Impact of COVID-19 on cancer care in India: a cohort study.

BACKGROUND: The COVID-19 pandemic has disrupted health-care systems, leading to concerns about its subsequent impact on non-COVID disease conditions. The diagnosis and management of cancer is time sensitive and is likely to be substantially affected by these disruptions. We aimed to assess the impact of the COVID-19 pandemic on cancer care in India. METHODS: We did an ambidirectional cohort study at 41 cancer centres across India that were members of the National Cancer Grid of India to compare provision of oncology services between March 1 and May 31, 2020, with the same time period in 2019. We collected data on new patient registrations, number of patients visiting outpatient clinics, hospital admissions, day care admissions for chemotherapy, minor and major surgeries, patients accessing radiotherapy, diagnostic tests done (pathology reports, CT scans, MRI scans), and palliative care referrals. We also obtained estimates from participating centres on cancer screening, research, and educational activities (teaching of postgraduate students and trainees). We calculated proportional reductions in the provision of oncology services in 2020, compared with 2019. FINDINGS: Between March 1 and May 31, 2020, the number of new patients registered decreased from 112 270 to 51 760 (54% reduction), patients who had follow-up visits decreased from 634 745 to 340 984 (46% reduction), hospital admissions decreased from 88 801 to 56 885 (36% reduction), outpatient chemotherapy decreased from 173634 to 109 107 (37% reduction), the number of major surgeries decreased from 17 120 to 8677 (49% reduction), minor surgeries from 18 004 to 8630 (52% reduction), patients accessing radiotherapy from 51 142 to 39 365 (23% reduction), pathological diagnostic tests from 398 373 to 246 616 (38% reduction), number of radiological diagnostic tests from 93 449 to 53 560 (43% reduction), and palliative care referrals from 19 474 to 13 890 (29% reduction). These reductions were even more marked between April and May, 2020. Cancer screening was stopped completely or was functioning at less than 25% of usual capacity at more than 70% of centres during these months. Reductions in the provision of oncology services were higher for centres in tier 1 cities (larger cities) than tier 2 and 3 cities (smaller cities). INTERPRETATION: The COVID-19 pandemic has had considerable impact on the delivery of oncology services in India. The long-term impact of cessation of cancer screening and delayed hospital visits on cancer stage migration and outcomes are likely to be substantial. FUNDING: None. TRANSLATION: For the Hindi translation of the abstract see Supplementary Materials section.

Protease-activated receptor-1 impedes prostate and intestinal tumor progression in mice.

Essentials Protease activated receptor-1 (PAR-1) has been proposed to drive cancer progression. Surprisingly, PAR-1 deletion accelerated tumor progression in two distinct experimental settings. PAR-1 deletion was shown to limit the apoptosis of transformed epithelial cells. Thrombin- and activated protein C-mediated PAR-1 activation have unique effects on tumor cell biology. SUMMARY: Background Multiple studies have implicated protease-activated receptor-1 (PAR-1), a G-protein-coupled receptor activated by proteolytic cleavage of its N-terminus, as one target coupling thrombin-mediated proteolysis to tumor progression. Objective To analyze the role of PAR-1 in the setting of two distinct spontaneously developing tumor models in mice. Methods We interbred PAR-1-deficient mice with Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, which spontaneously develop prostate tumors, and adenomatous polyposis coli Min (APCMin/+ ) mice, which spontaneously develop intestinal adenomas. Results Analyses of TRAMP mice with advanced disease (30 weeks) revealed that PAR-1 deficiency resulted in significantly larger and more aggressive prostate tumors. Prostates collected at an earlier time point (12 weeks of age) revealed that PAR-1 promotes apoptosis in transformed epithelia. In vitro analyses of TRAMP-derived cells revealed that activated protein C-mediated PAR-1 cleavage can induce tumor cell apoptosis, suggesting that tumor cell-intrinsic PAR-1 functions can limit tumor progression. Paralleling results in TRAMP mice, PAR-1-deficient APCMin/+ mice developed three-fold more adenomas than PAR-1-expressing mice, and the adenomas that formed were significantly larger. Moreover, loss of PAR-1 expression was shown to limit apoptosis in transformed intestinal epithelial cells. Conclusions Together, these results demonstrate a previously unrecognized role for PAR-1 in impeding tumor progression in vivo. These results also offer a cautionary note suggesting that long-term PAR-1 inhibition could increase malignancy risk in some contexts.

Analgesic opioid use in a health-insured epilepsy population during 2012.

RATIONALE: Analgesic opioid use has increased dramatically in the general population. Although opioid analgesics are not indicated for the treatment of epilepsy, frequent opioid use has been reported in the epilepsy population. It is not clear whether comorbid disorders and/or epilepsy-associated injuries due to seizures foster opioid use. Our primary objective was to compare the prevalence of analgesic opioid use in an insured patient population with epilepsy to a matched control population without epilepsy. After observing increased frequency of opioid use in people with epilepsy compared with matched controls, we assessed the contribution of age, gender, pain diagnosis, and psychiatric illness as possible drivers regarding the use of opioids. METHODS: Health insurance claims and membership data from nine United States (U.S.) health plans for the year 2012 were analyzed. Individuals with epilepsy (n=10,271) were match-paired at a 1:2 ratio to individuals without epilepsy (n=20,542) within each health plan using propensity scores derived from age group, gender, and insurance type. Matched comparison groups had 53% females and 47% males with an average age of 34 years for the group with epilepsy and 33 years for controls. Each matched comparison group included 66% of individuals with commercial insurance, 30% with Medicaid insurance, and 4% with Medicare coverage. Based on prescriptions filled at least once during 2012, prevalence of analgesic opioid use was determined. The percentages of individuals with diagnosis for specific pain conditions and those with psychiatric diagnoses were also determined for the two comparison groups. RESULTS: Analgesic opioids were used by 26% of individuals in the group with epilepsy vs. 18% of matched controls (p<0.001). Compared with matched controls, the group with epilepsy had a significantly higher percentage of individuals with all 16 pain conditions examined: joint pain or stiffness (16% vs. 11%), abdominal pain (14% vs. 9%), headache (14% vs. 5%), pain in limb (12% vs. 7%), chest pain (11% vs. 6%), sprain of different parts (9% vs. 7%), sinusitis (9% vs. 7%), migraine (8% vs. 2%), lumbago (8% vs. 6%), backache (6% vs. 4%), cervicalgia (6% vs. 3%), fracture (5% vs. 3%), fibromyalgia (4% vs. 3%), chronic pain (3% vs. 1%), sciatica (1.4% vs. 1%), and jaw pain (0.4% vs. 0.1%) (all p<0.001). The prevalence of pain diagnosis was 51% in the group with epilepsy and 39% in the matched control group (p<0.0001). The prevalence of 'psychiatric diagnoses' was 27% in the group with epilepsy and 12% in the matched control group (p<0.0001). CONCLUSION: The prevalences of analgesic opioid use, psychiatric diagnoses, and 16 pain conditions were significantly higher in the patient population with epilepsy than in the control population without epilepsy. Our study also showed how opioid use rate varied by gender, age category, and depression. The reasons for the greater prevalence of opioid use in people with epilepsy are unclear. It seems that increased pain prevalence is an important driver for the higher frequency of opioid use in people with epilepsy. Psychiatric illness and other factors also appear to contribute. Further analysis including more detailed clinical information that cannot be obtained through claims data alone will be required to provide more insight into opioid use in people with epilepsy. If opioid use is higher in people with epilepsy as our results suggest, physicians managing patients with epilepsy need to pay special attention to safe opioid prescribing habits in order to prevent adverse outcomes such as abuse, addiction, diversion, misuse, and overdose.

Vascular endothelial growth factor: Evidence for autocrine signaling in hepatocellular carcinoma cell lines affecting invasion.

BACKGROUND AND AIM: Vascular endothelial growth factor (VEGF) is a well-known pivotal regulator of tumor angiogenesis. Apart from endothelial cells, it is also expressed in nonendothelial cells, including tumor cells themselves. Hence the aim of this study was to investigate the autocrine effects of VEGF in hepatocellular carcinoma (HCC) -derived cell lines. MATERIALS AND METHODS: Two hepatocellular carcinoma cell lines (Hep3B and HepG2) were screened for expression of VEGF by quantitative real-time polymerase chain reaction (PCR) and its receptors VEGF-R1, VEGF-R2, and neuropilin-1 expression by reverse transcriptase-PCR, respectively. Furthermore, VEGF transcript was silenced by siRNA and the effects on cell migration, viability, and proliferation were determined by the wound healing assay, MTT assay, and propidium iodide staining, respectively. RESULTS: Both Hep3B and HepG2 cell lines expressed VEGF and all the three receptors at high levels. VEGF siRNA inhibited VEGF expression significantly in both Hep3B and HepG2 cell lines. Silencing of VEGF showed decreased migration in the Hep3B cell line. In both cell lines tested, there was decreased cell viability but no effect on cellular proliferation. CONCLUSION: Our data indicates that autocrine signaling of VEGF through its receptors exists in HCC cell lines, which has important implications for tumor invasion, metastasis, and for designing interventional strategies.

Melanoma vaccines, revisited: a review, update.

Melanoma vaccines are usually administered after surgical resection of the tumor with the hope of eradicating the micrometastases, in high-risk patients. As we previously reported, most of the melanoma vaccines failed to show any major impact on the disease, except for the autologous whole cell vaccine. This can be explained by the heterogeneous nature of cutaneous melanoma that expresses various levels of melanoma antigens, peptides and has various genetic profiles among different patients. From an immunological point of view, it is illogic to eliminate the tumor and its specific antigens then apply allogenic type of therapy and expect a tumor response. Therefore, it is more logical is to utilize the tumor site as a source for the tumor-specific antigens. In the meantime, patients with in-transit metastases can give us an excellent opportunity to evaluate the local and systemic effects of intralesional (intratumoral) therapy, and various agents have been utilized with equivocal results. On the other hand, intralesional administration of 2 cytokines seemed to process the tumor antigens and activates thymic-derived lymphocytes (T cells). This can induce an antitumor immune response in vivo, i.e., autoimmunization (auto-vaccination), specific to each patient, and overcome tumor heterogeneity regardless to its antigenic or genetic profiles.

Common comorbidities in women and men with epilepsy and the relationship between number of comorbidities and health plan paid costs in 2010.

The objectives of this observational study were to determine the prevalence of the most common comorbidities in women and men with epilepsy and to demonstrate the relationship of these comorbidities to health plan paid costs. Data for 6621 members with epilepsy (52% women, 48% men) from eight commercial health plans were analyzed. The presence of comorbidities in people with epilepsy was identified by searching health insurance claims for 29 prespecified comorbidity-specific diagnosis codes. More women (50%) than men (43%) with epilepsy had one or more of the 29 comorbidities (p<0.05). The top 10 comorbidities for women and their relative prevalences were psychiatric diagnosis (16%), hypertension (12%), asthma (11%), hyperlipidemia (11%), headache (7%), diabetes (6%), urinary tract infection (5%), hypothyroidism (5%), anemia (5%), and migraine (4%). For men, the top 10 comorbidities and their relative prevalences were psychiatric diagnosis (15%), hyperlipidemia (12%), hypertension (12%), asthma (8%), diabetes (5%), headache (4%), cancer (4%), coronary artery disease (3%), anemia (3%), and gastroesophageal reflux disease (3%). Seven of the top 10 comorbidities were common to both women and men. Psychiatric diagnosis was the only comorbidity among the top five comorbidities for all age groups. The presence of one comorbidity approximately tripled the health-care cost for that member compared with the cost for members who had no comorbidities. Additional comorbidities generally further increased costs. The increase in health-care cost per member per month ($) with increase in number of comorbidities was greater for men than for women (p<0.05).

Anterior neck lipoma with anterior mediastinal extention - a rare case report.

Lipomas are the most common benign mesenchymal tumour. Thirteen percent of lipomas are seen in head and neck region. Anterior neck lipoma is a rare one. Anterior neck lipoma with mediastinal extension is extremely rare. We are presenting a case of 52 years old male reported to Central Referral Hospital, Sikkim Manipal Institute of Medical Sciences, Gangtok, Sikkim with complains of swelling in left side of neck for last 18 months along with occasional history of dyspnoea. Physical examination, ultrasound, computed tomography and fine needle aspiration cytology are in favor of lipoma. Due to its location up to the anterior mediastinum, the surgery could not be done in this hospital and patient was referred to higher center having cardiothoracic surgical back up.

Demographic and clinical profile of oral squamous cell carcinoma patients: a retrospective study.

BACKGROUND: Oral cancers are one of the ten leading cancers in the world. However, in India, it is one of the most common cancer and constitutes a major public health problem. AIM: The purpose of this study was to evaluate, retrospectively, the epidemiologic profile of patients with oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: OSCC cases were retrospectively analyzed from January 2008 to September 2010 for age, gender, occupation, duration of the symptoms, habits (tobacco and alcohol consumption), site of primary tumor, and TNM staging, and the findings were formulated to chart the trends in central India population. RESULTS: Male to female ratio was 4.18:1. Mean age was 49.73 years. The most common site of presentation of tumor was in mandibular alveolus region. Tobacco chewing was the major cause for the development of OSCC. Maximum number of patients, i.e., 201 (68.14%) were presented within 6 months of onset of symptoms. Majority of patients were presented in Stage III (82.37%). Correlation between the two variables, i.e., site to habits, staging to site involved, staging to duration of the disease, staging to habits, and staging to age of the patient, were found to be statistically nonsignificant (P>0.05). CONCLUSIONS: The aim of the study was the demographic description of oral squamous cell carcinoma. Most of the cases report at advanced stages of the disease which often leads to delay in the management coupled with the fact that health care centers are burdened with long waiting lists. Strategies to overcome the present situation must be undertaken by oral health programs for the early diagnosis and prevention and management and follow up of oral cancer.

Large gastric lipoma.

Gastric lipoma is a rare benign tumor and seen in five percent of gastro-intestinal lipomas and accounts for less than one percent of all gastric tumors. Gastric lipomas are located submucosally and usually in antral region of Stomach. Computed tomography is considered as valuable tool in the diagnosis of gastrointestinal lipomas. Due to their relative rarity, gastric lipomas are often left out of the differential diagnosis for upper gastro-intestinal submucosal masses. We report a case of 70 year female that presented with upper abdominal pain since last two years. Abdominal Computed tomography revealed a large gastric lipoma in antral region. Patient refused for any surgical intervention due to old age. Patient was provided symptomatic treatment and was under regular followup.

Effect of ether- and water-soluble fractions of Carica papaya ethanol extract in experimentally induced hyperlipidemia in rats.

CONTEXT: The papaya is the fruit of the plant Carica papaya L. (Caricaceae) used in India. Fruit and latex are both rich in an enzyme called papain. It is used as a folk remedy for contraception and abortion. OBJECTIVE: The present study explored the anti-hyperlipidemic effect of the ether- and water-soluble fractions of C. papaya ethanol extract in olive oil-induced hyperlipidemic rats. The study also involved chromatographic studies of extract and fractions. MATERIALS AND METHODS: Flash chromatography was done for the most active fraction. The extract and fractions were administered orally at doses of 200 and 400 mg/kg body weight in rats. Olive oil (5 mL/kg oral dose) was administered 30 min after treatment. Blood was collected and centrifuged at 3000 rpm for 15-20 min and subjected to biochemical analysis. RESULT: The study dose-dependently inhibited the total cholesterol (TC), triglycerides (TG), low-density lipoproteins (LDL) level, and significantly increased high-density lipoprotein (HDL) level. Phytochemical screening revealed the presence of fats in the ether fraction, whereas the water fraction revealed the presence of tannins, alkaloids, glycosides. UV λ(max) was found to be 217 nm with a melting point of 41°C for the isolated component. DISCUSSION AND CONCLUSION: The anti-hyperlipidemic effect was evaluated in olive oil-loaded rats. Acute treatment caused stimulatory effect on HDL level and inhibition in TC and TG elevation induced by olive oil. The extract and water fraction showed protective action by increasing the HDL cholesterol level.

Chemical properties of biocrude oil from the hydrothermal liquefaction of Spirulina algae, swine manure, and digested anaerobic sludge.

This study explores the influence of wastewater feedstock composition on hydrothermal liquefaction (HTL) biocrude oil properties and physico-chemical characteristics. Spirulina algae, swine manure, and digested sludge were converted under HTL conditions (300°C, 10-12 MPa, and 30 min reaction time). Biocrude yields ranged from 9.4% (digested sludge) to 32.6% (Spirulina). Although similar higher heating values (32.0-34.7 MJ/kg) were estimated for all product oils, more detailed characterization revealed significant differences in biocrude chemistry. Feedstock composition influenced the individual compounds identified as well as the biocrude functional group chemistry. Molecular weights tracked with obdurate carbohydrate content and followed the order of Spirulina

Modeling of cyclooxygenase-2 and 5-lipooxygenase inhibitory activity of apoptosis-inducing agents potentially useful in prostate cancer chemotherapy: derivatives of diarylpyrazole.

The structure-activity models of the twenty derivatives for COX-2 and ten derivatives of 1,5-diarylpyrazole for 5-LOX inhibitory activity have been investigated using Combinatorial Protocol in Multiple Linear Regression (CP-MLR) with topological descriptors which were calculated from DRAGON software. Among the descriptor classes considered collectively in the study the COX-2 inhibitory activity was, however, correlated with topological (TOPO) and Galvez topological charge indices (GVZ). Modified Burden eigenvalues (BCUT) and 2D autocorrelations (2DAUTO) classes of descriptors have shown correlation to 5-LOX inhibitory activity. The developed models and participating descriptors in them have suggested that the substitutional modification in the diarylpyrazole moiety may have sufficient scope in optimization of prevailing inhibitory activities of these analogues.

Quantitative structure-activity relationship study on affinity profile of a series of 1,8-naphthyridine antagonists toward bovine adenosine receptors.

The affinity profiles for the bovine adenosine receptors, A(1) and A(2A), of a series of 1,8-naphthyridine derivatives were quantitatively analyzed using physicochemical and structural parameters of the substituents, present at varying positions of the molecules. The derived significant correlation, for bovine A(1) receptor, suggested that a R(1) substituent having a higher van der Waals volume, a R(2) substituent being a hydrogen-bond donor and a R(3) substituent able to transmit a higher field effect are helpful in augmenting the pK(i) of a compound. Similarly the study, pertaining to bovine A(2A) receptor, revealed that a less bulky substituent at R(2) and a strong electron-withdrawing substituent at R(3) are desirable in improving the binding affinity of a compound while substituents at R(1) remain insignificant to any interaction.

Quantitative structure-activity relationship study of ATP-sensitive potassium channel openers: derivatives of 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide.

The inhibitory activity of glucose-induced insulin secretion on isolated rat pancreatic islets and the contractile activity of KCl-depolarized rat aorta rings of the derivatives of 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide are quantitatively analyzed using multiple regression analysis. The study has helped to ascertain the role of different substituents in explaining these observed inhibitory activities. From a derived most significant correlation equation, it was concluded that a less hydrophobic 3-substituent and a less bulky 7-substituent in addition to a 3-aminoisopropyl and a 6-chloro substituent are advantageous to enhance the inhibitory action of a compound towards rat pancreatic islets. On the other hand, the more hydrophobic 6- and 7-substituents augment the contractile activity. The analysis, in this way, provided the grounds for rationalizing the substituent selection in designing the improved potency compounds in the series.

Quantitative structure-activity relationship study of novel rhinacanthins and related naphthoquinone esters as anticancer agents.

The anticancer activity of rhinacanthins and related naphthoquinone esters is quantitatively analyzed through Fujita-Ban and Hansch approaches. The analyses have helped to ascertain the role of different substituents in explaining the observed inhibitory actions of these compounds. From both approaches it appeared that naphthalene ring instead of benzene ring, dimethyl substitution at R(1) and R(2), and hydrogen-bond acceptor substituents at R(3) (Figure 1) are advantageous to improve the activity of a compound against KB cell lines. This in turn leads to the suggestion that the rhinacanthin-N scaffold is the structural entity that needs exploration for new potential compounds. Further, in the Fujita-Ban analysis, it is observed that the compounds bearing a OMe substitution, relative to H, at R(4) have a slight positive contribution to pIC(50) (KB) whereas the substituents H or OMe at R(5), relative to OH, have negative contributions. In conformity with these findings, the Hansch approach revealed that a more hydrophobic group at R(4) and a more hydrophilic group at R(5) positions are beneficial in raising the activity. The two quantitative structure-activity relationship (QSAR) analyses, differing in parametric approach, therefore, provided the grounds for rationalizing the substituent selection to design more potent compounds of the series.

A quantitative structure-activity relationship study of novel, potent, orally active, selective VEGFR-2 and PDGFRalpha tyrosine kinase inhibitors: derivatives of N-phenyl-N'-{4-(4-quinolyloxy)phenyl}urea as antitumor agents.

The tyrosine kinase inhibitory action of the derivatives of N-Phenyl-N'-{4-(4-quinolyloxy)phenyl}urea is quantitatively analyzed using multiple regression analysis. The analysis has helped to ascertain the role of different substituents in explaining the observed inhibitory actions of these compounds for two receptors, namely vascular endothelial growth factor receptor 2 (VEGFR-2) and platelet-derived growth factor receptor alpha (PDGFRalpha). From a derived significant correlation equation for inhibition of VEGFR-2, it was concluded that a less hydrophobic molecule with ortho-substituent(s), exerting less steric hindrance and para-substituent devoid of hydrogen-bond acceptor property augment the inhibition action. Besides, a 3-substituent transmitting a higher negative field effect is advantageous to improve the pIC(50) value of a compound. The correlation equation, derived for the inhibition of PDGFRalpha, has revealed that a less hydrophobic molecule, having a 3-substituent which transmits a more negative resonance effect, is helpful in raising its activity. Likewise, in the middle phenyl ring, absence of a fluoro substituent augments the inhibitory activity. Based on derived QSAR equations pertaining to VEGF-2 and PDGFalpha receptors, the drawn guidelines for selection of substituents, may be used to synthesize potent compounds in future.

Quantitative structure-activity relationship study of human A3 adenosine receptor antagonists: derivatives of 2-aryl-1,2,4-triazolo [4,3-alpha]quinoxaline.

A quantitative structure-activity relationship (QSAR) study was conducted on the antagonistic activities of derivatives of 2-aryl-1,2,4-triazolo[4,3-alpha]quinoxaline at the human A3 adenosine receptor. As per the structural framework, the title analogues were subdivided into two congeneric series, namely the 1,4-dione and the 4-amino-1-one series. A majority of substituents occurred at the R- and a limited number at the X-positions in both of these series. In the case of the 1,4-dione series, the derived significant QSAR equation revealed that those substituents exhibiting a larger field effect at R renders the molecule to more efficiently bind at the receptor site. The study also extrapolated the requirement of electron-donor substituents at the X-position which, at present, is regarded as insensitive to any interaction due to limited substitution. However, the X-position may be explored in a further synthetic study. From the derived correlation equation for the 4-amino-1-one series, it appeared that a strong electron-withdrawing substituent at R will enhance the pK(i) value of a compound while a strong electron-donor at this position will have a detrimental effect on it. Based on correlation equations, derived using different electronic parameters, it may be interpreted that the two series of compounds attain different orientation inside the recognition site of the receptor.

Quantitative structure-activity relationship study of benzylsulfanyl imidazoles as cytokine release inhibitors.

Benzylsulfanyl imidazole derivatives (Figure 1) have shown their ability to inhibit the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) from peripheral blood mononuclear cells or human whole blood. Such anticytokine actions of these congeners are quantitatively studied using Fujita-Ban and Hansch type analyses. The Fujita-Ban study resulted in the contributions of different substituents and the parent moiety for the inhibitions of cytokines TNF-alpha and IL-1beta. The substituents that have a higher positive contribution to the given activity, relative to substituents of the parent moiety at different positions were then used to obtain a trend for the active analogues. None of the substituents present at X, Y, 2-R and 3-R, appears to be advantageous over the substituents of the parent moiety for inhibition of both the cytokines. However, the substituents at 4-R, 5-R and 6-R help to improve the inhibitory actions of the compounds for both cytokines. The optimal activities seem to be manifested by compounds in which 4-R, 5-R and 6-R are substituted respectively by OH (or SOCH3 and SO2CH3), Cl and OH for inhibition of TNF-alpha, whereas by SOCH3 (or SO2CH3 and OH), H and OH for inhibition of IL-1beta. The Hansch type analysis, on the other hand, revealed that the F-substituents of the X-position and a less bulky structural moiety such as--S(CH2)2--at the Y-incision are advantageous in improving the inhibitory action towards TNF-alpha. Similarly, a less bulky/polar substituent present at 2-R and not having a hydrogen-bond donor property, while a more hydrophobic substituent at 3-R and hydrogen-bond acceptor substituent at 4-R are helpful in augmenting inhibitory activity of a compound. However, for inhibition of cytokine IL-1beta, it emerged that the X-substituents that transmits a higher negative resonance effect, the Y-substituent that offers less molecular bulk are beneficial. The R-substituents, being more electron donors at the meta-position, less hydrophobic at the para-position and offering smaller refractivity (less bulky and or polar) at the ortho-position are likewise helpful in improving the activity of a compound.

Aberrant DNA methylation silences the novel heat shock protein H11 in melanoma but not benign melanocytic lesions.

BACKGROUND: The heat shock protein H11 is silenced in melanoma cell lines, where its forced expression by demethylation with Aza-C triggers apoptosis. OBJECTIVE: To examine whether H11 is silenced by aberrant DNA methylation in melanoma as compared to nevi and normal skin tissues. METHODS: Cell suspensions from benign intradermal nevi, atypical nevi and malignant melanoma tissues were used in reverse-transcriptase PCR and methylation-specific PCR. Paraffin-embedded tissues were stained with H11 antibody. RESULTS: H11 is methylated in 60-75% of melanoma and atypical nevi, but not in normal skin or most benign nevi. Methylation is inversely correlated with H11 expression. CONCLUSION: The heat shock protein H11 is silenced by aberrant DNA methylation in melanoma, but not benign melanocytic lesions or normal skin melanocytes. The data suggest that H11 is a promising target for the molecular therapy of melanoma.

Quantitative structure-activity relationship study of 5-iodo- and diaryl-analogues of tubercidin: inhibitors of adenosine kinase.

The adenosine kinase inhibitory (AKI) activity of 5-iodo and diaryl analogues of tubercidin is quantitatively analyzed using Fujita-Ban and Hansch type analyses. The Fujita-Ban analysis being a non-parametric approach assigned the highest contribution to Cl at the X-position, C6H4-4-Cl, C6H5, 2-furanyl and I at the Y-position and CH2NH2 and CH3 at the Z-position. In addition, a OH substituent at the C-position also emerged as a better choice possibly due to its engagement in hydrogen bonding with some active site function. Thus a compound having Cl, C6H4-4-Cl, CH2NH2 and OH respectively at X-, Y-, Z- and C-positions is predicted to have a potency nearly 1.5 orders of magnitude higher than the most potent compound of the parent data set. The Hansch type analysis, on the other hand, is a parametric approach and is carried out on two sub-sets of original compounds. This sub-division is based on size and nature of the substituents present at the X- and Y-positions. For the compounds in the first sub-set the derived significant correlation equation suggested that the substituent at the Y-position exhibiting a higher field effect and a substituent such as Cl and CH2NH2 at X- and Z-positions, respectively, are important for a compound to show increased AKI activity. Thio/alkylthio at X and CH2OCH3 at Z, on the other hand, lead to a detrimental effect. Similarly for the compounds in the second subset, the derived significant correlation equation showed that a substituent at the X-position having a higher negative field effect, a substituent at the Y-position having bulky groups and the C-position occupied by a OH group are essential for enhancement of the activity of a compound.