A unique case of rectal cancer with coexistence of multiple pathways of carcinogenesis.

BACKGROUND: Colorectal cancer with a global incidence of 10% has multiple pathways implicated in its carcinogenesis. WNT signaling is the principal underlying pathway via APC gene, while defective mismatch repair genes and epigenetic changes also are known to contribute. CASE PRESENTATION: Here, we present an unusual case of rectal adenocarcinoma in a woman, with germline MSH6 and PMS1 mutations, and simultaneous somatic APC and TP53 mutations treated with surgery and adjuvant capecitabine. CONCLUSIONS: The case is unique suggesting a possible interaction between the two pathways and contributing to carcinogenesis in this patient. This also suggests need for a thorough germline and somatic mutation evaluation in select colorectal cancer patients to direct a tailored therapy.

Initial comparative analysis of pulmonary involvement on HRCT between vaccinated and non-vaccinated subjects of COVID-19.

OBJECTIVES: To compare the high-resolution computed tomography (HRCT)-derived severity score in COVID-19 patients between those who had earlier received the vaccine against the SARS-CoV-2 and those who did not. METHODS: A retrospective cross-sectional analysis of HRCT of the chest was done in correlation with the vaccination status of clinically diagnosed COVID-19 patients. The variable under evaluation was the CT severity score, whereby differential analysis of the variability on this parameter between incompletely (single dose) vaccinated, completely (both doses) vaccinated, and non-vaccinated individuals was the outcome. RESULTS: The analysis included 826 patients of which 581 did not receive any vaccination whereas 196 patients received incomplete (single dose) vaccination and 49 received complete vaccination. Mean CT severity score was lower in completely vaccinated patients (3.5 ± 6.3) vis-à-vis incompletely vaccinated (10.1 ± 10.5) and non-vaccinated (10.1 ± 11.4) individuals. The mean CT score was significantly lower in completely vaccinated patients of lower ages (≤ 60 years) compared to patients above that age. The incidence of severe disease (CT score ≥ 20) was significantly higher in the incompletely vaccinated and non-vaccinated patients compared to that in the completely vaccinated group. CONCLUSIONS: CT severity scores in individuals receiving both doses of SARS-CoV-2 vaccination were less severe in comparison to those receiving a single dose of vaccine or no vaccine at all. KEY POINTS: • Patients who received complete two doses of vaccination had significantly low mean CT scores compared to the partially vaccinated patients and non-vaccinated patients. • The mean CT scores were significantly lower in completely vaccinated patients of lower ages (< 60 years) while patients > 60 years did not show significantly different CT scores between the vaccinated and non-vaccinated groups. • Consolidations and ground-glass opacities were significantly lower in the group receiving complete vaccination as compared to the unvaccinated and incompletely vaccinated patients.

Installation of Pargyline, a LSD1 Inhibitor, in the HDAC Inhibitory Template Culminated in the Identification of a Tractable Antiprostate Cancer Agent.

Pragmatic insertion of pargyline, a LSD1 inhibitor, as a surface recognition part in the HDAC inhibitory pharmacophore was planned in pursuit of furnishing potent antiprostate cancer agents. Resultantly, compound 14 elicited magnificent cell growth inhibitory effects against the PC-3 and DU-145 cell lines and led to remarkable suppression of tumor growth in human prostate PC-3 and DU-145 xenograft nude mouse models. The outcome of the enzymatic assays ascertained that the substantial antiproliferative effects of compound 14 were mediated through HDAC6 isoform inhibition as well as selective MAO-A and LSD1 inhibition. Moreover, the signatory feature of LSD1 inhibition by 14 in the context of H3K4ME2 accumulation was clearly evident from the results of western blot analysis. Gratifyingly, hydroxamic acid 14 demonstrates good human hepatocytic stability and good oral bioavailability in rats and exhibits enough promise to emerge as a therapeutic for the treatment of prostate cancer in the near future.

Isoindoline scaffold-based dual inhibitors of HDAC6 and HSP90 suppressing the growth of lung cancer in vitro and in vivo.

This study reports the synthesis of a series of 2-aroylisoindoline hydroxamic acids employing N-benzyl, long alkyl chain and acrylamide units as diverse linkers. In-vitro studies led to the identification of N-benzyl linker-bearing compound (10) and long chain linker-containing compound (17) as dual selective HDAC6/HSP90 inhibitors. Compound 17 displays potent inhibition of HDAC6 isoform (IC50 = 4.3 nM) and HSP90a inhibition (IC50 = 46.8 nM) along with substantial cell growth inhibitory effects with GI50 = 0.76 µM (lung A549) and GI50 = 0.52 µM (lung EGFR resistant H1975). Compound 10 displays potent antiproliferative activity against lung A549 (GI50 = 0.37 µM) and lung H1975 cell lines (GI50 = 0.13 µM) mediated through selective HDAC6 inhibition (IC50 = 33.3 nM) and HSP90 inhibition (IC50 = 66 nM). In addition, compound 17 also modulated the expression of signatory biomarkers associated with HDAC6 and HSP90 inhibition. In the in vivo efficacy evaluation in human H1975 xenografts, 17 induced slightly remarkable suppression of tumor growth both in monotherapy as well as the combination therapy with afatinib (20 mg/kg). Moreover, compound 17 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner suggesting that dual inhibition of HDAC6 and HSP90 can modulate immunosuppressive ability of tumor area.

Steering the antitumor drug discovery campaign towards structurally diverse indolines.

Indoline framework is often perpended as a privileged heterocycle present in medicinally valuable compounds of natural and synthetic origin. This review article presents the rational approaches/strategies employed for the design of anticancer indolines along with the structure activity relationship and mechanistic insights revealed in the in-vitro and in-vivo assays. The chemist has always been fascinated towards the indoline ring for the construction of antitumor scaffolds owing to its versatility as evidenced by its existence in scaffolds inducing antiproliferative effects via diverse mechanisms. To the delight of medicinal chemist, the applicability of indoline has also been expanded towards the design of dual inhibitors (multitargeting anticancer agents) as well as PROTACS. Overall, it can be concluded that indoline moiety is a magic bullet and the scaffolds containing this ring are foraying towards detailed preclinical and clinical stage investigations by leaps and bounds.

1-Arylsulfonyl indoline-benzamides as a new antitubulin agents, with inhibition of histone deacetylase.

We report structure-activity relationships of 1-arylsulfonyl indoline based benzamides. The benzamide (9) exhibits striking tubulin inhibition with an IC50 value of 1.1 µM, better than that of combretastain A-4 (3), and substantial antiproliferative activity against a variety of cancer cells, including MDR-positive cell lines with an IC50 value of 49 nM (KB), 79 nM (A549), 63 nM (MKN45), 64 nM (KB-VIN10), 43 nM (KB-S15), and 46 nM (KB-7D). Dual inhibitory potential of compound 9 was found as it demonstrated significant inhibitory potential against HDAC1, 2 and 6 in comparison to MS-275 (6). Some key interactions of 9 with the amino acid residues of the active site of tubulin and with amino acid residues of HDAC 1 isoform have been figured out by molecular modeling. Compound 9 also demonstrated significant in vivo efficacy in the human non-small cell lung cancer A549 xenograft model as well as B-cell lymphoma BJAB xenograft tumor model.

1-Aroylindoline-hydroxamic acids as anticancer agents, inhibitors of HSP90 and HDAC.

A series of 1-aroylindoline-hydroxamic acids have been synthesized in the present study. The results of the biological evaluation led to the identification of compound 12 as dual HDAC6/HSP90 inhibitor. Compound 12 displayed striking inhibitory effects towards the HDAC6 isoform and HSP 90 protein with IC50 values of 1.15 nM (HDAC6) and 46.3 nM (HSP90). Compound 12 also exhibited 113, 139 and 246 fold higher selectivity for HDAC6 over HDAC 1, HDAC 3 and HDAC 8 isoforms and was endowed with significant cytotoxic effects with GI50 values ranging 1.04-1.61 µM against lung A549, colorectal HCT116, leukemia HL60, and EGFR T790M mutant lung H1975 cell lines. Another interesting finding of the study was substantial cytotoxic effects of compounds particularly against lung H1975 (NSCLC) cell lines with IC50 = 0.26 µM which may be mediated through HSP90 inhibition. Compound 8 as such was devoid of HDAC inhibitory activity.

Invasive placental disorders: a prospective US and MRI comparative analysis.

BACKGROUND: Invasive placental disorders are potentially life-threatening. Its diagnosis and evaluation of degree of invasiveness is vital in surgical and treatment planning. PURPOSE: To compare the role of various imaging modalities used in current practice for evaluation of invasive placental disorders, and evaluate the validity of certain imaging signs for prediction of invasive placenta. MATERIAL AND METHODS: Twenty-two patients, which were clinically stratified as a risk group for underlying invasive placental abnormality, underwent Doppler sonography and magnetic resonance imaging (MRI). Abnormal placental invasiveness was assessed using various Doppler sonography and MRI signs described in the existing literature. We systematically evaluated the utility of each of these modalities and signs, and compared the roles played by them separately and in combination. All the cases were correlated with surgical and pathological findings. RESULTS: Nine patients had surgical and pathological confirmation of placental adhesive disorders, of which eight were predicted correctly by MRI (true positive) while one was misdiagnosed as normal placenta (false negative). All the nine cases were correctly identified by Doppler sonography. MRI was more accurate in predicting bladder invasion, identifying 5/6 cases. CONCLUSION: Both MRI and Doppler sonography are useful for detection of invasive placental disorders. However, MRI is a better predictor of bladder invasion.

Ring-opened tetrahydro-γ-carbolines display cytotoxicity and selectivity with histone deacetylase isoforms.

This study is focused on modification of the indole moiety and the N1-zinc binding domain of tubastatin A, and the effects of such changes on biological activity. Fourteen N-substituted indoles (5-18) were synthesized and structure-activity relationship studies indicated that the change of the tetrahydro-γ-carboline in tubastatin A led to substituted indoles (compounds 7, 11, and 15) which showed significant improvements of selective inhibition for HDAC6 over HDAC1 and HDAC2 in comparison to ACY1215, a compound undergoing clinical trials. In addition, attachment of different hydroxamic acid groups, the zinc binding motif at the N1 position, contributes to the antiproliferative activity in cancer cells. Several synthetic compounds exhibited potent growth inhibition in a broad spectrum of tumor cell lines, induced irreversible growth arrest capacities by suppressing colony formation ability and activated the apoptosis pathway. The data provide compelling evidence that our newly synthesized compounds with type B to D hydroxamic acid groups as the zinc binding motif at the N1 position are potent selective inhibitors of HDAC6 and could be investigated preclinically as potential anticancer drugs.

An updated patent review: xanthine oxidase inhibitors for the treatment of hyperuricemia and gout (2011-2015).

INTRODUCTION: Xanthine oxidase (XO) is a versatile molybdoflavoprotein, widely distributed, occurring in milk, kidney, lung, heart, and vascular endothelium. Catalysis by XO to produce uric acid and reactive oxygen species leads to many diseases. Anti hyperuricemic therapy by xanthine oxidase inhibitors has been mainly employed for the treatment of gout. Area covered: This review covers the patent literature (2011-2015) and also presents the interesting strategies/rational approaches employed for the design of xanthine oxidase inhibitors reported recently. Expert opinion: Recent literature indicates that various non purine scaffolds have been extensively investigated for xanthine oxidase inhibition. The significant potential endowed by heteroaryl based compounds, in particularly fused heterocycles clearly highlights their clinical promise and the need for detailed investigation. Studies by various research groups have also revealed that the flavone framework is open for isosteric replacements and structural modifications for yielding potent non purine xanthine oxidase inhibitors. In addition, various plant extracts recently reported to possess significant xanthine oxidase inhibitory potential presents enough promise to initiate a screening program for the identification of other plant extracts and phytoconstituents possessing inhibitory potential towards the enzyme.

Magnetic resonance neurographic confirmation of extensive Plexiform neurofibroma in neurofibromatosis-1 presenting as ambiguous genitalia.

Genitourinary involvement of neurofibromatosis is uncommon and genital neurofibromatosis is even rarer. Involvement of clitoris by neurofibroma can lead to clitoromegaly masquerading as a male penis. We report such a case of ambiguous genitalia in a 7-year-old female child presenting with clitoromegaly since birth, in which magnetic resonance imaging (MRI) revealed the presence of extensive neurofibromatosis in the clitoris and lumbosacral regions. We emphasize the central role of MRI in evaluation of hormonal and non-hormonal causes of ambiguous genitalia. We further discuss the merits of including MR neurography in the imaging protocol for comprehensive delineation of neurofibromatosis.

Magnetic resonance spectroscopy - Revisiting the biochemical and molecular milieu of brain tumors.

BACKGROUND: Magnetic resonance spectroscopy (MRS) is an established tool for in-vivo evaluation of the biochemical basis of human diseases. On one hand, such lucid depiction of 'live biochemistry' helps one to decipher the true nature of the pathology while on the other hand one can track the response to therapy at sub-cellular level. Brain tumors have been an area of continuous interrogation and instigation for mankind. Evaluation of these lesions by MRS plays a crucial role in the two aspects of disease management described above. SCOPE OF REVIEW: Presented is an overview of the window provided by MRS into the biochemical aspects of brain tumors. We systematically visit each metabolite deciphered by MRS and discuss the role of deconvoluting the biochemical aspects of pathologies (here in context of brain tumors) in the disease management cycle. We further try to unify a radiologist's perspective of disease with that of a biochemist to prove the point that preclinical work is the mother of the treatment we provide at bedside as clinicians. Furthermore, an integrated approach by various scientific experts help resolve a query encountered in everyday practice. MAJOR CONCLUSIONS: MR spectroscopy is an integral tool for evaluation and systematic follow-up of brain tumors. A deeper understanding of this technology by a biochemist would help in a swift and more logical development of the technique while a close collaboration with radiologist would enable definitive application of the same. GENERAL SIGNIFICANCE: The review aims at inciting closer ties between the two specialists enabling a deeper understanding of this valuable technology.

Early investigational tubulin inhibitors as novel cancer therapeutics.

INTRODUCTION: Microtubules represent one of the most logical and strategic molecular targets amongst the current targets for chemotherapy, alongside DNA. In the past decade, tubulin inhibitors as cancer therapeutics have been an area of focus due to the improved understanding and biological relevance of microtubules in cellular functions. Fueled by the objective of developing novel chemotherapeutics and with the aim of establishing the benefits of tubulin inhibition, several clinical trials have been conducted with others ongoing. AREA COVERED: At present, the antitubulin development pipeline contains an armful of agents under clinical investigation. This review focuses on novel tubulin inhibitors as cancer therapeutics. The article covers the agents which have completed the phase II studies along with the agents demonstrating promising results in phase I studies. EXPERT OPINION: Countless clinical trials evaluating the efficacy, safety and pharmacokinetics of novel tubulin inhibitors highlights the scientific efforts being paid to establish their candidature as cancer therapeutics. Colchicine binding site inhibitors as vascular disrupting agents (VDAs) and new taxanes appear to be the most likely agents for future clinical interest. Numerous agents have demonstrated clinical benefits in terms of efficacy and survival in phase I and II studies. However conclusive benefits can only be ascertained on the basis of phase III studies.

A survey on oral hygiene methods practiced by patients attending Dentistry Department at a Tertiary Care Hospital from Central Gujarat.

OBJECTIVE: Oral hygiene is important not only for maintaining health of teeth and gingivae in an individual but also for good and uneventful regeneration and healing of tissues, when one has undergone one or other dental treatments. This makes it important to have an understanding of oral hygiene practices employed by the population. MATERIALS AND METHODOLOGY: This descriptive cross-sectional hospital-based survey was carried out to know oral hygiene methods practiced by patients who visited Department of Dentistry at a Tertiary Care Hospital attached to medical college from Central Gujarat. While examining and recording their history, their mode of oral hygiene practice was also noted. Recorded data were entered in Microsoft Excel and analyzed in SPSS Statistics Version 17.0. The study reports proportions of the variables under study in percentages. RESULTS: The patients ranged from 4 to 80 years in age with equal numbers from both genders. The number of participants using modern and scientific material and instrument for oral hygiene was good. However, majority of them performed it only once a day, and none after every meal or at bed time. CONCLUSION: There is a need to improve the frequency of oral hygiene procedure among the studied population as well as use of dental floss needs to be increased.

Design strategies, structure activity relationship and mechanistic insights for purines as kinase inhibitors.

Kinases control a diverse set of cellular processes comprising of reversible phosphorylation of proteins. Protein kinases play a pivotal role in human tumor cell proliferation, migration and survival of neoplasia. In the recent past, purine based molecules have emerged as significantly potent kinase inhibitors. In view of their promising potential for the inhibition of kinases, this review article focuses on purines which have progressed as kinase inhibitors during the last five years. A detailed account of the design strategies employed for the synthesis of purine analogs exerting inhibitory effects on diverse kinases has been presented. Apart from presenting the design strategies, the article also highlights the structure activity relationship along with mechanistic insights revealed during the biological evaluation of the purine analogs for kinase inhibition. The interactions with the amino acid residues responsible for kinase inhibitory potential of purine based molecules have also been discussed. In this assemblage, purine based protein kinase inhibitors patented in the past have also been summarized in the tabular form. This compilation will be of great interest for the researchers working in the area of protein kinase inhibitors.

Congenital facial nerve aplasia: MR depiction of a rare anomaly.

We report two infants presenting with unilateral congenital facial palsy since birth. Magnetic resonance imaging (MRI) in both the cases revealed complete unilateral aplasia of facial nerve. To our knowledge, this is the first reported MR depiction of nonsyndromic isolated facial nerve aplasia. Imaging features and the pertinent anatomy is discussed along with a brief review of literature.

Synthesis and evaluation of naphthoflavones as a new class of non purine xanthine oxidase inhibitors.

In view of reported xanthine oxidase inhibitory potential of naphthopyrans and flavones, naphthoflavones as hybrids of the two were designed, synthesized and evaluated for in vitro xanthine oxidase inhibitory activity in the present study. The results of the assay revealed that the naphthoflavones possess promising inhibitory potential against the enzyme with IC50 values ranging from 0.62 to 41.2 µM. Structure activity relationship indicated that the nature and placement of substituents on the phenyl ring at 2nd position remarkably influences the inhibitory activity. Substitution of halo and nitro groups at ortho and para position of the phenyl ring (2nd position) remarkably favored the activity. NF-4 with p-fluoro phenyl ring was the most potent inhibitor with IC50 value of 0.62 µM. Enzyme kinetics study was also performed to investigate the inhibition mechanism and it was found that the naphthoflavones displayed mixed type inhibition. The basis of significant inhibition of xanthine oxidase by NF-4 was rationalized by molecular modeling studies.

4,6-Diaryl/heteroarylpyrimidin-2(1H)-ones as a new class of xanthine oxidase inhibitors.

A series of 4,6-diaryl/heteroarylpyrimidones was synthesized employing silica-supported fluoroboric acid under solvent-free conditions in a microwave reactor. The catalytic influence of HBF4-SiO2 was investigated in detail to optimize the reaction conditions. The synthesized compounds were evaluated for in vitro xanthine oxidase (XO) inhibitory activity for the first time. Structure-activity relationship analyses are also presented. Among the synthesized compounds, VA-5, -9, -10, -12, -22, -23, and -25 were the active inhibitors with IC50 values ranging from 6.45 to 13.46 µM. Compound VA-25 with a pyridinyl ring as ring A and a thiophenyl ring as ring B emerged as the most potent XO inhibitor (IC50 = 6.45 µM) in comparison to allopurinol (IC50 = 12.24 µM). Some of the important interactions of VA-25 with the amino acid residues of the active site of XO were figured out by molecular modeling studies.

Microwave assisted synthesis of naphthopyrans catalysed by silica supported fluoroboric acid as a new class of non purine xanthine oxidase inhibitors.

A series of naphthopyrans was synthesized employing silica supported fluoroboric acid under solvent free conditions in a microwave reactor. The catalytic influence of HBF4-SiO2 was investigated in detail to optimize the reaction conditions. The synthesised compounds were evaluated for in vitro xanthine oxidase inhibitory activity for the first time. Structure-activity relationship analyses have also been presented. Among the synthesised compounds, NP-17, NP-19, NP-20, NP-23, NP-24, NP-25 and NP-26 were the active inhibitors with an IC50 ranging from 4 to 17 µM. Compound NP-19 with a thiophenyl ring at position 1 emerged as the most potent xanthine oxidase inhibitor (IC50=4 µM) in comparison to allopurinol (IC50=11.10 µM) and febuxostat (IC50=0.025 µM). The basis of significant inhibition of xanthine oxidase by NP-19 was rationalized by its molecular docking at MTE binding site of xanthine oxidase.