 showed slightly higher curcumin absorption compared to HPMC-400.

Impact of route-dependent phase-II gut metabolism and enterohepatic circulation on the bioavailability and systemic disposition of resveratrol in rats and humans: A comprehensive whole body physiologically-based pharmacokinetic modeling.

Resveratrol, a natural polyphenolic phytoalexin, is a dietary supplement that improves the outcomes of metabolic, cardiovascular, and other age-related diseases due to its diverse pharmacological activities. Although there have been several preclinical and clinical investigations of resveratrol, the contributions of gut phase-II metabolism and enterohepatic circulation to the oral bioavailability and pharmacokinetics of resveratrol remain unclear. Furthermore, a physiologically-based pharmacokinetic (PBPK) model that accurately describes and predicts the systemic exposure profiles of resveratrol in clinical settings has not been developed. Experimental data were acquired from several perspectives, including in vitro protein binding and blood distribution, in vitro tissue S9 metabolism, in situ intestinal perfusion, and in vivo pharmacokinetics and excretion studies. Using these datasets, an in-house whole-body PBPK model incorporating route-dependent phase-II (glucuronidation and sulfation) gut metabolism and enterohepatic circulation processes was constructed and optimized for chemical-specific parameters. The developed PBPK model aligned with the observed systemic exposure profiles of resveratrol in single and multiple dosing regimens with an acceptable accuracy of 0.538-0.999-fold errors. Furthermore, the model simulations elucidated the substantial contribution of gut first-pass metabolism to the oral bioavailability of resveratrol and suggested differential effects of enterohepatic circulation on the systemic exposure of resveratrol between rats and humans. After partial modification and verification, our proposed PBPK model would be valuable to optimize dosage regimens and predict food-drug interactions with resveratrol-based natural products in various clinical scenarios.