Toxicities of CAR T-cell therapy: a review of current literature.

The chimeric antigen receptor (CAR) design, first invented by Zelig Eshhar, paved the way for the use of genetically modified T-cells in targeted therapy against cancer cells. Since then, it has gone through many generations, especially with the integration of co-stimulation in the second and third-generation CARs. However, it also mounts a hyperactive immune response named as cytokine release syndrome with the release of several cytokines eventually resulting in multiple end-organ toxicities. The severity of cytokine release syndrome depends upon certain factors such as the tumor burden, choice of co-stimulation, and degree of lymphodepletion, and can manifest as pulmonary edema, vascular leak, renal dysfunction, cardiac problems, hepatic failure, and coagulopathy. Many grading criteria have been used to define these clinical manifestations but they lack harmonization. Neurotoxicity has also been significantly associated with CAR T-cell therapy but it has not been studied much in previous literature. This review aims to provide a comprehensive account of the clinical manifestations, diagnosis, management, and treatment of CAR T-cell associated neurotoxicity.

Linear and nonlinear optical characterization of tellurium dioxide (α-TeO2) for generation of terahertz radiation using time-domain spectroscopy.

This paper reports the linear and nonlinear optical characterization of α-T e O 2 crystal in the optical and terahertz domains for efficient terahertz (THz) generation using a difference frequency mixing technique. We have ascertained the optical properties such as refractive index, absorption coefficients, real and imaginary dielectric constants, and coherence length l c=280m m at 1.77 THz range using an indigenously developed THz spectrometer. The value of refractive index was ascertained from temporal and spectral THz profiles of the crystal and employed for calculating the Type I phase-matching angle, i.e., Î¸=21.15∘ for the generation of tunable radiation between the 0.1 and 1.9 THz range. The figure of merits in the optical and THz domains lie between the 0.02-0.015 range. The effective bandwidth of the crystal lies between the 0.1 and 3.0 THz range.

Low level detection of acetone vapor by improvised design of high "Q" tunable frequency Helmholtz photoacoustic cell using UV, mid- IR and THz sources.

The paper reports the designing and fabrication aspects of a high "Q = 492.3" Helmholtz photoacoustic (PA) cell employed for the trace level detection of acetone, a biomarker by using 266 nm- UV, Mid-IR (5.4-10.6 micron) and 0.11 Terahertz (THz) sources. The designed Helmholtz PA cell is made of Aluminum and possesses a natural frequency tunable between 1.4 to 4.4 kHz range using a movable piston arrangement of the microphone sensor. Numerous types of disorders, including diabetes, asthma, lung cancer, etc., can be diagnosed using the acetone concentration obtained through breath analysis. The comparative study is related to the response of different types of excitation mechanisms contributed by electronics, vibrational and rotational modes of acetone. The low-level detection (LoD) limit for acetone is of the order of 5.06 & 7.92 ppbV, and 15.3 pptV, respectively, in UV, Mid-IR, and THz region. This study contributes to the development of a highly sensitive, non-invasive acetone detection and quantification modality.

Optimized biotransformation of acid-treated water melon peel hydrolyzate into ethanol / Biotransformação otimizada de hidrolisado de casca de melancia tratada com ácido em etanol

Abstract Today, global focus of research is to explore the solution of energy crisis and environmental pollution. Like other agricultural countries, bulk quantities of watermelon peels (WMP) are disposed-off in environment as waste in Pakistan and appropriate management of this waste is the need of hour to save environment from pollution. The work emphasizes the role of ethanologenic yeasts to utilize significant sugars present in WMP for low-cost bioethanol fermentation. Dilute hydrochloric acid hydrolysis of WMP was carried out on optimized conditions employing RSM (response surface methodology) following central composite design (CCD). This experimental design is based on optimization of ethanologenesis involving some key independent parameters such as WMP hydrolysate and synthetic media ratio (X1), incubation temperature (X2) and incubation temperature (X3) for maximal ethanol yield exploiting standard (Saccharomyces cerevisiae K7) as well as experimental (Metchnikowia cibodasensisY34) yeasts. The results revealed that maximal ethanol yields obtained from S. cerevisiae K7 was 0.36±0.02 g/g of reducing sugars whereas M. cibodasensisY34, yielded 0.40±0.01 g ethanol/g of reducing sugars. The yeast isolate M. cibodasensisY34 appeared as promising ethanologen and embodies prospective potential for fermentative valorization of WMP-to-bioethanol.

Resumo Hoje, o foco global da pesquisa é explorar a solução da crise energética e da poluição ambiental. Como em outros países agrícolas, grandes quantidades de cascas de melancia (WMP) são descartadas como resíduos no meio ambiente no Paquistão, mas a gestão adequada desses resíduos é a mais recente solução para salvar o meio ambiente da poluição. O trabalho enfatiza o papel das leveduras etanologênicas para utilizar açúcares significativos presentes no WMP para fermentação de bioetanol de baixo custo. A hidrólise de ácido clorídrico diluído de WMP foi realizada em condições otimizadas empregando RSM (metodologia de superfície de resposta) e seguindo o projeto de composto central (CCD). Este projeto experimental é baseado na otimização da etanologenesis envolvendo alguns parâmetros independentes importantes, como hidrolisado de WMP e razão de meio sintético (X1), temperatura de incubação (X2) e temperatura de incubação (X3) para rendimento máximo de etanol explorando o padrão (Saccharomyces cerevisiae K7) também como leveduras experimentais (Metchnikowia cibodasensis Y34). Os resultados revelaram que os rendimentos máximos de etanol obtidos a partir de S. cerevisiae K7 foi de 0,36 ± 0,02 g / g de açúcares redutores, enquanto M. cibodasensis Y34 rendeu 0,40 ± 0,01 g de etanol / g de açúcares redutores. O isolado de levedura M. cibodasensis Y34 apareceu como um etanologeno promissor e incorpora um potencial prospectivo para a valorização fermentativa de WMP em bioetanol.

Optimized biotransformation of acid-treated water melon peel hydrolyzate into ethanol / Biotransformação otimizada de hidrolisado de casca de melancia tratada com ácido em etanol

Today, global focus of research is to explore the solution of energy crisis and environmental pollution. Like other agricultural countries, bulk quantities of watermelon peels (WMP) are disposed-off in environment as waste in Pakistan and appropriate management of this waste is the need of hour to save environment from pollution. The work emphasizes the role of ethanologenic yeasts to utilize significant sugars present in WMP for low-cost bioethanol fermentation. Dilute hydrochloric acid hydrolysis of WMP was carried out on optimized conditions employing RSM (response surface methodology) following central composite design (CCD). This experimental design is based on optimization of ethanologenesis involving some key independent parameters such as WMP hydrolysate and synthetic media ratio (X1), incubation temperature (X2) and incubation temperature (X3) for maximal ethanol yield exploiting standard (Saccharomyces cerevisiae K7) as well as experimental (Metchnikowia cibodasensisY34) yeasts. The results revealed that maximal ethanol yields obtained from S. cerevisiae K7 was 0.36±0.02 g/g of reducing sugars whereas M. cibodasensisY34, yielded 0.40±0.01 g ethanol/g of reducing sugars. The yeast isolate M. cibodasensisY34 appeared as promising ethanologen and embodies prospective potential for fermentative valorization of WMP-to-bioethanol.

Hoje, o foco global da pesquisa é explorar a solução da crise energética e da poluição ambiental. Como em outros países agrícolas, grandes quantidades de cascas de melancia (WMP) são descartadas como resíduos no meio ambiente no Paquistão, mas a gestão adequada desses resíduos é a mais recente solução para salvar o meio ambiente da poluição. O trabalho enfatiza o papel das leveduras etanologênicas para utilizar açúcares significativos presentes no WMP para fermentação de bioetanol de baixo custo. A hidrólise de ácido clorídrico diluído de WMP foi realizada em condições otimizadas empregando RSM (metodologia de superfície de resposta) e seguindo o projeto de composto central (CCD). Este projeto experimental é baseado na otimização da etanologenesis envolvendo alguns parâmetros independentes importantes, como hidrolisado de WMP e razão de meio sintético (X1), temperatura de incubação (X2) e temperatura de incubação (X3) para rendimento máximo de etanol explorando o padrão (Saccharomyces cerevisiae K7) também como leveduras experimentais (Metchnikowia cibodasensis Y34). Os resultados revelaram que os rendimentos máximos de etanol obtidos a partir de S. cerevisiae K7 foi de 0,36 ± 0,02 g / g de açúcares redutores, enquanto M. cibodasensis Y34 rendeu 0,40 ± 0,01 g de etanol / g de açúcares redutores. O isolado de levedura M. cibodasensis Y34 apareceu como um etanologeno promissor e incorpora um potencial prospectivo para a valorização fermentativa de WMP em bioetanol.

Optimized biotransformation of acid-treated water melon peel hydrolyzate into ethanol

Abstract Today, global focus of research is to explore the solution of energy crisis and environmental pollution. Like other agricultural countries, bulk quantities of watermelon peels (WMP) are disposed-off in environment as waste in Pakistan and appropriate management of this waste is the need of hour to save environment from pollution. The work emphasizes the role of ethanologenic yeasts to utilize significant sugars present in WMP for low-cost bioethanol fermentation. Dilute hydrochloric acid hydrolysis of WMP was carried out on optimized conditions employing RSM (response surface methodology) following central composite design (CCD). This experimental design is based on optimization of ethanologenesis involving some key independent parameters such as WMP hydrolysate and synthetic media ratio (X1), incubation temperature (X2) and incubation temperature (X3) for maximal ethanol yield exploiting standard (Saccharomyces cerevisiae K7) as well as experimental (Metchnikowia cibodasensisY34) yeasts. The results revealed that maximal ethanol yields obtained from S. cerevisiae K7 was 0.36±0.02 g/g of reducing sugars whereas M. cibodasensisY34, yielded 0.40±0.01 g ethanol/g of reducing sugars. The yeast isolate M. cibodasensisY34 appeared as promising ethanologen and embodies prospective potential for fermentative valorization of WMP-to-bioethanol.

Resumo Hoje, o foco global da pesquisa é explorar a solução da crise energética e da poluição ambiental. Como em outros países agrícolas, grandes quantidades de cascas de melancia (WMP) são descartadas como resíduos no meio ambiente no Paquistão, mas a gestão adequada desses resíduos é a mais recente solução para salvar o meio ambiente da poluição. O trabalho enfatiza o papel das leveduras etanologênicas para utilizar açúcares significativos presentes no WMP para fermentação de bioetanol de baixo custo. A hidrólise de ácido clorídrico diluído de WMP foi realizada em condições otimizadas empregando RSM (metodologia de superfície de resposta) e seguindo o projeto de composto central (CCD). Este projeto experimental é baseado na otimização da etanologenesis envolvendo alguns parâmetros independentes importantes, como hidrolisado de WMP e razão de meio sintético (X1), temperatura de incubação (X2) e temperatura de incubação (X3) para rendimento máximo de etanol explorando o padrão (Saccharomyces cerevisiae K7) também como leveduras experimentais (Metchnikowia cibodasensis Y34). Os resultados revelaram que os rendimentos máximos de etanol obtidos a partir de S. cerevisiae K7 foi de 0,36 ± 0,02 g / g de açúcares redutores, enquanto M. cibodasensis Y34 rendeu 0,40 ± 0,01 g de etanol / g de açúcares redutores. O isolado de levedura M. cibodasensis Y34 apareceu como um etanologeno promissor e incorpora um potencial prospectivo para a valorização fermentativa de WMP em bioetanol.

A detailed multi-omics analysis of GNB2 gene in human cancers.

The Guanine-nucleotide binding protein 2 (GNB2) encodes for ß2 subunit (Gß2) of the G-protein complex. Keeping in view the increased demand of reliable biomarkers in cancer, the current study was planned to extensively explored GNB2 expression variation and its roles in different cancers using online available databases and diverse methodology. In view of our results, the GNB2 was notably up-regulated relative to corresponding controls in twenty three cancer types. As well, the elevated expression of GNB2 was found to be associated with the reduced overall survival (OS) of the Liver Hepatocellular Carcinoma (LIHC) and Rectum Adenocarcinoma (READ) only out of all analyzed cancer types. This implies GNB2 plays vital role in the tumorigenesis of LIHC and READ. Several additional analysis also explored six critical pathways and few important correlations related to GNB2 expression and different other parameters such as promoter methylation, tumor purity, CD8+ T immune cells infiltration, and genetic alteration, and chemotherapeutic drugs. In conclusion, GNB2 gene has been identified in this study as a shared potential biomarker (diagnostic and prognostic) of LIHC and READ.

Pattern of third molar impactions in north-eastern peninsular Malaysia: A 10-year retrospective study.

BACKGROUND: Third molar impaction, if left untreated, has the potential to cause several complications. The evaluation of surgical difficulty of impacted third molar extraction aids in better formulation of treatment plan by minimizing surgical complications. OBJECTIVE: This study aimed to determine the prevalence of third molar impaction and related pathologic conditions in a cohort of patients living in North-eastern Peninsular Malaysia. METHODS: In this retrospective study, 490 orthopantomograms (OPGs) of patients who were referred to the Oral and Maxillofacial Surgery department between January 2010 and December 2019 were assessed. Data including age, gender, ethnicity, frequency of third molar impactions, their angulations and levels of eruption, retromolar space, and associated pathologic conditions were collected. Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) version 24.0. The significance level was set to P < 0.05. RESULTS: A total of 490 patients with a mean age of 28.87 years (range: 20-64) demonstrated 1957 impacted third molars (1022 mandibular + 935 maxillary). Impacted third molars were more likely present in females than males (1:2.20) (p < 0.05); and in Malay-ethnic (44.49%) patients followed by Chinese (34.45%) and Indians (21.02%). Mesioangular was the most common angulation of impaction both in the maxilla (24.68%) and mandible (18.34%). The most common pattern of third molar impaction was IIA (61.67%), and the retromolar space was significantly larger in males (13.6 mm; P < 0.05) than females (11.6 mm). The most frequently occurring pathological condition associated with third molars impaction is dental caries in the second or third molar (15.38%). CONCLUSIONS: This study highlights mesioangular impaction with their occlusal plane at the same level as the occlusal plane of the adjacent tooth being the most prevalent pattern of third molar impaction in North-eastern Peninsular Malaysia.

Linear and nonlinear temperature-dependent transmission/absorption characteristics of cadmium telluride crystal for terahertz generation.

This paper reports on the temperature-dependent investigation of linear and nonlinear transmission/absorption characteristics of CdTe crystal in the 300-408 K range using 780-970 nm tunable wavelengths of 140 fs pulses obtained from a Ti:Sapphire laser at 80 MHz repetition rate. The same pulses were also used for terahertz generation. The linear transmission/absorption properties were measured using a specially improvised temperature-tuned spectrophotometer in the 500-1500 nm wavelength range. The linear absorption of 750 nm wavelength gradually increases with respect to a rise in the temperature, and transmission becomes zero at 408 K. Nonlinear absorption induced by femtosecond pulses shows a sudden drop of 18% in transmission above the 800 nm range, due to electron-phonon interaction, which affects the strength of the terahertz signal. It is also responsible for change in the temperature along with the linear shift in the refractive index of the crystal.

Temperature dependent time resolved mid-IR photoacoustic spectroscopy of a nerve gas simulant DMMP.

The paper reports the temperature dependent pulsed photoacoustic spectroscopy of Dimethyl methylphosphonate (DMMP) a nerve gas simulant between 50 and 180 °C temperature range. The time domain PA spectra are recorded using two mid-IR wavelengths i.e. 3374 nm, 3495 nm of pulse duration 1.5 ns at 1 kHz repetition rate obtained from optical parametric oscillator. Two anti-symmetric stretching vibrational modes of (CH3P) and (CH3O) groups of DMMP molecules have very strong vibrational peaks at 2861.2 cm-1 (3495 nm) and 2963.8 cm-1 (3374 nm), respectively. In addition, we have also recorded the PA spectra of acetone at the vibrational frequency 3115.2 cm-1 (3210 nm), which is the strong vibrational mode of CH band. The comparison of two PA spectra of DMMP and acetone recorded using similar PA cavity help us to understand the effect of other functional groups with respect to different excitation wavelengths. The presence of additional acoustic modes in the PA spectra of DMMP (3374 nm) above the boiling point confirms the slow process of thermal decomposition. Finally, the low level detection limit of DMMP in air is of the of the order of 0.91 ppbV.

Magnetite and Green Rust: Synthesis, Properties, and Environmental Applications of Mixed-Valent Iron Minerals.

Mixed-valent iron [Fe(II)-Fe(III)] minerals such as magnetite and green rust have received a significant amount of attention over recent decades, especially in the environmental sciences. These mineral phases are intrinsic and essential parts of biogeochemical cycling of metals and organic carbon and play an important role regarding the mobility, toxicity, and redox transformation of organic and inorganic pollutants. The formation pathways, mineral properties, and applications of magnetite and green rust are currently active areas of research in geochemistry, environmental mineralogy, geomicrobiology, material sciences, environmental engineering, and environmental remediation. These aspects ultimately dictate the reactivity of magnetite and green rust in the environment, which has important consequences for the application of these mineral phases, for example in remediation strategies. In this review we discuss the properties, occurrence, formation by biotic as well as abiotic pathways, characterization techniques, and environmental applications of magnetite and green rust in the environment. The aim is to present a detailed overview of the key aspects related to these mineral phases which can be used as an important resource for researchers working in a diverse range of fields dealing with mixed-valent iron minerals.

Blocking of cytokines signalling attenuates evoked and spontaneous neuropathic pain behaviours in the paclitaxel rat model of chemotherapy-induced neuropathy.

BACKGROUND: Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a serious dose-limiting neurotoxic effect of cancer drug treatment. The underlying mechanism(s) of this debilitating condition, which lacks effective drug treatment, is incompletely understood. However, neural-immune interactions, involving increased expression and release of cytokines, are believed to be involved. Here, we examined, in the paclitaxel rat model of CIPNP, whether plasma levels of 24 cytokines/chemokines change after paclitaxel treatment, and whether blocking of signalling of some of those cytokines would reverse/attenuate behavioural signs of CIPNP. METHODS: To achieve these objectives luminex, pharmacological and behavioural experiments were performed on male Wistar rats (250-300 g) 31 days after the last injection of paclitaxel (1 mg/kg, i.p. on four alternate days) as well as on control (vehicle-treated) rats. RESULTS: Compared with control rats, plasma levels of IL-1α, IL-1ß, IL-6, TNF-α, INF-γ and MCP-1 were significantly upregulated in paclitaxel-treated rats. Blocking of TNF-α signalling with etanercept (2 mg/kg, i.p.) or IL-1ß with IL-1 receptor antagonist (IL-1ra; 3 mg/kg, i.p.), significantly attenuated established mechanical and cold hypersensitivity as well as spontaneous pain behaviour (spontaneous foot lifting) 24 and 48 h postdrug treatment. Pharmacological blockade of MCP-1/CCL2 signalling with a highly selective CCR2 receptor antagonist (S504393, 5 mg/kg, i.p.) also significantly reduced evoked, but not spontaneous, pain behaviours of CIPNP in paclitaxel-treated rats at the same time points. CONCLUSIONS: The findings support the notion that cytokines/chemokines, particularly TNF-α, IL-1 and MCP-1, are involved in the pathophysiology of CIPNP and suggest that strategies that target their inhibition may be effective in treating CIPNP. SIGNIFICANCE: This study demonstrates that paclitaxel-treated rats exhibit, in addition to indices of mechanical and cold hypersensitivity, a behavioural sign of spontaneous pain, the principal compliant of patients with neuropathic pain. This was accompanied by upregulation in plasma levels of key cytokines/chemokines (IL-1α, IL-1ß, IL-6, TNF-α, INF-γ and MCP-1) 31 days post-treatment. However, it is noteworthy that cytokine release, rather than nerve injury per se, may be causative of NP in this model of CIPNP. Nevertheless, our findings that pharmacological blockade of TNF-α, IL-1ß and MCP-1 attenuated both evoked and spontaneous pain suggest that strategies that target inhibition of these cytokines may be effective in treating CIPNP.

Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents.

Cancer cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. Current study concludes that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrial biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas inhibition of complex-II or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with wild type (WT) cells. Gross OXPHOS deficiencies promoted increased release of apoptosis-inducing factor from mitochondria compared with WT or complex-I-deficient cells, suggesting that cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted by complex-I-deficiency but not by complex-II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross OXPHOS deficiency whereas a reverse trend was observed with apicidin. Together, these finding provide a new strategy for differential mitochondrial targeting in cancer therapy.

Bursectomy for gastric cancer: What does the evidence indicate?

Radical resection of the bursa omentalis (radical bursectomy) as part of a curative resection for gastric cancer has been advised for close to a century. However, the postulated associated morbidity and lack of a clear benefit in terms of survival preclude its routine use. To objectively review the available evidence on the role of bursectomy as part of a curative resection for gastric cancer. A systematic search of the scientific literature was carried out using Embase, PubMed, MedLine and the Cochrane central register of controlled trials for the years 1965-2013 to obtain access to all publications, especially randomized controlled trials (RCTs), systematic reviews and meta-analyses involving bursectomy in gastric cancer with the appropriate specific search terms, namely, "bursectomy," "stomach cancer," "gastric cancer," "survival," "morbidity," "outcomes" and "RCTs". Using the above search strategy, a total of 29 publications was retrieved of which five publications were identified describing bursectomy and its outcomes in gastric cancer. These included three retrospective cohort studies and two publications from a single RCT. Bursectomy do not appear to add the morbidity or mortality of the overall surgery. However, it did not appear to significantly improve overall survival neither in the retrospective cohort studies nor in the only RCT. The evidence to date is insufficient to suggest any additional benefit of routine bursectomy to a radical gastrectomy with D2 lymphadenectomy for gastric cancer. Results of an on-going RCT are awaited to determine if bursectomy may further improve overall survival in patients with advanced T-stage of disease.

Coincidental diagnosis of tuberculous lymphadenitis: a case report.

The aim of this case report was to present a case of multiple calcified tuberculous lymph nodes found on a panoramic radiograph coincidently diagnosed in an endodontic clinic. A detailed discussion on the differential diagnosis of similar such calcification found in the same region is also presented. A 14-year-old girl was referred to our department with the complaint of painless swelling in the left side of the lower jaw. Clinical and radiographical examinations were performed, leading to the initial diagnosis of chronic periapical abscess. The patient's medical history was re-evaluated. Advanced imaging and excisional biopsy were performed in order to confirm the final diagnosis. Regarding the presenting signs and symptoms of bilateral carious mandibular molars, a periapical inflammatory process was considered in the provisional diagnosis. A thorough examination and investigations were suggestive of cervical tuberculous lymphadenitis (scrofula), and the patient underwent excision of the same. The clinician should consider the possibility of chronic granulomatous inflammatory lesions in the differential diagnosis of radiopaque lesions.

A genetic model for gallbladder carcinogenesis and its dissemination.

Gallbladder cancer, although regarded as the most common malignancy of the biliary tract, continues to be associated with a dismal overall survival even in the present day. While complete surgical removal of the tumour offers a good chance of cure, only a fraction of the patients are amenable to curative surgery owing to their delayed presentation. Moreover, the current contribution of adjuvant therapies towards prolonging survival is marginal, at best. Thus, understanding the biology of the disease will not only enable a better appreciation of the pathways of progression but also facilitate the development of an accurate genetic model for gallbladder carcinogenesis and dissemination. This review provides an updated, evidence-based model of the pathways of carcinogenesis in gallbladder cancer and its dissemination. The model proposed could serve as the scaffolding for elucidation of the molecular mechanisms involved in gallbladder carcinogenesis. A better understanding of the pathways involved in gallbladder tumorigenesis will serve to identify patients at risk for the cancer (and who thus could be offered prophylactic cholecystectomy) as well as aid oncologists in planning the most suitable treatment for a particular patient, thereby setting us on the vanguard of transforming the current treatment paradigm for gallbladder cancer.

1,2,4-triazine analogs as novel class of therapeutic agents.

1,2,4-Triazine nucleus is a prominent structural core system present in numerous pharmacologically active compounds. Till date, various 1,2,4-triazine analogs, possesing a wide range of potent pharmacological activities, have been reported. This review is an attempt to compile the medicinal chemistry aspects of various synthesized 1,2,4-triazine analogs reported so far.

Molecular analyses of novel ASAH1 mutations causing Farber lipogranulomatosis: analyses of exonic splicing enhancer inactivating mutation.

Farber lipogranulomatosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the ASAH1 gene. In the largest ever study, we identified and characterized ASAH1 mutations from 11 independent Farber disease (FD) families. A total of 13 different mutations were identified including 1 splice, 1 polypyrimidine tract (PPT) deletion and 11 missense mutations. Eleven mutations were exclusive to the Indian population. The IVS6+4A>G splice and IVS5-16delTTTTC PPT deletion mutations resulted in skipping of exon 6 precluding thereby the region responsible for cleavage of enzyme precursor. A missense mutation (p.V198A) resulted in skipping of exon 8 due to inactivation of an exonic splicing enhancer (ESE) element. This is the first report of mutations affecting PPT and ESE in the ASAH1 gene resulting in FD.