An Insight on Microfluidic Organ-on-a-Chip Models for PM2.5-Induced Pulmonary Complications.

Pulmonary diseases like asthma, chronic obstructive pulmonary disorder, lung fibrosis, and lung cancer pose a significant burden to global human health. Many of these complications arise as a result of exposure to particulate matter (PM), which has been examined in several preclinical and clinical trials for its effect on several respiratory diseases. Particulate matter of size less than 2.5 µm (PM2.5) has been known to inflict unforeseen repercussions, although data from epidemiological studies to back this are pending. Conventionally utilized two-dimensional (2D) cell culture and preclinical animal models have provided insufficient benefits in emulating the in vivo physiological and pathological pulmonary conditions. Three-dimensional (3D) structural models, including organ-on-a-chip models, have experienced a developmental upsurge in recent times. Lung-on-a-chip models have the potential to simulate the specific features of the lungs. With the advancement of technology, an emerging and advanced technique termed microfluidic organ-on-a-chip has been developed with the aim of identifying the complexity of the respiratory cellular microenvironment of the body. In the present Review, the role of lung-on-a-chip modeling in reproducing pulmonary complications has been explored, with a specific emphasis on PM2.5-induced pulmonary complications.

Disable 2, A Versatile Tissue Matrix Multifunctional Scaffold Protein with Multifaceted Signaling: Unveiling Role in Breast Cancer for Therapeutic Revolution.

The Disabled-2 (DAB2) protein, found in 80-90% of various tumors, including breast cancer, has been identified as a potential tumor suppressor protein. On the contrary, some hypothesis suggests that DAB2 is associated with the modulation of the Ras/MAPK pathway by endocytosing the Grb/Sos1 signaling complex, which produces oncogenes and chemoresistance to anticancer drugs, leading to increased tumor growth and metastasis. DAB2 has multiple functions in several disorders and is typically under-regulated in several cancers, making it a potential target for treatment of cancer therapy. The primary function of DAB2 is the modulation of transforming growth factor- ß (TGF-ß) mediated endocytosis, which is involved in several mechanisms of cancer development, including tumor suppression through promoting apoptosis and suppressing cell proliferation. In this review, we will discuss in detail the mechanisms through which DAB2 leads to breast cancer and various advancements in employing DAB2 in the treatment of breast cancer. Additionally, we outlined its role in other diseases. We propose that upregulating DAB2 could be a novel approach to the therapeutics of breast cancer.

Disabled-2, a versatile tissue matrix multifunctional scaffold protein with multifaceted signaling: Unveiling its potential in the cancer battle.

A multifunctional scaffold protein termed Disabled-2 (Dab2) has recently gained attention in the scientific community and has emerged as a promising candidate in the realm of cancer research. Dab2 protein is involved in a variety of signaling pathways, due to which its significance in the pathogenesis of several carcinomas has drawn considerable attention. Dab2 is essential for controlling the advancement of cancer because it engages in essential signaling pathways such as the Wnt/ß-catenin, epidermal growth factor receptor (EGFR), and transforming growth factor-beta (TGF-ß) pathways. Dab2 can also repress epithelial-mesenchymal transition (EMT) which is involved in tumor progression with metastatic expansion and adds another layer of significance to its possible impact on cancer spread. Furthermore, the role of Dab2 in processes such as cell growth, differentiation, apoptosis, invasion, and metastasis has been explored in certain investigative studies suggesting its significance. The present review examines the role of Dab2 in the pathogenesis of various cancer subtypes including breast cancer, ovarian cancer, gastric cancer, prostate cancer, and bladder urothelial carcinoma and also sheds some light on its potential to act as a therapeutic target and a prognostic marker in the treatment of various carcinomas. By deciphering this protein's diverse signaling, we hope to provide useful insights that may pave the way for novel therapeutic techniques and tailored treatment approaches in cancer management. Preclinical and clinical trial data on the impact of Dab2 regulation in cancer have also been included, allowing us to delineate role of Dab2 in tumor suppressor function, as well as its correlation with disease stage classification and potential therapy options. However, we observed that there is very scarce data in the form of studies on the evaluation of Dab2 role and treatment function in carcinomas, and further research into this matter could prove beneficial in the generation of novel therapeutic agents for patient-centric and tailored therapy, as well as early prognosis of carcinomas.

d-α-tocopheryl polyethylene glycol 1000 succinate surface scaffold polysarcosine based polymeric nanoparticles of enzalutamide for the treatment of colorectal cancer: In vitro, in vivo characterizations.

In this study, Enzalutamide (ENZ) loaded Poly Lactic-co-Glycolic Acid (PLGA) nanoparticles coated with polysarcosine and d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) were prepared using a three-step modified nanoprecipitation method combined with self-assembly. A three-factor, three-level Box-Behnken design was implemented with Design-Expert® software to evaluate the impact of three independent variables on particle size, zeta potential, and percent entrapment efficiency through a numeric optimization approach. The results were corroborated with ANOVA analysis, regression equations, and response surface plots. Field emission scanning electron microscopy and transmission electron microscope images revealed nanosized, spherical polymeric nanoparticles (NPs) with a size distribution ranging from 178.9 ± 2.3 to 212.8 ± 0.7 nm, a zeta potential of 12.6 ± 0.8 mV, and entrapment efficiency of 71.2 ± 0.7 %. The latter increased with higher polymer concentration. Increased polymer concentration and homogenization speed also enhanced drug entrapment efficiency. In vitro drug release was 85 ± 22.5 %, following the Higuchi model (R2 = 0.98) and Fickian diffusion (n < 0.5). In vitro cytotoxicity assessments, including Mitochondrial Membrane Potential Estimation, Apoptosis analysis, cell cycle analysis, Reactive oxygen species estimation, Wound healing assay, DNA fragmentation assay, and IC50 evaluation with Sulforhodamine B assay, indicated low toxicity and high efficacy of polymeric nanoparticles compared to the drug alone. In vivo studies demonstrated biocompatibility and target specificity. The findings suggest that TPGS surface-scaffolded polysarcosine-based polymer nanoparticles of ENZ could be a promising and safe delivery system with sustained release for colorectal cancer treatment, yielding improved therapeutic outcomes.

Fabrication of D-α-tocopheryl polyethylene glycol 1000 succinates and human serum albumin conjugated chitosan nanoparticles of bosutinib for colon targeting application; in vitro-in vivo investigation.

For more effective chemotherapy and targeted treatment of colorectal cancer, this study seeks to develop chitosan (CH)-human serum albumin (HAS)-D-α-tocopheryl polyethylene glycol 1000 (TPGS) nanoparticles (BOS-CH-HSA-TPGS-NPs) coated with Bosutinib (BOS). Nuclear magnetic resonance (NMR) indicated that chitosan's structure was modified by carbodiimide coupling with HSA. We used a Box-Behnken design to find the ideal region for particle size, zeta potential, and entrapment efficiency, eventually emerging at a formulation with these values: 187.14 ± 3.2 nm, 76.2 ± 0.96 %, and 21.1 ± 2.3 mV. Differential scanning calorimetry (DSC), Transmission electron microscopy (TEM), X-ray diffraction (XRD), Atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FTIR), High-performance liquid chromatography (HPLC) were all used to characterize the sample in detail. At a phosphate buffer pH of 7.4, in vitro drug release tests showed both Higuchi model release (0.954) and Fickian diffusion (n = 0.5). Compared to free BOS, HCT116 cell lines showed considerably higher cytotoxicity in in vitro cytotoxicity assays. In male albino Wistar rats, the BOS-CH-HSA-TPGS-NPs also showed enhanced pharmacokinetics, targeting efficiency, and biocompatibility. When used to the treatment of colorectal cancer, the BOS-CH-HSA-TPGS NPs show promise as a sustained-release therapy with improved therapeutic effects by addressing the challenges of poor solubility, poor permeability, and toxic side effects.

CD44 targeted delivery of hyaluronic acid-coated polymeric nanoparticles against colorectal cancer.

Aim: To develop hyaluronic acid (HA)-coated poly-lactic-co-glycolic acid (PLGA)-polysarcosine (PSAR) coupled sorafenib tosylate (SF) polymeric nanoparticles for targeted colon cancer therapy. Materials & methods: PLGA-PSAR shells were encapsulated with SF via nanoprecipitation. Interactions were examined with transmission electron microscopy, revealing formulation component interactions. Results: The optimized HA-coated polymeric nanoparticles (238.8 nm, -6.1 mV, 68.361% entrapment) displayed enhanced controlled release of SF. These formulations showed superior cytotoxicity against HCT116 cell lines compared with free drug (p < 0.05). In vivo tests on male albino Wistar rats demonstrated improved pharmacokinetics, targeting and biocompatibility. HA-coated PLGA-PSAR-coupled SF polymeric nanoparticles hold potential for effective colorectal therapy. Conclusion: Colon cancer may be precisely targeted by HA-coated PLGA-PSA-coupled SF polymeric nanoparticles.

Combating relapsed and refractory Mantle cell lymphoma with novel therapeutic armamentarium: Recent advances and clinical prospects.

Mantle cell lymphoma (MCL) is a rare, aggressive subtype of non-Hodgkin's lymphoma (NHL), accounting for 5% of all cases. Due to its virulence factor, it is an incurable disease and keeps relapsing despite an intensive treatment regimen. Advancements in research and drug discovery have shifted the treatment strategy from conventional chemotherapy to targeted agents and immunotherapies. The establishment of the role of Bruton tyrosine kinase led to the development of ibrutinib, a first-generation BTK inhibitor, and its successors. A conditioning regimen based immunotherapeutic agent like ibritumumob, has also demonstrated a viable response with a favorable toxicity profile. Brexucabtagene Autoleucel, the only approved CAR T-cell therapy, has proven advantageous for relapsed/refractory MCL in both children and adults. This article reviews certain therapies that could help update the current approach and summarizes a few miscellaneous agents, which, seldom studied in trials, could alleviate the regression observed in traditional therapies. DATA AVAILABILITY: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Harnessing three-dimensional (3D) cell culture models for pulmonary infections: State of the art and future directions.

Pulmonary infections have been a leading etiology of morbidity and mortality worldwide. Upper and lower respiratory tract infections have multifactorial causes, which include bacterial, viral, and rarely, fungal infections. Moreover, the recent emergence of SARS-CoV-2 has created havoc and imposes a huge healthcare burden. Drug and vaccine development against these pulmonary pathogens like respiratory syncytial virus, SARS-CoV-2, Mycobacteria, etc., requires a systematic set of tools for research and investigation. Currently, in vitro 2D cell culture models are widely used to emulate the in vivo physiologic environment. Although this approach holds a reasonable promise over pre-clinical animal models, it lacks the much-needed correlation to the in vivo tissue architecture, cellular organization, cell-to-cell interactions, downstream processes, and the biomechanical milieu. In view of these inadequacies, 3D cell culture models have recently acquired interest. Mammalian embryonic and induced pluripotent stem cells may display their remarkable self-organizing abilities in 3D culture, and the resulting organoids replicate important structural and functional characteristics of organs such the kidney, lung, gut, brain, and retina. 3D models range from scaffold-free systems to scaffold-based and hybrid models as well. Upsurge in organs-on-chip models for pulmonary conditions has anticipated encouraging results. Complexity and dexterity of developing 3D culture models and the lack of standardized working procedures are a few of the setbacks, which are expected to be overcome in the coming times. Herein, we have elaborated the significance and types of 3D cell culture models for scrutinizing pulmonary infections, along with the in vitro techniques, their applications, and additional systems under investigation.

Psychosocial and Cultural Processes Underlying the Epidemiological Paradox within U.S. Latino Sexual Risk: A Systematic Review.

According to the epidemiological paradox, less acculturated Latina/o youth display fewer sexual risk behaviors. A systematic review was performed on psychosocial and cultural mechanisms potentially underlying the epidemiological paradox in sexual risk behaviors of U.S. Latina/o youth across acculturation measures (between January 2000 to October 2022). Thirty-five publications (n = 35) with forty-eight analyses of underlying mechanisms met the inclusion criteria. Thirty-one results from twenty-three publications found supporting evidence that one of the five factors was an underlying mechanism in the epidemiological paradox (n = 13 parenting practices, n = 4 peer influences, n = 4 familismo values, n = 4 religiosity, n = 6 traditional gender norms) as, generally protective, mediators or moderators in the link between acculturation and sexual risk behaviors. Studies varied in the sexual risk behavior examined and measurement of acculturation, but primarily employed cross-sectional designs and recruited samples through schools. Mechanisms that enhance close ties and unity of the family, such as those of familismo values and positive parenting, reduce the likelihood of sexual risk behaviors as Latina/o youth become more acculturated. Future directions are discussed which may provide guidance for risk prevention and intervention.

Revamping the innate or innate-like immune cell-based therapy for hepatocellular carcinoma: new mechanistic insights and advanced opportunities.

A cancerous tumour termed hepatocellular carcinoma (HCC) is characterized by inflammation and subsequently followed by end-stage liver disease and necrosis of the liver. The liver's continuous exposure to microorganisms and toxic molecules affects the immune response because normal tissue requires some immune tolerance to be safeguarded from damage. Several innate immune cells are involved in this process of immune system activation which includes dendritic cells, macrophages, and natural killer cells. The liver is an immunologic organ with vast quantities of innate and innate-like immune cells subjected to several antigens (bacteria, fungal or viral) through the gut-liver axis. Tumour-induced immune system engagement may be encouraged or suppressed through innate immunological systems, which are recognized promoters of liver disease development in pre-HCC conditions such as fibrosis or cirrhosis, ultimately resulting in HCC. Immune-based treatments containing several classes of drugs have transformed the treatment of several types of cancers in recent times. The effectiveness of such immunotherapies relies on intricate interactions between lymphocytes, tumour cells, and neighbouring cells. Even though immunotherapy therapy has already reported to possess potential effect to treat HCC, a clear understanding of the crosstalk between innate and adaptive immune cell pathways still need to be clearly understood for better exploitation of the same. The identification of predictive biomarkers, understanding the progression of the disease, and the invention of more efficient combinational treatments are the major challenges in HCC immunotherapy. The functions and therapeutic significance of innate immune cells, which have been widely implicated in HCC, in addition to the interplay between innate and adaptive immune responses during the pathogenesis, have been explored in the current review.

Role of natural P-gp inhibitor in the effective delivery for chemotherapeutic agents.

Multi-drug resistance has shown to be one of the leading threats faced currently in many chemotherapeutic agents. Permeability glycoprotein (P-gp) is an efflux transporter in membrane, an integral part of ATP-binding cassette (ABC) transporters widely distributed in the body for cellular uptake. It is present enormously in cancerous cells and is in charge of generating transporter mediated resistance to treatments of tumorous cells in addition to blocking the entry of chemotherapeutic drugs into the cell. Natural P-gp inhibitors are derived from natural plant sources possessing basic structures like alkaloids, flavonoids, phenolics, terpenoids, saponins, sapogenins, sterols, coumarins and miscellaneous structures acting on P-gp substrate for inhibition of multi-drug resistance via inhibiting the efflux pump. They do not depict their action on the healthy cells and thus it is proven to be more effective and less toxic than synthetic P-gp inhibitor leading to enhancement in bioavailability of chemotherapeutic drugs. The significant objective of the present review is surfing through the impact of natural P-gp inhibitors having basic structures derived from the plant sources and how it inhibits the resistance of chemotherapeutic drugs together with how well it delivers chemotherapy medicines.

Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer's disease.

Dysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer's disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate local neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex several years before amyloid deposition. We find the same early cingulate FC disruption and neuronal hyperactivity in AppNL-F mice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astrocytic calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral disruptions. In conclusion, we show that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.

Long-term ovarian hormone deprivation alters functional connectivity, brain neurochemical profile and white matter integrity in the Tg2576 amyloid mouse model of Alzheimer's disease.

Premenopausal bilateral ovariectomy is considered to be one of the risk factors of Alzheimer's disease (AD). However, the underlying mechanisms remain unclear. Here, we aimed to investigate long-term neurological consequences of ovariectomy in a rodent AD model, TG2576 (TG), and wild-type mice (WT) that underwent an ovariectomy or sham-operation, using in vivo MRI biomarkers. An increase in osmoregulation and energy metabolism biomarkers in the hypothalamus, a decrease in white matter integrity, and a decrease in the resting-state functional connectivity was observed in ovariectomized TG mice compared to sham-operated TG mice. In addition, we observed an increase in functional connectivity in ovariectomized WT mice compared to sham-operated WT mice. Furthermore, genotype (TG vs. WT) effects on imaging markers and GFAP immunoreactivity levels were observed, but there was no effect of interaction (Genotype × Surgery) on amyloid-beta-and GFAP immunoreactivity levels. Taken together, our results indicated that both genotype and ovariectomy alters imaging biomarkers associated with AD.

Analysis of Gastrointestinal and Hepatic Manifestations of SARS-CoV-2 Infection in 892 Patients in Queens, NY.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA virus responsible for coronavirus disease 2019 (COVID-19).1,2 The virus enters cells via the angiotensin-converting enzyme 2 receptor, which is present in enterocytes in the ileum and colon.3 Gastrointestinal (GI) manifestations include diarrhea, nausea, vomiting, and abdominal pain, and the prevalence of GI symptoms varies greatly, with a range between 2% and 57%.4 In addition, abnormal liver chemistries are reported commonly.4 As a medical center at the forefront of the early epidemic in the United States, we seek to contribute to the growing body of literature that outlines the gastrointestinal and hepatic manifestations of COVID-19.

Common functional networks in the mouse brain revealed by multi-centre resting-state fMRI analysis.

Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories worldwide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a mouse default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. RSN spatial specificity was enhanced in datasets acquired at higher field strength, with cryoprobes, in ventilated animals, and under medetomidine-isoflurane combination sedation. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations.

Author Correction: Quasi-Periodic Patterns of Neural Activity improve Classification of Alzheimer's Disease in Mice.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The autism- and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour.

Copy-number variants of the CYFIP1 gene in humans have been linked to autism spectrum disorders (ASD) and schizophrenia (SCZ), two neuropsychiatric disorders characterized by defects in brain connectivity. Here, we show that CYFIP1 plays an important role in brain functional connectivity and callosal functions. We find that Cyfip1-heterozygous mice have reduced functional connectivity and defects in white matter architecture, similar to phenotypes found in patients with ASD, SCZ and other neuropsychiatric disorders. Cyfip1-deficient mice also present decreased myelination in the callosal axons, altered presynaptic function, and impaired bilateral connectivity. Finally, Cyfip1 deficiency leads to abnormalities in motor coordination, sensorimotor gating and sensory perception, which are also known neuropsychiatric disorder-related symptoms. These results show that Cyfip1 haploinsufficiency compromises brain connectivity and function, which might explain its genetic association to neuropsychiatric disorders.

Bottom-up sensory processing can induce negative BOLD responses and reduce functional connectivity in nodes of the default mode-like network in rats.

The default mode network is a large-scale brain network that is active during rest and internally focused states and deactivates as well as desynchronizes during externally oriented (top-down) attention demanding cognitive tasks. However, it is not sufficiently understood if salient stimuli, able to trigger bottom-up attentional processes, could also result in similar reduction of activity and functional connectivity in the DMN. In this study, we investigated whether bottom-up sensory processing could influence the default mode-like network (DMLN) in rats. DMLN activity was examined using block-design visual functional magnetic resonance imaging (fMRI) while its synchronization was investigated by comparing functional connectivity during a resting versus a continuously stimulated brain state by unpredicted light flashes. We demonstrated that the BOLD response in DMLN regions was decreased during visual stimulus blocks and increased during blanks. Furthermore, decreased inter-network functional connectivity between the DMLN and visual networks as well as decreased intra-network functional connectivity within the DMLN was observed during the continuous visual stimulation. These results suggest that triggering of bottom-up attention mechanisms in sedated rats can lead to a cascade similar to top-down orienting of attention in humans and is able to deactivate and desynchronize the DMLN.

Attitude towards oral hygiene among different socio-economic groups in Jaipur city, Rajasthan.

BACKGROUND: Socio-economic status is a total measure of a person's work experience and of an individual or family economic and social position in relation to others, based on income, education and occupation. OBJECTIVE: The study was conducted to determine the differences in attitudes of people from different socioeconomic statuses towards their oral hygiene. METHOD: A cross sectional study was conducted among subjects of various socioeconomic groups. Socioeconomic status and oral hygiene data was collected using Aggarwal scale having 22 items questionnaire addressing various aspects of knowledge and attitude of subjects towards oral health, and simplified Oral Hygiene Index (OHI- S), respectively. Statistical analysis was done using chi- square test and frequency distribution (P< 0.05 taken as significant). RESULTS: Among 500 subjects, 260 (52%) were found to have good oral hygiene, and most of them (43.46%) were from lower middle class group. A highly significant association was found between the oral hygiene and socioeconomic status (p=0.000). CONCLUSION: It could be concluded that the socioeconomic status is not the only factor that determines a person's attitude towards oral hygiene, but other factors such as lack of awareness, lack of availability of dentist nearby, fear and anxiety also play an important role.

Hypersynchronicity in the default mode-like network in a neurodevelopmental animal model with relevance for schizophrenia.

BACKGROUND: Immune activation during pregnancy is an important risk factor for schizophrenia. Brain dysconnectivity and NMDA receptor (NMDAR) hypofunction have been postulated to be central to schizophrenia pathophysiology. The aim of this study was to investigate resting-state functional connectivity (resting-state functional MRI-rsfMRI), microstructure (diffusion tension imaging-DTI) and response to NMDAR antagonist (pharmacological fMRI-phMRI) using multimodal MRI in offspring of pregnant dams exposed to immune challenge (maternal immune activation-MIA model), and determine whether these neuroimaging readouts correlate with schizophrenia-related behaviour. METHODS: Pregnant rats were injected with Poly I:C or saline on gestational day 15. The maternal weight response was assessed. Since previous research has shown behavioural deficits can differ between MIA offspring dependent on the maternal response to immune stimulus, offspring were divided into three groups: controls (saline, n = 11), offspring of dams that gained weight (Poly I:C WG, n = 12) and offspring of dams that lost weight post-MIA (Poly I:C WL, n = 16). Male adult offspring were subjected to rsfMRI, DTI, phMRI with NMDAR antagonist, behavioural testing and histological assessment. RESULTS: Poly I:C WL offspring exhibited increased functional connectivity in default mode-like network (DMN). Poly I:C WG offspring showed the most pronounced attenuation in NMDAR antagonist response versus controls. DTI revealed no differences in Poly I:C offspring versus controls. Poly I:C offspring exhibited anxiety. CONCLUSIONS: MIA offspring displayed a differential pathophysiology depending on the maternal response to immune challenge. While Poly I:C WL offspring displayed hypersynchronicity in the DMN, altered NMDAR antagonist response was most pronounced in Poly I:C WG offspring.