Oxidative Coupling and Self-Assembly of Polyphenols for the Development of Novel Biomaterials.

In recent years, the development of biomaterials from green organic sources with nontoxicity and hyposensitivity has been explored for a wide array of biotherapeutic applications. Polyphenolic compounds have unique structural features, and self-assembly by oxidative coupling allows molecular species to rearrange into complex biomaterial that can be used for multiple applications. Self-assembled polyphenolic structures, such as hollow spheres, can be designed to respond to various chemical and physical stimuli that can release therapeutic drugs smartly. The self-assembled metallic-phenol network (MPN) has been used for modulating interfacial properties and designing biomaterials, and there are several advantages and challenges associated with such biomaterials. This review comprehensively summarizes current challenges and prospects of self-assembled polyphenolic hollow spheres and MPN coatings and self-assembly for biomedical applications.

Assessment of neurovascular channels in lateral maxillary sinus wall using cone-beam computed tomography: An imperative clinicians guide for implant placements.

Background: The aim of this study is to evaluate the location and radio morphometric features of the posterior superior alveolar artery (PSAA) in patients undergoing rehabilitation of posterior maxilla and other sinus augmentation surgical procedures by cone-beam computed tomography (CBCT). Materials and Methods: A total of 816 CBCT scans were included. Various radio morphometric measurements were done to assess the PSAA location, diameter, and distances to the sinus floor and alveolar crest. Results: The PSAA was mostly intraosseous in the maximum in the age group 31-51 years (56%), in males (53.4%), and in dentate patients (57.4%). The artery tends to be wider in older patients. Distances to the sinus floor or the alveolar crest tend to be shorter in women. Conclusions: This study suggests that CBCT is a valuable pre-surgical tool and the evaluation of the PSAA on CBCT images could reduce the likelihood of excess bleeding during surgery in the maxillary posterior region.

Arsenic and fluoride in groundwater triggering a high risk: Probabilistic results using Monte Carlo simulation and species sensitivity distribution.

The widespread presence of arsenic (As) and fluoride (F-) in groundwater poses substantial risks to human health on a global scale. These elements have been identified as the most prevalent geogenic contaminants in groundwater in northern Mexico. Consequently, this study aimed to evaluate the human health and ecological risks associated with the content of As and F- in the Meoqui-Delicias aquifer, which is in one of Mexico's most emblematic irrigation districts. Concentrations of As and F- were measured in 38 groundwater samples using ICP-MS and ion chromatography, respectively. Overall, these elements showed a similar trend across the aquifer, revealing a positive correlation between them and pH. The concentration of As and F- in the groundwater ranged from 5.3 µg/L to 303 µg/L and from 0.5 mg/L to 8.8 mg/L, respectively. Additionally, the levels of As and F- surpassed the established national standards for safe drinking water in 92% and 97% of samples, respectively. Given that groundwater is used for both agricultural purposes and human activities, this study also assessed the associated human health and ecological risks posed by these elements using Monte Carlo simulation and Species Sensitivity Distribution. The findings disclosed a significant noncarcinogenic health risk associated with exposure to As and F-, as well as an unacceptable carcinogenic health risk to As through water consumption for both adults and children. Furthermore, a high ecological risk to aquatic species was identified for F- and high to medium risks for As in the sampling sites. Therefore, the findings in this study provide valuable information for Mexican authorities and international organizations (e.g., WHO) about the adverse effects that any exposure without treatment to groundwater from this region represents for human health.

Nucleotide-induced ClpC oligomerization and its non-preferential association with ClpP isoforms of pathogenic Leptospira.

Bacterial caseinolytic protease-chaperone complexes participate in the elimination of misfolded and aggregated protein substrates. The spirochete Leptospira interrogans possess a set of Clp-chaperones (ClpX, ClpA, and ClpC), which may associate functionally with two different isoforms of LinClpP (ClpP1 and ClpP2). The L. interrogans ClpC (LinClpC) belongs to class-I chaperone with two active ATPase domains separated by a middle domain. Using the size exclusion chromatography, ANS dye binding, and dynamic light scattering analysis, the LinClpC is suggested to undergo nucleotide-induced oligomerization. LinClpC associates with either pure LinClpP1 or LinClpP2 isoforms non-preferentially and with equal affinity. Regardless, pure LinClpP isoforms cannot constitute an active protease complex with LinClpC. Interestingly, the heterocomplex LinClpP1P2 in association with LinClpC forms a functional proteolytic machinery and degrade ß-casein or FITC-casein in an energy-independent manner. Adding either ATP or ATPγS further fosters the LinClpCP1P2 complex protease activity by nurturing the functional oligomerization of LinClpC. The antibiotic, acyldepsipeptides (ADEP1) display a higher activatory role on LinClpP1P2 protease activity than LinClpC. Altogether, this work illustrates an in-depth study of hetero-tetradecamer LinClpP1P2 association with its cognate ATPase and unveils a new insight into the structural reorganization of LinClpP1P2 in the presence of chaperone, LinClpC to gain protease activity.

Biomechanical analysis and comparison between 'Zeta' miniplate design and conventional miniplate system for fixation of fracture segments in transition zone of parasymphysis body region of mandible - an in vitro study.

The parasymphysis area of the mandible is highly dynamic because it is subjected to both occlusal and muscular forces. As a result, the fractures in this transition zone have a special pattern, posing a challenge for surgeons whether to use one miniplate versus two miniplates, as per Champy's recommendations. The commonest complication resulting to treat this area is mental nerve paraesthesia due to the dissection and stretching of the nerve. Hence, an in vitro research study of a newly designed 'Zeta' miniplate is performed, to evaluate the biomechanical behaviour using finite element (FE) analysis and biomechanical analysis along with a comparison study with the conventional miniplate configurations. The results showed that the Zeta miniplate produces the lowest stresses 17.511 MPa and the least total structural deformation of 0.0011 mm after applying the maximum occlusal bite force. On application of torsional load, total structural deformation was 0.0004 mm and von Mises (VM) stress value was 0.24 MPa which was lowest when compared with the two miniplate system. Hence, the newly developed Zeta miniplate is superior in terms of stability. Another benefit of its design is that it helps in preventing mental nerve paraesthesia and tooth root damage while fixing and stabilising the fractured bony segments.

Nanoemulsions a Delivery System in the Making for Tumor Targeting Therapeutics: Evaluation and Characterization to Meet Clinical Challenges.

Cancer is a complex disease characterized by the uncontrolled and unregulated growth of cells followed by invasion and proliferation from the site of origin to other sites of the body. Conventional chemotherapy largely kills rapidly expanding and dividing cancer cells by impairing DNA synthesis and mitosis. It is associated with various types of adverse effects ranging from simple nausea and appetite loss to serious ones like bone marrow depression and compromised immunity etc., due to their non-selectivity and inability to differentiate. The ideal feature of a delivery system is delivering the drug to the target place to achieve the most therapeutic impact while having the least toxicity. With the advent of novel drug delivery systems, it has been easier to deliver the drug to the target site. Utilizing new techniques and technology makes it a feasible approach to target cancer cells. Nanoemulsions are isotropic mixtures of transparent or translucent oil globules dispersed in an aqueous phase that is kinetically stable and supported by an interfacial coating of surfactant and co-surfactant molecules with droplet sizes in the nanometre range. Nanoemulsions are the delivery system of choice in case of cancer because of certain key attributes, including biodegradability, biocompatibility, large surface area nonimmunogenicity, and release behavior control. At the same time, nanoemulsions have been engineered for various reasons, including enhanced biological half-life, target-specific binding ability, and imaging capability at different therapy levels by modifying the characteristics of nanoemulsions. This review focuses on current cancer treatment challenges and the role of nanoemulsions in treating cancer with their production methods, characterization methods, application, and quality attributes, which would help them make it to the clinics where cancer treatment is going on.

Exploring TLR signaling pathways as promising targets in cervical cancer: The road less traveled.

Cervical cancer is the leading cause of cancer-related deaths for women globally. Despite notable advancements in prevention and treatment, the identification of novel therapeutic targets remains crucial for cervical cancer. Toll-like receptors (TLRs) play an essential role in innate immunity as pattern-recognition receptors. There are several types of pathogen-associated molecular patterns (PAMPs), including those present in cervical cancer cells, which have the ability to activate toll-like receptors (TLRs). Recent studies have revealed dysregulated toll-like receptor (TLR) signaling pathways in cervical cancer, leading to the production of inflammatory cytokines and chemokines that can facilitate tumor growth and metastasis. Consequently, TLRs hold significant promise as potential targets for innovative therapeutic agents against cervical cancer. This book chapter explores the role of TLR signaling pathways in cervical cancer, highlighting their potential for targeted therapy while addressing challenges such as tumor heterogeneity and off-target effects. Despite these obstacles, targeting TLR signaling pathways presents a promising approach for the development of novel and effective treatments for cervical cancer.

Hyaluronic acid-oleylamine and chitosan-oleic acid conjugate-based hybrid nanoparticle delivery via. dissolving microneedles for enhanced treatment efficacy in localized breast cancer.

Microneedle technology offers a minimally invasive treatment strategy to deliver chemotherapeutics to localized tumors. Amalgamating the surface functionalized nanoparticles with microneedle technology can potentially deliver drugs directly to tumors and subsequently target cancer cells via, overexpressed receptors on the cell surface, thereby enhancing the treatment efficacy while reducing side effects. Here, we report cetuximab anchored hyaluronic acid-oleylamine and chitosan-oleic acid-based hybrid nanoparticle (HA-OA/CS-OA NPT)-loaded dissolving microneedles (MN) for targeted delivery of cabazitaxel (CBT) in localized breast cancer tumor. The HA-OA/CS-OA NPT was characterized for their size, surface charge, morphology, physicochemical characteristics, drug release behavior, and in vitro anti-cancer efficacy. The HA-OA/CS-OA NPT were of ~125 nm size, showed enhanced cytotoxicity and cellular uptake, and elicited a superior apoptotic response against MDA-MB-231 cells. Subsequently, the morphology and physicochemical characteristics of HA-OA/CS-OA NPT-loaded MN were also evaluated. The fabricated microneedles were of ~550 µm height and showed loading of nanoparticles equivalent to ~250 µg of CBT. The ex vivo skin permeation study revealed fast dissolution of microneedles upon hydration, while the drug permeation across the skin exhibited ~4-fold improvement in comparison to free drug-loaded MN. In vivo studies performed on DMBA-induced breast cancer in female SD rats showed a marked reduction in tumor volume after administration of drug and nanoparticle-loaded microneedles in comparison to intravenous administration of free drug. However, the HA-OA/CS-OA NPT-MN showed the highest tumor reduction and survival rate, with the lowest body weight reduction in comparison to other treatment groups, indicating its superior efficacy and low systemic toxicity. Overall, the dissolving microneedle-mediated delivery of targeted nanoparticles loaded with chemotherapeutics offers a superior alternative to conventional intravenous chemotherapy.

Ovarian Cystic Lymphangioma.

Lymphangioma are benign, slow-growing and rare lymphatic tumors, which may emerge at any location in the body with ovary being a very rare location. Axillary region and neck are the most common sites, while retroperitoneum and mesentery account for <1%. We present a case of a young female of 33 years who had symptomatic pelvic mass and was presented with a complaint of lower abdominal pain of six-month duration and weight loss. Investigation revealed an oval-shaped complex cystic density lesion in the right adnexal region, which was likely neoplastic. Elective laparotomy with right ovarian cystectomy was performed. Histopathological examination revealed ovarian lymphangioma.

Biopolymer-based tumor microenvironment-responsive nanomedicine for targeted cancer therapy.

Nanomedicine has opened up new avenues for cancer treatment by enhancing drug solubility, permeability and targeted delivery to cancer cells. Despite its numerous advantages over conventional therapies, nanomedicine may exhibit off-target drug distribution, harming nontarget regions. The increased permeation and retention effect of nanomedicine in tumor sites also has its limitations, as abnormal tumor vasculature, dense stroma structure and altered tumor microenvironment (TME) may result in limited intratumor distribution and therapeutic failure. However, TME-responsive nanomedicine has exhibited immense potential for efficient, safe and precise delivery of therapeutics utilizing stimuli specific to the TME. This review discusses the mechanistic aspects of various TME-responsive biopolymers and their application in developing various types of TME-responsive nanomedicine.

Lipid-coated nanocrystals of paclitaxel as dry powder for inhalation: Characterization, in-vitro performance, and pharmacokinetic assessment.

BACKGROUND: Nanocrystals can be produced as a dry powder for inhalation (DPIs) to deliver high doses of drug to the lungs, owing to their high payload and stability to the shear stress of aerosolization force. Furthermore, lipid-coated nanocrystals can be formulated to improve the drug accumulation and retention in lung. OBJECTIVE: The present work involved the fabrication of paclitaxel nanocrystals using hydrophilic marine biopolymer fucoidan as a stabilizer. Thereafter, fabricated nanocrystals (FPNC) were surface-modified with phospholipid to give lipid-coated nanocrystals (Lipo-NCs). METHODS: The nanocrystals were fabricated by antisolvent crystallization followed by the probe sonication. The lipid coating was achieved by thin film hydration followed ultrasonic dispersion technique. Prepared nanocrystals were lyophilized to obtain a dry powder of FPNC and Lipo-NCs, used later for physicochemical, microscopic, and spectroscopic characterization to confirm the successful formation of desired nanocrystals. In-vitro and in-vivo investigations were also conducted to determine the role of nanocrystal powder in pulmonary drug delivery. RESULTS: Lipo-NCs exhibited slower drug release, excellent flow properties, good aerosolization performance, higher drug distribution, and prolonged retention in the lungs compared to FPNC and pure PTX. CONCLUSION: Lipid-coated nanocrystals can be a novel formulation for the maximum localization of drugs in the lungs, thereby enhancing therapeutic effects and avoiding systemic side effects in lung cancer therapy.

Clinical Profile of Triple-Negative Breast Cancer: A Hospital-Based Study.

Introduction Triple-negative breast cancer (TNBC) is a new concept and an important area of investigation. In Western country's literature, different studies reported on TNBC and all indicated the poor prognostic aspect of this molecular subtype over other types of breast cancer. However, there is a scarcity of comprehensive data from India. Hence, the present study was carried out to look at the epidemiological and clinical characteristics of TNBC in the Indian population. Methods The present study was performed between January 2020 and June 2021 at a tertiary care hospital in Eastern India. A total of 150 patients with TNBC were enrolled in the study. The epidemiological and clinical features of enrolled patients were collected and reviewed. Results The median age of patients at TNBC presentation was 45.53 years (24 to 74 years). The median tumor size was reported to be 5.32 cm. Of 150 patients, 94(62.67%) showed enlarged lymph nodes and 56 (37.33%) patients had no lymph node enlargement. In the present study, 85 (56.67%) patients were in the pre/perimenopausal stage at presentation, whereas 65 (43.33%) patients were in the postmenopausal stage. Upon evaluating the spread of TNBC, it was observed that a maximum of patients 60 (40%) were at the T4 stage and 56 (37.33%) at the N0 condition. The clinical staging of TNBC reported a maximum of 74 (49.33%) patients at the IIA, and IIB stages followed by 53 (35.33%) patients at the IIIA, IIIB, and IIIC stages and a minimum of 11 (7.33%) patients at stage IV. Only five (3.33%) patients were reported with a family history of breast cancer. Of all patients, 126 (84%) had detected early breast cancer thereby applicable for surgery at the time of presentation, whereas 71 (47.33%) patients were eligible for radiation therapy and 138 (92%) patients received chemotherapy. A total of 112 (74.67%) patients were found alive after 24 months of follow-up, 22 (4.67%) patients were observed with remission, and 11 (7.33%) patients died due to TNBC progression. During the course of follow-up, five (3.33%) patients were lost in the study.  Conclusion TNBC is an aggressive malignancy that has a high risk of systemic relapses in the first two years after diagnosis. For more mature evidence on TNBC, longer follow-up of patients is necessary.

Design, synthesis, characterization, in vitro cytotoxic, antimicrobial, antioxidant studies, DFT, thermal and molecular docking evaluation of biocompatible Co(II) complexes of N4O4-macrocyclic ligands.

Bioactive cobalt (II) macrocyclic complexes [Co(N4O4ML1)Cl2]-[Co(N4O4ML3)Cl2] have been synthesized by using the macrocyclic ligands [N4O4ML1], [N4O4ML2], and [N4O4ML3] that have an N4O4 core. These three macrocyclic ligands were all isolated in pure form, together with their complexes. Microanalytical investigations, FT-IR NMR, Mass, magnetic moments, electronic, PXRD, TGA, and EPR spectrum studies were used to analyse their structures. For these complexes, an octahedral geometry is proposed for the metal ion. By using molecular weights and conductivity measurements the monomeric and non-electrolytic nature has been confirmed. The Coats-Redfern and FWO methods are used to determine the thermodynamic characteristics of the ligands and their Co(II) complexes. The molecular modelling using the DFT technique displays the bond angle, bond lengths and quantum chemical properties. To determine their ability to prevent the growth of harmful fungus and bacteria, the ligands [N4O4ML1]- [N4O4ML3] and their complexes were tested in vitro against A. Niger, C. albicans and B. subtilis, S. aureus, E. coli and S. typhi fungal and bacterial organisms, respectively. By using DPPH free radical scavenger assays, the in vitro antioxidant capabilities of each compound were evaluated. The [Co(N4O4ML3)Cl2] antioxidative capabilities revealed significant radical scavenging power. The MTT assay was used to assess the toxicity of all the synthesised compounds under inquiry on MCF-7, HeLa, and A549 cancer cells. The findings revealed that the ligand and the compounds gave outstanding IC50 values in the range of 9.07-36.25 (uM) at a concentration of 25 ppm. Among all the substances evaluated, [Co(N4O4ML3)Cl2] complex was discovered to be the most active and least cytotoxic. Additionally, docking investigations of the produced compounds were carried out in order to validate the biological outcomes.

Cardiovascular disease and lung cancer.

Lung cancer is the second most common cancer worldwide and the leading cause of cancer-related death. While survival rates have improved with advancements in cancer therapeutics, additional health challenges have surfaced. Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in patients with lung cancer. CVD and lung cancer share many risk factors, such as smoking, hypertension, diabetes, advanced age, and obesity. Optimal management of this patient population requires a full understanding of the potential cardiovascular (CV) complications of lung cancer treatment. This review outlines the common shared risk factors, the spectrum of cardiotoxicities associated with lung cancer therapeutics, and prevention and management of short- and long-term CVD in patients with non-small cell (NSCLC) and small cell (SCLC) lung cancer. Due to the medical complexity of these patients, multidisciplinary collaborative care among oncologists, cardiologists, primary care physicians, and other providers is essential.

Role of Phytoconstituents in Cancer Treatment: A Review.

Over the years, natural compounds have become a significant advancement in cancer treatment, primarily due to their effectiveness, safety, bio-functionality, and wide range of molecular structures. They are now increasingly preferred in drug discovery due to these attributes. These compounds, whether occurring naturally or with synthetic modifications, find applications in various fields like biology, medicine, and engineering. While chemotherapy has been a successful method for treating cancer, it comes with systemic toxicity. To address this issue, researchers and medical practitioners are exploring the concept of combinational chemotherapy. This approach aims to reduce toxicity by using a mix of natural substances and their derivatives in clinical trials and prescription medications. Among the most extensively studied natural anticancer compounds are quercetin, curcumin, vincristine, and vinblastine. These compounds play crucial roles as immunotherapeutics and chemosensitizers, both as standalone treatments and in combination therapies with specific mechanisms. This review article provides a concise overview of the functions, potentials, and combinations of natural anticancer compounds in cancer treatment, along with their mechanisms of action and clinical applications.

Developing, validating, and comparing an analytical method to simultaneously detect z-drugs in urine samples using the QuEChERS approach with both liquid chromatography and gas chromatography-tandem mass spectrometry.

Detecting z-drugs, a sedative-hypnotic medication, is also misused for criminal activities. Therefore, the analysis of urine samples is crucial for clinical and forensic purposes. We conducted a study where we developed, validated, and compared an analytical method for simultaneously detecting z-drugs in urine samples. Our approach uses the QuEChERS method for sample preparation, combined with liquid chromatography (LC) and gas chromatography (GC) coupled with tandem mass spectrometry (MS/MS). We optimized the QuEChERS method to effectively extract z-drugs from urine samples while minimizing matrix effects and achieving high recovery rates. After extraction, we split the samples into two parts for analysis using LC-MS/MS and GC-MS/MS. We validated our methods, and the results showed good linearity over a broad concentration range (1-200 ng/mL) for each z-drug. The limits of detection and quantification were within clinically relevant ranges, ensuring sensitivity for detecting z-drugs in urine samples. We compared the two chromatographic techniques by analyzing a set of urine samples spiked with known concentrations of z-drugs using both LC-MS/MS and GC-MS/MS methods and then applied to the real samples. The results were statistically analyzed to assess any significant differences in accuracy and precision above 95 %, and both methods offered reliable and consistent results with the samples as well. In conclusion, our analytical method coupled with both LC-MS/MS and GC-MS/MS using the QuEChERS approach provides a comprehensive and robust solution for the simultaneous detection of z-drugs in urine samples. The choice between the two chromatographic techniques can be based on the specific z-drugs of interest and the required analytical performance. This method holds promise for applications in clinical toxicology, forensic analysis, and monitoring z-drug usage.

In Vitro Modulation of Genotoxicity and Oxidative Stress by Polyphenol-Rich Fraction of Chinese Ladder Brake (Pteris vittata L.).

Pteris vittata L. is a terrestrial genus growing in moist, shady forests and on hillsides. The plant has considerable ethnomedicinal importance. Investigations have been carried out on chemical profiling and antioxidant compounds from some genera of pteridophytes but studies on the biological properties of P. vittata are lacking. Therefore, the present study investigates antioxidant, antigenotoxic, and antiproliferative potential of the aqueous fraction of P. vittata (PWE). A battery of assays were carried out to assess the antioxidant potential of the PWE. SOS chromotest and DNA nicking assay were used to evaluate the antigenotoxicity of the fraction. The cytotoxic effect of PWE was analyzed using MTT and Neutral Single Cell Gel Electrophoresis comet assay. EC50 of 90.188 µg/ml, 80.13 µg/ml, 142.836 µg/ml, and 12.274 µg/ml was obtained in DPPH, superoxide anion scavenging, reducing power and lipid peroxidation assays, respectively. PWE was potent in inhibiting Fenton's reagent-induced nicking of pBR322 plasmid. The fraction significantly inhibited hydrogen peroxide (H2O2) and 4-nitroquinoline-N-oxide (4NQO) induced mutagenicity and a reduction in induction factor was found with increased PWE concentration. GI50 of 147.16 µg/ml was obtained in MTT assay in human MCF-7 breast cancer cell line. PWE induced apoptosis as confirmed from confocal microscopy studies. The protective effects can be attributed to the presence of the phytochemicals in PWE. These results will be helpful in the development of functional food characteristics, as well as unravel the benefits of pteridophytes as promoters of health.

Evidence-based clinical practice guideline for management of urinary tract infection and primary vesicoureteric reflux.

We present updated, evidence-based clinical practice guidelines from the Indian Society of Pediatric Nephrology (ISPN) for the management of urinary tract infection (UTI) and primary vesicoureteric reflux (VUR) in children. These guidelines conform to international standards; Institute of Medicine and AGREE checklists were used to ensure transparency, rigor, and thoroughness in the guideline development. In view of the robust methodology, these guidelines are applicable globally for the management of UTI and VUR. Seventeen recommendations and 18 clinical practice points have been formulated. Some of the key recommendations and practice points are as follows. Urine culture with > 104 colony forming units/mL is considered significant for the diagnosis of UTI in an infant if the clinical suspicion is strong. Urine leukocyte esterase and nitrite can be used as an alternative screening test to urine microscopy in a child with suspected UTI. Acute pyelonephritis can be treated with oral antibiotics in a non-toxic infant for 7-10 days. An acute-phase DMSA scan is not recommended in the evaluation of UTI. Micturating cystourethrography (MCU) is indicated in children with recurrent UTI, abnormal kidney ultrasound, and in patients below 2 years of age with non-E. coli UTI. Dimercaptosuccinic acid scan (DMSA scan) is indicated only in children with recurrent UTI and high-grade (3-5) VUR. Antibiotic prophylaxis is not indicated in children with a normal urinary tract after UTI. Prophylaxis is recommended to prevent UTI in children with bladder bowel dysfunction (BBD) and those with high-grade VUR. In children with VUR, prophylaxis should be stopped if the child is toilet trained, free of BBD, and has not had a UTI in the last 1 year. Surgical intervention in high-grade VUR can be considered for parental preference over antibiotic prophylaxis or in children developing recurrent breakthrough febrile UTIs on antibiotic prophylaxis.

FAK Drives Resistance to Therapy in HPV-Negative Head and Neck Cancer in a p53-Dependent Manner.

PURPOSE: Radiation and platinum-based chemotherapy form the backbone of therapy in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). We have correlated focal adhesion kinase (FAK/PTK2) expression with radioresistance and worse outcomes in these patients. However, the importance of FAK in driving radioresistance and its effects on chemoresistance in these patients remains unclear. EXPERIMENTAL DESIGN: We performed an in vivo shRNA screen using targetable libraries to identify novel therapeutic sensitizers for radiation and chemotherapy. RESULTS: We identified FAK as an excellent target for both radio- and chemosensitization. Because TP53 is mutated in over 80% of HPV-negative HNSCC, we hypothesized that mutant TP53 may facilitate FAK-mediated therapy resistance. FAK inhibitor increased sensitivity to radiation, increased DNA damage, and repressed homologous recombination and nonhomologous end joining repair in mutant, but not wild-type, TP53 HPV-negative HNSCC cell lines. The mutant TP53 cisplatin-resistant cell line had increased FAK phosphorylation compared with wild-type, and FAK inhibition partially reversed cisplatin resistance. To validate these findings, we utilized an HNSCC cohort to show that FAK copy number and gene expression were associated with worse disease-free survival in mutant TP53, but not wild-type TP53, HPV-negative HNSCC tumors. CONCLUSIONS: FAK may represent a targetable therapeutic sensitizer linked to a known genomic marker of resistance.

Nur77 influences immunometabolism to regulate the release of proinflammatory cytokines and the formation of lipid bodies during Mycobacterium tuberculosis infection of macrophages.

Infection of macrophages with Mycobacterium tuberculosis induces innate immune responses designed to clear the invading bacterium. However, bacteria often survive within the intracellular environment by exploiting these responses triggered by macrophages. Here, the role of the orphan nuclear receptor Nur77 (Nr4a1) in regulating the response of macrophages infected with M. tuberculosis (Mtb) has been delineated. Nur77 is induced early during infection, regulates metabolism by binding directly at the promoter of the TCA cycle enzyme, isocitrate dehydrogenase 2 (IDH2), to act as its repressor, and shifts the balance from a proinflammatory to an anti-inflammatory phenotype. Depletion of Nur77 increased transcription of IDH2 and, consequently, the levels of intracellular succinate, leading to enhanced levels of the proinflammatory cytokine IL-1ß. Further, Nur77 inhibited the production of antibacterial nitric oxide and IL-1ß in a succinate dehydrogenase (SDH)-dependent manner, suggesting that its induction favors bacterial survival by suppressing bactericidal responses. Indeed, depletion of Nur77 inhibited the intracellular survival of Mtb. On the other hand, depletion of Nur77 enhanced lipid body formation, suggesting that the fall in Nur77 levels as infection progresses likely favors foamy macrophage formation and long-term survival of Mtb in the host milieu.