Initial Experiences in Adolescents and Young Adults with T-Cell Acute Lymphoblastic Leukemia/Lymphoma Treated with the Modified BFM 2002 Protocol in a Resource-Constrained Setting.

Prutha Jinwala T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) in adolescents and young adults (AYAs) is a clinically aggressive malignancy and life-threatening at diagnosis. Intensive chemotherapy protocols, inspired by the Berlin-Frankfurt-Münster (BFM) regimen, along with central nervous system (CNS) prophylaxis, have achieved a 75 to 85% 5-year disease-free survival rate. However, in cases of marrow and CNS relapses, second-line chemotherapy is usually ineffective. This study aimed to assess the safety and efficacy of the BFM 2002 protocol and to correlate clinical profiles and prognostic factors with survival outcomes in AYA T-ALL/LBL patients. We retrospectively analyzed data from T-ALL/LBL patients treated at the Department of Medical Oncology, Sri Aurobindo Institute of Medical Sciences (SAIMS), Indore, between 2018 and 2021. Twenty-one patients aged 15 to 29 years were studied for their clinical course and laboratory parameters over 36 months. Diagnosis and risk stratification were performed following the guidelines of the BFM 2002 protocol. All patients received treatment and monitoring according to this pediatric-inspired protocol. The median age of the patients was 17 years (range: 15-28 years). Eleven patients presented with mediastinal lymph node enlargement, 10% exhibited CNS involvement, and none had testicular involvement. Eleven patients had marrow blasts greater than 25%, indicative of acute lymphoblastic leukemia. All 21 patients were treated according to the intensive modified BFM 2002 protocol and achieved morphological remission after a median follow-up of 24 months (range: 18-36 months). Seventeen patients achieved minimal residual disease (MRD) negativity post-induction. MRD at day 33 showed a significant association with the probability of disease relapse ( p = 0.0015). There were five deaths (24%), one due to toxicity and four due to relapse. The study recorded an 18-month overall survival of 76%. These results were achieved despite financial constraints. Data were entered into a spreadsheet, and statistical analysis was performed using IBM SPSS version 23. Continuous data are presented as ranges and medians, while categorical variables are shown as percentages and numbers. A chi-squared test for association, with a significance level set at p < 0.05, was conducted as indicated. AYA T-ALL/LBL requires intensive treatment regimens. With biological characterization of LBL/ALL and close therapy monitoring, encouraging outcomes can be achieved even in resource-limited settings.

Effect of process and machine parameters on physical properties of extrudate during extrusion cooking of sorghum, horse gram and defatted soy flour blends.

Extrusion cooking of sorghum (Sorghum vulgaris), horse gram (Dolichos biflorus) and defatted soy (Glycine max) flour blends was done to prepare snacks by using a Brabender single-screw laboratory extruder. The combined effect of moisture content, blend ratio of feed, barrel temperature and screw speed of extruder on physical parameters of extrudate was studied. It was observed that 15% moisture content of feed, 80:10:10 (sorghum flour: horse gram flour: defatted soy flour) of blend ratio, 130 °C barrel temperature and 130 rpm of screw speed gave the highest sectional expansion index and longitudinal expansion index of extrudate, while 12% moisture content, 75:15:10 of blend ratio of feed, 135 °C of barrel temperature and 135 rpm of screw speed gave lowest bulk density of extrudate. A central composite rotable design (CCRD) of response surface methodology was used to develop prediction model. Second order quadratic regression model fitted adequately in the variation. The significance was established at p ≤ 0.05. It was also observed that increasing feed moisture content results in a higher density and lower expansion of extrudate. Increasing barrel temperature and screw speed reduced density but increased expansion of extrudate.

Evidence for paclitaxel from three new endophytic fungi of Himalayan yew of Nepal.

Taxus wallichiana, collected from the Himalayan region of Nepal, yielded, among others, three different endophytic fungi including Sporormia minima, Trichothecium sp., and an unidentified dimorphic fungus. Each was shown to produce paclitaxel in a culture medium. Each of these fungi represents a new report as a paclitaxel producer. The production of paclitaxel was confirmed by an immunoassay that utilized monoclonal antibodies, TLC chromatography as well as high performance liquid chromatography combined with on-line mass spectrometry.

An antiproliferative norditerpene dilactone, Nagilactone C, from Podocarpus neriifolius.

An ethanolic extract of Podocarpus neriifolius D. Don (Podocarpaceae) showed antiproliferative activity against two major tumor cell lines, viz. human HT-1080 fibrosarcoma and murine color 26-L5 carcinoma. Bioassay guided fractionation showed the highest antiproliferative activity in chloroform-soluble fraction. Nagilactone C, the major constituent of this fraction was isolated and characterized by using NMR, IR and FAB-MS spectroscopic methods. Nagilactone C possessed potent antiproliferative activity against human fibrosarcoma and murine colon carcinoma tumor cell lines exhibiting ED50 values of 2.3 and 1.2 microg/ml, respectively. Hence, nagilactone C could be the active constituent present in this plant.

Toxicokinetics and structure-activity relationships of nine para-substituted phenols in rat embryos in vitro.

The purpose of this study was to examine the toxicokinetics of embryo uptake following exposure to a variety of chemically related phenols in rat embryo culture. The uptake of nine radiolabeled para-substituted phenols by day 10 (9-13 somite stage) rat embryos in vitro was determined from 1 to 42 hrs after being placed in culture media containing various phenols. Uptake was rapid, having a half-life of 3 hr or less, with 7 of the nine compounds having uptake half-times of less than one hour. The equilibrium concentration in the embryo ranged from 53 to 136% of the media concentration, indicating only a factor of 2 in maximum discrimination against the compound for any of the phenols studied. The fraction of radioactivity remaining unbound in the media decreased with increasing log P (octanol/water partition coefficient). The binding was calculated to be 50% for log P = 1.77 from the fitted regression equation and decreased by a factor of 5.9 for every decade increase in P. When hepatocytes were also present in the media the equilibrium concentration in the embryos was less than when hepatocytes were absent. With the limited data, four of the phenols appeared to have no (i.e., zero) equilibrium level when hepatocytes were present. Thus the metabolites produced by the hepatocytes appeared to have less affinity for the embryo than the parent phenol. Toxicodynamic information as given by the effective concentration of the phenol in the embryo to cause somite or tail teratological effects was best predicted by the measured unbound fraction.

Zinc supplementation in protein energy malnutrition.

A pair-matched controlled study was done with 30 children (15 males, 15 females) of mild to moderate PEM in test and equal number in control groups, aged 8-24 months old. At the beginning, in both test and control groups parents were advised to provide sufficient amount of home cooked foods so that the child received on an average 100-150 Kcal/kg/day of energy and 2-3 g/kg/day of protein. Vitamin supplements were provided to all children in both groups. In addition, the test group received a supplementation of 5.625 mg of elemental zinc daily orally while controls received a placebo. Evaluation at the end of 3 months showed that children in test group had a weight gain of 3.742 +/- 0.488 kg against 2.035 +/- 0.383 kg of the control group. Similarly, weight velocity was 5.752 +/- 0.818 g/kg/day in test group against 3.153 +/- 0.617 g/kg/day of the control group. These differences in weight gain and weight velocity were highly significant (p < 0.001). Serum zinc levels, initially and at the end of study were 87.5 +/- 9.6 micrograms/dl and 121.0 +/- 10.1 micrograms/dl, respectively in test group in comparison to 91.2 +/- 9.8 micrograms/dl and 91.0 +/- 10.1 micrograms/dl in controls. This difference was also highly significant (p < 0.001). The daily total calorie intake remained comparable in both groups. Our observations suggest that zinc supplementation during nutritional rehabilitation of mild to moderate PEM hastens the recovery.

Comparative in vitro percutaneous absorption of p-substituted phenols through rat skin using static and flow-through diffusion systems.

The objective of this study was to compare the in vitro percutaneous absorption of phenol and eight p-substituted phenolic derivatives using the static and flow-through diffusion systems. The variability of the cumulative percentage absorption data was also examined. Clipped dorsal skin was removed from female Fischer 344 rats (90 days old), cut on a dermatome to approximately 350 mum thick, placed in a diffusion cell and treated with chemical (4 mug/cm(2), ethanol). The 72-hr cumulative absorption into the receptor fluid for the phenols in both systems ranged from 15.4 to 97.6% of the dose. Absorption was greater than 70% in both systems for phenols with a log octanol: water partition coefficient (log P) value between 1.4 and 3.5. The percentage of the dose remaining in the skin and washed from the skin and cell top at 72 hr in both systems ranged from 1.8 to 56.2% and from 0.7 to 45.2%, respectively. There were significant differences in absorption between the two systems with five of the phenols. Absorption was significantly lower for acetamido-, chloro- and cyanophenol in the static system and phenol and heptyloxyphenol in the flow-through system. However, the differences in absorption for phenol and chlorophenol were small (<4%) and may not be that biologically relevant. Phenols absorbed the least (<70%), were also on the extremes of the log P range examined and had the most variable absorption data. Both systems appear to be equivalent means to investigate in vitro percutaneous absorption of chemicals, but it is critical to recognize that the data can vary, especially for chemicals not absorbed well.

Dermal absorption of chemicals: effect of application of chemicals as a solid, aqueous paste, suspension, or in volatile vehicle.

The purpose of this study was to investigate the dermal absorption of chemicals in different physical forms when applied to female F344 rats. Chemicals were applied either as a solid, aqueous paste, suspension, or dissolved in the volatile vehicle ethanol. The chemicals investigated were [14C]-2-sec-butyl-4,6-dinitrophenol (DNBP, 4.2 mumol), 2,4,5,2',4',5'-[14C]-hexachlorobiphenyl (HCB, 2.3 mumol), and 3,4,3',4'-[14C]-tetrachlorobiphenyl (TCB, 0.5 mumol). The chemicals were applied on the clipped mid-dorsal region of the rat over a 2.54-cm2 treatment area, which was then occluded. Urine and feces were collected and assayed for radioactivity. Twenty-four hours post-application, the treated skin was washed with a mixture (1:1) of soap and water, dried, and reoccluded. The animals were sacrificed at 120 h by exsanguination under ether anesthesia. Radioactivity in the blood, skin (treated and untreated), and carcass was assayed. Dermal absorption of DNBP-derived radioactivity was approximately 50% of the recovered dose after application in the four physical forms, and the major route of excretion was via the urine. Twelve percent of the absorbed dose of DNBP was retained in the body. Dermal penetration of HCB-derived radioactivity was 5-8% of the recovered dose after application in the four forms, and the major route of excretion was via the feces. Greater than 90% of the absorbed dose of HCB-derived radioactivity was retained in the body. Dermal penetration of TCB-derived radioactivity was 6-8% of the recovered dose in the four forms, and the major route of excretion was via the feces. Approximately 21% of the absorbed dose was retained in the body at 120 h. Absorption of each chemical applied either as solid, aqueous paste, or suspension was compared to the absorption of the same chemical in ethanol. Absorption of HCB applied as a solid was significantly higher (p less than or equal to .05) as compared to HCB applied in ethanol. There were no other significantly differences in the comparisons of absorption. The data indicate that the chemicals examined in this study can penetrate the skin as readily when applied either as a solid, aqueous paste, or suspension, as when applied in the volatile vehicle ethanol.

Carbamate resistance in mosquitos. The metabolism of propoxur by susceptible and resistant larvae of Culex pipiens fatigans.

Toxicity tests on Culex pipiens fatigans with propoxur (o-isopropoxyphenyl methylcarbamate) and carbofuran (2,2-dimethyl-2,3-dihydrobenzofuranyl-7-methylcarbamate) indicated that both compounds are fast-acting insecticides. Transfer of treated larvae to fresh water results in their partial recovery from knockdown.Propoxur is metabolized by resistant and susceptible larvae by their homogenate-reduced nicotinamide-adenine dinucleotide phosphate (NADPH(2)) enzyme system and by the microsome-plus-soluble fraction of mouse-liver extracts to at least 10 organosoluble metabolites with the isopropoxy group intact. The major metabolites, which are primarily hydroxylation products or the result of degradation of these products, have tentatively been identified as: acetone plus o-hydroxyphenyl methylcarbamate, 2-isopropoxy-5-hydroxyphenyl methylcarbamate, 2-isopropoxyphenyl carbamate, and 2-isopropoxyphenyl N-hydroxymethylcarbamate. Upon incubation of water-soluble products from treated larvae with beta-glucosidase, beta-glucuronidase, aryl sulfatase and acid phosphatase, the conjugates are hydrolysed, liberating mainly hydroxylated carbamates.The results indicate that slower absorption as well as faster detoxification by hydroxylation mechanisms, together with conjugation with polar molecules and elimination, are major factors in resistance of mosquito larvae to substituted-aryl methylcarbamate insecticides.