Novel modifications of PARP inhibitor veliparib increase PARP1 binding to DNA breaks.

Catalytic poly(ADP-ribose) production by PARP1 is allosterically activated through interaction with DNA breaks, and PARP inhibitor compounds have the potential to influence PARP1 allostery in addition to preventing catalytic activity. Using the benzimidazole-4-carboxamide pharmacophore present in the first generation PARP1 inhibitor veliparib, a series of 11 derivatives was designed, synthesized, and evaluated as allosteric PARP1 inhibitors, with the premise that bulky substituents would engage the regulatory helical domain (HD) and thereby promote PARP1 retention on DNA breaks. We found that core scaffold modifications could indeed increase PARP1 affinity for DNA; however, the bulk of the modification alone was insufficient to trigger PARP1 allosteric retention on DNA breaks. Rather, compounds eliciting PARP1 retention on DNA breaks were found to be rigidly held in a position that interferes with a specific region of the HD domain, a region that is not targeted by current clinical PARP inhibitors. Collectively, these compounds highlight a unique way to trigger PARP1 retention on DNA breaks and open a path to unveil the pharmacological benefits of such inhibitors with novel properties.

The Prognostic, Diagnostic, and Therapeutic Potential of TRAIL Signalling in Cardiovascular Diseases.

TNF-related apoptosis-inducing ligand (TRAIL) was originally discovered, almost 20 years ago, for its ability to kill cancer cells. More recent evidence has described pleiotropic functions, particularly in the cardiovascular system. There is potential for TRAIL concentrations in the circulation to act as prognostic and/or diagnostic factors for cardiovascular diseases (CVD). Pre-clinical studies also describe the therapeutic capacity for TRAIL signals, particularly in the context of atherosclerotic disease and diseases of the myocardium. Because diabetes mellitus significantly contributes to the progression and pathogenesis of CVDs, in this review we highlight recent evidence for the prognostic, diagnostic, and therapeutic potential of TRAIL signals in CVDs, and where relevant, the impact of diabetes mellitus. A greater understanding of how TRAIL signals regulate cardiovascular protection and pathology may offer new diagnostic and therapeutic avenues for patients suffering from CVDs.

A comprehensive study of p53 protein.

The protein p53 has been extensively investigated since it was found 43 years ago and has become a "guardian of the genome" that regulates the division of cells by preventing the growth of cells and dividing them, that is, inhibits the development of tumors. Initial proof of protein existence by researchers in the mid-1970s was found by altering and regulating the SV40 big T antigen termed the A protein. Researchers demonstrated how viruses play a role in cancer by employing viruses' ability to create T-antigens complex with viral tumors, which was discovered in 1979 following a viral analysis and cancer analog research. Researchers later in the year 1989 explained that in Murine Friend, a virus-caused erythroleukemia, commonly found that p53 was inactivated to suggest that p53 could be a "tumor suppressor gene." The TP53 gene, encoding p53, is one of human cancer's most frequently altered genes. The protein-regulated biological functions of all p53s include cell cycles, apoptosis, senescence, metabolism of the DNA, angiogenesis, cell differentiation, and immunological response. We tried to unfold the history of the p53 protein, which was discovered long back in 1979, that is, 43 years of research on p53, and how p53's function has been developed through time in this article.

Clinical Profile and Predictors of Outcome in Children with Acute Fulminant Myocarditis Receiving Intensive Care: A Single Center Experience.

Acute myocarditis in children is associated with high morbidity and mortality, with limited data on intravenous immunoglobulin (IVIG) treatment and outcome. Our goal was to describe clinical, treatment profile, and predictors of outcome in children with acute fulminant myocarditis (AFM) receiving intensive care. Case records of 120 children with clinical diagnosis of acute myocarditis from January 2008 to December 2018 were analyzed retrospectively. AFM was seen in 89 (74.2%) children of which nearly two-thirds (54 [60.7%]) were hypotensive at admission. The median (interquartile range [IQR]) ejection fraction on echocardiography was 25 (18.5-36%). Eighty-two children (68.3%) received IVIG. Intensive care needs were mechanical ventilation ( n = 71; 59.2%) and inotrope support ( n = 89; 74.2%); median inotrope score being 30 (IQR: 20-55). Twenty-one children died (17.5%). Fever ( p = 0.004), arrhythmia ( p = 0.03), shock ( p = 0.015), higher inotrope score ( p = 0.0001), need for ventilation ( p = 0.025), acidosis ( p = 0.013), AKI ( p = 0.0001), transaminitis ( p = 0.0001), and multiorgan dysfunction ( p = 0.0001) were associated with mortality. The mortality was significantly less in IVIG treated group (12.1 vs. 28.9%; p = 0.02). On multiple logistic regression, MODS ( p = 0.002) was independent predictor of mortality while IVIG treatment ( p = 0.004) was favorably associated with survival. AFM complicated by multiorgan dysfunction carried a poor prognosis. IVIG was associated with survival benefit.

Accidental Pathological Findings in Asymptomatic Maxillary Sinuses in Patients Referred for Head and Neck Cone-Beam Computed Tomography: A Cross-sectional Study Analysis.

Background: The aim of the present study was to detect the prevalence of accidental pathological findings in asymptomatic maxillary sinuses in patients referred for head and neck cone-beam computed tomography (CBCT) examination for varied reasons. Methods: The present cross-sectional study included a detailed analysis of CBCT scans of 150 patients aged between 18 and 70 years reporting for varied dental complaints for detecting accidental pathological findings in maxillary sinuses while the patients did not have any complaint pertaining to sinuses. Results: The findings of the present study revealed 58% patients to have pathological findings in maxillary sinuses while they were asymptomatic for sinuses. Furthermore, the prevalence of mucosal thickening was found in 29.3% of the patients while 36.7% patients presented with polypoidal mucosal thickening. Conclusion: Higher prevalence of pathologies in asymptomatic maxillary sinuses found in the present study emphasized significance of a thorough examination of routine dental patients by dento-maxillofacial radiologists with necessary investigations to be advised in the form of higher imaging modalities like CBCT, if necessary.

Efficacy and Safety of Intravenous Labetalol in Acute Hypertensive Crisis in Children.

OBJECTIVE: To determine the efficacy and safety of intravenous (IV) labetalol in the management of hypertensive crisis in children. METHODS: A retrospective chart review of 56 consecutive children (age > 1 mo to ≤ 12 y) with hypertensive crisis admitted to a pediatric intensive care unit (PICU) from July 2009 to 2019. RESULTS: The proportion of children attaining the primary endpoint (target 95th percentile in > 12 to ≤ 48 h) was significantly more in the group receiving labetalol as first-line or add-on (n = 23) as compared to those not receiving labetalol (n = 33) (62% vs. 30.3%, p = 0.03). Higher proportion of neurological recovery was seen in the labetalol group (56.2% vs. 18.7%, p = 0.02). The proportion of children with hypotension before 12 h was similar in both treatment groups (13% vs. 15%, p = 0.82). The practice variations between two periods of 5 y each (2009-2013 and 2014-2019) showed significantly more use of labetalol in the latter cohort (53% for 2014-2019 vs. 25% for 2009-2013, p = 0.03). CONCLUSION: Labetalol, when used alone or as an add-on drug, was more efficacious than IV nitroprusside/nitroglycerine in attaining the primary endpoint in children up to ≤ 12 y of age with hypertensive crisis. Labetalol was safe and associated with higher neurological recovery.

Serum ceruloplasmin as cancer marker in oral pre-cancers and cancers.

BACKGROUND AND AIM: Oxidative stress leads to a compensatory increase in levels of serum ceruloplasmin in patients with such imbalances. Greater than normal serum ceruloplasmin levels are noticed in numerous cancers including the leukemias and Hodgkin's lymphoma. The purpose of the present study was to estimate and evaluate the efficacy of serum ceruloplasmin levels as a potential biomarker in the early detection of oral potentially malignant epithelial lesions (PMELs) including leukoplakia, oral submucous fibrosis (OSMF), and oral squamous cell carcinoma (OSCC) patients. MATERIALS AND METHODS: The present observational study was conducted over a period of 2 years wherein 100 subjects aged between 18 to 60 years were divided into four groups with Group A consisting of 25 healthy controls, Group B and C with 25 patients each, clinically diagnosed with oral leukoplakia and OSMF and Group D with 25 patients clinically diagnosed and histopathologically proven OSCC. The patients were subjected to incisional biopsy after routine hematological investigation while the same sera samples were used for analysis of serum ceruloplasmin levels. STATISTICAL ANALYSIS USED: Comparison of serum ceruloplasmin levels between the groups was performed using one way analysis of variance (one way ANOVA) test while P < 0.05 was considered statistically significant. RESULTS: The mean serum ceruloplasmin levels were found to be 43.19 ± 1.90mg/dl in subjects of group A, 47.68 ± 1.51mg/dl in group B, 47.74 ± 1.45mg/dl in group C and 47.73 ± 0.74mg/dl in group D. Using one-way ANOVA, statistically significant variations were found in the values of mean serum ceruloplasmin levels in subjects of the four groups (F-value = 59.58, P = 0.0001). CONCLUSIONS: The observations of the present study revealed that serum ceruloplasmin levels were found to be raised in all 3 study groups including oral leukoplakia, OSMF and OSCC as compared to the controls while the results were found to be statistically significant.

Impairment of olfactory and gustatory sensations in severe acute respiratory syndrome corona virus 2 (SARS-CoV-2 virus) disease.

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2 virus) disease had first appeared in December 2019 in Wuhan, China, and since then, it has emerged as a global threat to humanity. An early diagnosis and isolation are the most significant measures required to prevent its spread. Recent anecdotal evidence has suggested impairment of olfactory and gustatory sensations associated with corona virus disease (COVID-19). Angiotensin-converting enzyme-2 is an important aspect for the manifestations seen in this deadly viral disease. The associated olfactory and gustatory dysfunction can also lead to partial and/or complete loss of the ability to smell and taste in the early stages of disease onset. Evidence has also suggested that the presence of SARS-CoV-2 nucleic acid in human saliva makes it the carrier of the infectious viral disease and aids in its diagnosis. The present review focuses on the listed clinical manifestations in the form of olfactory and gustatory impairment in SARS-CoV-2 virus disease.

Calcifying Epithelial Odontogenic Cyst of Maxilla: A Clinical and Histological Rarity with Literature Review.

A cyst is defined as a pathological cavity which may or may not have an epithelial lining and which has a fluid, semi-fluid, or gaseous contents and is not formed by the accumulation of pus. The calcifying epithelial odontogenic cyst (CEOC) was first reported by Gorlin et al. in 1962. At that time, it was classified as a cyst related to the odontogenic apparatus. It was later renamed as calcifying cystic odontogenic tumor (CCOT) in the World Health Organization classification devised in 2005 due to its histological complexity, morphological diversity, and aggressive proliferation. CCOT was later recognized by numerous names including Gorlin cyst, calcifying ghost cell odontogenic cyst and/or dentogenic ghost cell tumor. It has a peak incidence during the second and third decades of life and does not demonstrate any gender predilection. Radiographically, CEOC may appear as a unilocular or multilocular radiolucent lesion with either well-circumscribed or poorly-defined margins and may also be observed in association with unerupted teeth. Calcification is an important radiographic feature for the interpretation of CEOC/CCOT. The typical histopathological features of CEOC include a fibrous wall and lining of the odontogenic epithelium with either columnar or cuboidal basal cells resembling ameloblasts. The treatment of choice for CEOC is conservative surgical enucleation; however, recurrence is also not found to be uncommon. Herein, we are reporting a case of the same in a 21-year-old female which was a great dilemma during the diagnostic workup.

TRAIL signals, extracellular matrix and vessel remodelling.

The extracellular matrix (ECM) is an essential part of the vasculature, not only providing structural support to the blood vessel wall, but also in its ability to interact with cells to regulate cell phenotype and function including proliferation, migration, differentiation and death - processes important in vascular remodelling. Increasing evidence implicates TNF-related apoptosis-inducing ligand (TRAIL) signalling in the modulation of vascular cell function and remodelling under normal and pathological conditions such as in atherosclerosis. TRAIL can also stimulate synthesis of multiple ECM components within blood vessels. This review explores the relationship between TRAIL signals, the ECM, and its implications in vessel remodelling in cardiovascular disease.

A "Western Diet" promotes symptoms of hepatic steatosis in spontaneously hypertensive rats.

Systemic hypertension, characterized by elevated blood pressure ≥140/90 mm Hg, is a major modifiable risk factor for cardiovascular disease. Hypertension also associates with non-alcoholic fatty liver disease (NAFLD), which is becoming common due to a modern diet and lifestyle. The aim of the present study was to examine whether a high-fat "Western" diet had effects on hypertension and associated NAFLD. Normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were placed on a normal chow or high-fat diet for 8 weeks; blood pressure was measured fortnightly and body weight recorded weekly. As expected, SHR had elevated blood pressure compared to WKY. Diet did not influence blood pressure. Compared to SHR, WKY rats gained more weight, associating with increased white adipose tissue weight. Normotensive rats also had higher plasma cholesterol and triglycerides in response to a "Western" diet, with no changes in plasma glucose levels. Neither strain developed atherosclerosis. Interestingly, high-fat diet-fed SHR had increased liver weight, associating with a significant level of hepatic lipid accumulation not observed in WKY. Further, they exhibited hepatocellular ballooning and increased hepatic inflammation, indicative of steatohepatitis. These findings suggest that a high-fat "Western" diet promotes features of NAFLD in SHR, but not WKY rats. Importantly, the high-fat diet had no effect on blood pressure.

Vascular transcriptome landscape of Trail-/- mice: Implications and therapeutic strategies for diabetic vascular disease.

Circulating plasma TRAIL levels are suppressed in patients with cardiovascular and diabetic diseases. To identify novel targets in vascular metabolic diseases, genome-wide transcriptome of aortic tissue from Trail-/- versus Trail+/+ mice were interrogated. We found 861 genes differentially expressed with TRAIL deletion. Gene enrichment analyses showed many of these genes were related to inflammation, cell-to-cell cytoskeletal interactions, and transcriptional modulation. We identified vascular protective and pathological gene clusters, with Ifi205 as the most significantly reduced vascular protective gene, whereas Glut1, the most significantly increased pathological gene with TRAIL deletion. We hypothesized that therapeutic targets could be devised from such integrated analysis and validated our findings from vascular tissues of diabetic mice. From the differentially expressed gene targets, enriched transcription factor (TF) and microRNA binding motifs were identified. The top two TFs were Elk1 and Sp1, with enrichment to eight gene targets common to both. miR-520d-3p and miR-377-3p were the top enriched microRNAs with TRAIL deletion; with four overlapping genes enriched for both microRNAs. Our findings offer an alternate in silico approach for therapeutic target identification and present a deeper understanding of gene signatures and pathways altered with TRAIL suppression in the vasculature.

Comparison of clinical efficacy of methylprednisolone and serratiopeptidase for reduction of postoperative sequelae after lower third molar surgery.

BACKGROUND: Surgical removal of mandibular third molars results in some degree of post-operative pain, swelling and trismus. These can be controlled by proper administration of local anesthesia, careful bone removal, minimal trauma to adjacent soft tissues and administration of methylprednisolone and serratiopeptidase drugs. The aim of the present study was to compare the efficacy of methylprednisolone and serratiopeptidase in controlling post-operative pain, swelling and trismus after surgical removal of impacted mandibular third molars. MATERIAL AND METHODS: The subjects were divided into two groups of 50 patients each undergoing surgical removal of mandibular third molars. Group A was given methylprednisolone 4mg orally every 8th hourly and Group B was given serratiopeptidase 10 mg every 12th hourly orally. Post-operatively pain, swelling and trismus were evaluated at the end of 1st, 3rd and 5thday. RESULTS: The results of this study showed that methylprednisolone is an effective analgesic, while serratiopeptidase has moderate analgesic activity. Serratiopeptidase is more effective than methylprednisolone in controlling post surgical swelling and trismus. Hence combination of these two drugs would be very effective than individual drug when widespread post-operative sequelae are expected after surgical removal of impacted lower third molars. CONCLUSIONS: We conclude that methylprednisolone affords better pain relief while serratiopeptidase exerts better anti-inflammatory and anti-swelling effects in the post-operative period. Synergistic combinations of these two drugs would however prove to be more effective when extensive post-operative sequelae are expected. Key words:Methylprednisolone, serratiopeptidase, pain, swelling, trismus, third molar.

Brown tumour of posterior maxilla associated with polydactyly, syndactyly and cardiac anomalies: a unique case report.

Brown tumour [BT] is an uncommon, non neoplastic complication of Hyperparathyroidism [HPT]. Skeletal changes are the main consequences of this endocrine condition. HPT manifest in three categories. Primary HPT is due to hyperfunction of one or more parathyroid gland, causing an increase of parathyroid hormone secretion resulting in hypercalcemia. Secondary HPT occurs due to chronic renal failure, decreased vitamin D production or with hypocalcemia. Tertiary HPT occurs when the parathyroid activity turns autonomous and excessive, leading to hypercalcemia. BT occurs frequently in the mandible than the maxilla. They are more common in women aged over 50y and majority of BT are asymptomatic. Radiographically, it appears as well defined radioluceny. The gross specimen usually shows a brown or reddish-brown colour. We report a relatively rare combination of maxillary posterior BT as a clinical manifestation of secondary HPT due to vitamin D deficiency with polydactyly, syndactyly and cardiac anomalies.

Synthesis and anticancer evaluation of furfurylidene 4-piperidone analogs.

Recently different series of compounds have been designed that utilize the 1,5-diaryl-3-oxo-1,4-pentadinenyl pharmacophore for the development of novel cytotoxic and anticancer agents. These compounds interact with cellular thiols and thiols are not part of nucleic acids. Hence, these compounds are free from the problem of mutagenicity and carcinogenicity. The Claisen-Schmidt reaction is used for synthesizing furfurylidene analogs in a basic medium. The title compounds were prepared by reacting furfurylidenes with aryl sulfonyl, benzoyl, acroylyl, or acetyl chloride. The resulting synthesized compounds were screened for their in vitro cytotoxic properties by MTT and SRB assays against leukemic and colon cancer cell lines. Acute toxicity was determined by OECD-423 guidelines. The in vivo anticancer activities were evaluated against Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. The MTT assay showed that compounds 2d and 3d have significant cytotoxicity against the Molt-4 human cell line as compared to the standard, 5-fluorouracil. In addition, the SRB assay indicated that the compounds 2, 2a, 2d, and 3d showed equipotent cytotoxicity against human leukemia cell lines as compared to the standard, doxorubicin. Compounds 2a and 2d showed significant anticancer activity against EAC in Swiss albino mice. This study revealed the potential of these molecules for further development as anticancer agents.

Acute respiratory distress during paradoxical reaction to antituberculous therapy in an 8-month-old child.

Paradoxical reaction during antituberculosis treatment (ATT) is commonly seen as tuberculous lymphadenitis of peripheral lymph node, cerebral tuberculomas, pulmonary infiltrates, and pleural disease. This phenomenon is more commonly associated with extrapulmonary tuberculosis and disseminated tuberculosis. Respiratory distress, as presentation of paradoxical reaction, is rare. We report an 8-month-old child with primary progressive tuberculosis without mediastinal adenopathy, who developed paradoxical reaction with extensive mediastinal adenopathy within 15 days of ATT and presented with severe respiratory distress. The child responded to short course of high-dose steroids.

Oral immunization with a live coxsackievirus/HIV recombinant induces gag p24-specific T cell responses.

BACKGROUND: The development of an HIV/AIDS vaccine has proven to be elusive. Because human vaccine trials have not yet demonstrated efficacy, new vaccine strategies are needed for the HIV vaccine pipeline. We have been developing a new HIV vaccine platform using a live enterovirus, coxsackievirus B4 (CVB4) vector. Enteroviruses are ideal candidates for development as a vaccine vector for oral delivery, because these viruses normally enter the body via the oral route and survive the acidic environment of the stomach. METHODOLOGY/PRINCIPAL FINDINGS: We constructed a live coxsackievirus B4 recombinant, CVB4/p24(73(3)), that expresses seventy-three amino acids of the gag p24 sequence (HXB2) and assessed T cell responses after immunization of mice. The CVB4 recombinant was physically stable, replication-competent, and genetically stable. Oral or intraperitoneal immunization with the recombinant resulted in strong systemic gag p24-specific T cell responses as determined by the IFN-gamma ELISPOT assay and by multiparameter flow cytometry. Oral immunization with CVB4/p24(73(3)) resulted in a short-lived, localized infection of the gut without systemic spread. Because coxsackieviruses are ubiquitous in the human population, we also evaluated whether the recombinant was able to induce gag p24-specific T cell responses in mice pre-immunized with the CVB4 vector. We showed that oral immunization with CVB4/p24(73(3)) induced gag p24-specific immune responses in vector-immune mice. CONCLUSIONS/SIGNIFICANCE: The CVB4/p24(73(3)) recombinant retained the physical and biological characteristics of the parental CVB4 vector. Oral immunization with the CVB4 recombinant was safe and resulted in the induction of systemic HIV-specific T cell responses. Furthermore, pre-existing vector immunity did not preclude the development of gag p24-specific T cell responses. As the search continues for new vaccine strategies, the present study suggests that live CVB4/HIV recombinants are potential new vaccine candidates for HIV.