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Biomedical subjects

J Jacob

Publications and source records attributed to J Jacob.

At least 19 recordsLinked to original sources
PubMed2026

Clinically actionable genomic alterations in breast cancer brain metastases.

BACKGROUND: Breast cancer brain metastases (BCBMs) represent a critical unmet clinical need in metastatic breast cancer (MBC) and the identification of novel therapeutic targets is urgently needed in this context. In this study, we describe clinically actionable targets in BCBMs using comprehensive genomic profiling. PATIENTS AND METHODS: Genomic DNA was extracted from formalin-fixed paraffin-embedded archival BCBM samples and analyzed using the commercially available Agilent SureSelect V6 whole exome sequencing (WES) kit and an Illumina NovaSeq 6000 platform. Pathogenic alterations were classified as actionable alterations (AAs) if they met the updated MBC or tumor-agnostic ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) I or II criteria of the ESCAT scale. RESULTS: WES data from 56 BCBM samples were available [33.9% hormone receptor (HR)-negative/human epidermal growth factor receptor (HER)2-negative; 25.0% HR-positive/HER2-negative; and 38% HER2-positive]. ESCAT I/II AAs were detected in 76.8% (n = 43) of all BCBMs and the most frequently detected AAs were in genes involved in the homologous recombination repair pathway (BRCA1/BRCA2/PALB2; 53.6% overall). Biallelic inactivation of BRCA1, BRCA2, or PALB2 was observed in 19.6% of samples, with higher rates in HER2-negative BCBMs (26% in HR-negative /HER2-negative and 21% in HR-positive/HER2-negative). ESCAT I/II PIK3CA/AKT1/PTEN pathway alterations were present in 48.2% of samples and, in particular, in 50% of HR-positive/HER2-negative BCBMs. No ESR1 mutation was detected in HR-positive/HER2-negative BCBMs. The prognostic impact of previously described AAs was evaluated overall and according to breast cancer subtype. Twenty-three BCBMs (41%) were classified as HER2-positive; among these, 3 (13%) presented a hotspot PIK3CA mutation and 7 (30%) presented a PTEN deletion. Among patients with HER2-positive BCBMs, the identification of a hotspot PIK3CA mutation was significantly associated with worse prognosis. CONCLUSIONS: ESCAT I/II actionable genomic alterations are frequent in BCBMs, highlighting the potential for genomically targeted treatments in this setting.

ESCAT↗
PubMed2006

Viper bite with continuous defibrination despite adequate treatment with antivenom.

A case of envenomation due to viperine snakebite poisoning is presented. Patient showed continuous defibrination, without any other signs of poisoning, which could not be reversed with more than double the usual dose of polyvalent antivenom. This phenomenon could be due to envenomation caused by a snake, probably from Viperidae family, which is not covered by the polyvalent antivenom available in India.

Adult↗
PubMed2005

In vitro and in vivo characterization of smooth small colony variants of Brucella abortus S19.

Brucella abortus is known to produce chronic infections in both humans and a variety of animal species. However, the mechanisms underlying the persistence of the bacteria in the presence of an ongoing immune response are still unknown. In this respect we made use of the observation that in vitro grown B. abortus S19 exhibits heterogenicity in colony size when plated onto TS agar, while experimental infection of mice uniformly results in the in vivo selection of the small colony variant. We demonstrate that the spontaneous smooth small colony variant is characterized not only by a slower growth rate in vitro but also by an increased tolerance to hyperosmotic medium and, most importantly, a less effective clearance from spleens and livers of experimentally infected mice. On a molecular level, a gene with homology to a formerly described galactoside transport ATP binding protein (mglA) was differentially expressed in small versus large colonies of B. abortus S19.

Animals↗
PubMed2005

Human selenoproteins at a glance.

The public perception of selenium has changed significantly over the last decades. Originally mainly known for its high toxicity, it was later recognized as an essential trace element and is now (despite its narrow therapeutic window) almost being marketed as a lifestyle drug. Indeed, some clinical and preclinical studies suggest that selenium supplementation may be beneficial in a large number of clinical conditions. However, its mode of action is unresolved in most of these cases. Selenocysteine - identified as the 21st amino acid used in ribosome-mediated protein synthesis - is incorporated in at least 25 specific, genetically determined human selenoproteins, many of which have only recently been discovered. Restoration of normal selenoprotein levels may be - apart from direct supranutritional effects - one possible explanation for the effects of selenium supplements. In this review we provide a brief but up-to-date overview of what is currently known about these 25 acknowledged human selenoproteins and their synthesis.

Animals↗
PubMed2005

Antimutagenic and anti-oxidant activities of the non-steroidal anti-inflammatory drug celecoxib.

1. Tumors arise and progress through the accumulation of serial genetic changes, including successive mutations, which involve activation of proto-oncogenes and inactivation of tumour suppressor genes, leading to the uncontrolled proliferation of progeny cells. The human body is continuously and unavoidably exposed to structurally diverse chemicals with established carcinogenic activity in animal models and/or mutagenic activity in short-term tests. 2. Celecoxib, a non-steroidal anti-inflammatory drug that specifically inhibits the enzyme cyclo-oxygenase-2, has been reported to be effective against certain types of cancers. The in vitro anti-oxidant and antimutagenic activities of the celecoxib were investigated in the present study using standard procedures. 3. The antimutagenic activity of celecoxib was determined using histidine mutant Salmonella typhimurium strains TA98, TA100, TA102 and TA1535 against directly acting mutagens (sodium azide (NaN3), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), 4-nitro-o-phenylenediamine (NPDA) and doxorubicin) and mutagens needing activation (2-acetamidofluorene (2-AF) and 7,12-dimethylbenz [a] anthracene (DMBA)). 4. Celecoxib inhibited NaN3-, MNNG- and NPDA-induced mutations of TA100. The antimutagenicity of celecoxib (0.2 mg/plate) against the NaN3-induced mutation of TA1535 was 39.8% (P < 0.001). The MNNG-induced mutation of TA1535 was also inhibited by 0.3 mg/plate celecoxib (46.0%; P < 0.05). At concentrations of 0.2 mg/plate, celecoxib significantly inhibited NPDA- and doxorubicin-induced mutations of TA98 by 52.5 and 58.0%, respectively (P < 0.001 and P < 0.05, respectively). 5. The antimutagenic activity of 0.3 mg/plate celecoxib against 2-AF- and DMBA-induced mutations of TA98 was 81.76 and 98.1%, respectively (P < 0.001). 6. The anti-oxidant activity of celecoxib was determined by the inhibition of lipid peroxidation and superoxide and hydroxyl radical-scavenging activities. 7. The IC50 values of celecoxib for hydroxyl radical-scavenging and the inhibition of lipid peroxidation were 1.97 +/- 0.06 and 1.99 +/- 0.05 micromol/mL, respectively. Celecoxib had no superoxide radical scavenging-activity up to a concentration of 2.6 micromol/mL. 8. The in vitro antimutagenic and anti-oxidant activities of celecoxib indicate its possible therapeutic use as a cancer chemopreventive agent.

2-Acetylaminofluorene↗
PubMed2005

Mydriasis due to Datura inoxia.

Unilateral, dilated unresponsive pupil may be secondary to a wide range of ocular and neurological disorders. "Gardener's pupil" is a pharmacological mydriasis caused by exposure to plants containing alkaloids. We report a case of mydriasis related to Datura inoxia, and detail a number of plants that have toxic effects. This report emphasises the importance of accurate history taking when evaluating fixed dilated pupil. We recommend that labelling of such poisonous plants should detail the local and systemic effects of accidental exposure, rather than merely the fact that they are poisonous.

Aged↗
PubMed2005

Clinical and laboratory features and response to treatment in patients presenting with vitamin B12 deficiency-related neurological syndromes.

AIMS AND OBJECTIVES: To study the clinical and laboratory features of patients admitted with vitamin B12 deficiency-related (B12def) neurological syndromes. SETTINGS AND DESIGN: A hospital-based retrospective and prospective study conducted at a referral teaching hospital. MATERIALS AND METHODS: Consecutive patients admitted with vitamin B12 deficiency-related neurological disorders during a three-year period from June 2000 to May 2003 were included. Data regarding clinical and laboratory features were obtained. Follow-up was done at least six months following treatment with parenteral vitamin B12. Chi-square test was used for statistical analysis. RESULTS: A total of 63 patients (52 males) with a mean age of 46.2 years were studied. The mean duration of symptoms at presentation was 10.3 months. Myeloneuropathy (54%) was the commonest neurological manifestation, followed by myeloneuropathy with cognitive dysfunction (34%), and peripheral neuropathy (9%). Neuropsychiatric manifestations and dementia were observed in 38% and 19% of patients respectively. All the patients had megaloblastic changes in the bone marrow smear. Eleven (17.5%) patients had both hemoglobin and the mean corpuscular volume (MCV) within the normal range. Follow-up after at least six months of therapy with parenteral B12 showed improvement in 54% patients. CONCLUSIONS: A high index of suspicion of B12def is required in patients presenting with myelopathy, cognitive decline, or neuropathy. A normal hemoglobin or MCV does not exclude B12def; therefore, other tests such as bone marrow smear and serum vitamin B12 assay are essential, as the condition is often reversible with treatment.

Adult↗
PubMed2004

Induction of gene expression of xenobiotic metabolism enzymes and ABC-transport proteins by PAH and a reconstituted PAH mixture in human Caco-2 cells.

It was shown recently that in epithelial Caco-2 cells the food contaminant benzo[a]pyrene (B[a]P) is metabolized and B[a]P-sulfate metabolites were transported out of the cells. The aim of this study was to investigate whether B[a]P and other polycyclic aromatic hydrocarbons (PAH) such as chrysene, phenanthrene, benzo[k]fluoranthene (B[k]F), dibenzo[a,l]pyrene (DB[a,l]P), and pyrene alone or in a mixture in a ratio as they occur in tobacco smoke have effects on gene expression of intestinal cytochrome P450 enzymes (CYP), Phase II enzymes and ATP-binding cassette (ABC)-transport proteins in the human Caco-2 cells. B[a]P induced its own metabolism. Treatment of the Caco-2 cells with B[a]P, chrysene, B[k]F, or DB[a,l]P induced mRNA expression of CYP1A1 and CYP1B1 specifically as measured by RT-PCR. In contrast, the mRNA expression of the microsomal epoxide hydrolase (mEH) was not affected by PAH. The gene expression of the Phase II enzymes UDP-glucuronosyltransferase 1A6 (UGT1A6) and UGT1A7 was also induced by these PAH but treatment with them had no effect on gene expression of sulfotransferases (SULT) at all. Of the ABC-transport proteins, MDR1 mRNA expression was induced by treatment with carcinogenic PAH, whereas MRP2 mRNA expression was not changed. The mixture of PAH also induced CYP1A1, CYP1B1, UGT1A6, and UGT1A7 mRNA expression. We conclude that B[a]P, chrysene, B[k]F, and DB[a,l]P have specific effects on intestinal CYP1A1, CYP1B1, UGT1A6, and UDP1A7 mRNA expression but no effects on the expression of SULT.

ATP-Binding Cassette Transporters↗
PubMed2004

Effect of asimadoline, a kappa opioid agonist, on pain induced by colonic distension in patients with irritable bowel syndrome.

BACKGROUND: Visceral hypersensitivity plays a major role in irritable bowel syndrome pathophysiology. Opioid kappa receptors on afferent nerves may modulate it and be the target for new irritable bowel syndrome treatments. AIM: This study evaluated the effect of the kappa opioid agonist asimadoline on perception of colonic distension and colonic compliance in irritable bowel syndrome patients. METHOD: Twenty irritable bowel syndrome female patients (Rome II criteria; 40 +/- 13 years) and hypersensitivity to colonic distension (Pain threshold < or = 32 mmHg) were included in a randomized double-blind cross-over trial comparing the effect of a single oral dose of asimadoline 0.5 mg or placebo on sensory thresholds (defined as a constant and sustained sensation) elicited by left colon phasic distension (5 mmHg steps, 5 min) up to a sensation of abdominal pain. Colonic compliance was compared by the slope of the pressure-volume curves. RESULTS: On asimadoline, pain threshold (mean +/- s.d.) (29.8 +/- 7.2 mmHg) was higher than on placebo (26.3 +/- 7.8 mmHg), difference not statistically significant (P = 0.1756, ANOVA). Area under curve of pain intensity rated at each distension step was significantly lower on asimadoline (89.3 +/- 33.9, ANOVA) than on placebo (108.1 +/- 29.7) (P = 0.0411). Thresholds of perception of nonpainful distensions were not altered on asimadoline, as compared with placebo. Colonic compliance was not different on placebo and asimadoline. CONCLUSION: Asimadoline decreases overall perception of pain over a wide range of pressure distension of the colon in irritable bowel syndrome patients, without altering its compliance. These data suggest that further studies should explore the potential benefit of asimadoline in treatment of pain in irritable bowel syndrome patients.

Acetamides↗
PubMed2004

Comparison of articaine and bupivacaine/lidocaine for sub-Tenon's anaesthesia in cataract extraction.

BACKGROUND: Articaine is the most widely used local anaesthetic for dental anaesthesia in Germany, Italy and The Netherlands and has recently been introduced and licensed for dental use in the UK. We have previously shown articaine to be superior to a standard mixture of bupivacaine 0.5%/lidocaine 2% for peribulbar anaesthesia. Sub-Tenon's anaesthesia arguably provides a safer method of anaesthetic delivery for cataract surgery. A blunt cannula is used in this technique, thus greatly reducing the risk of globe perforation, intrathecal injection and sight-threatening periocular haemorrhage. METHODS: We compared articaine and bupivacaine/lidocaine for sub-Tenon's anaesthesia in cataract surgery. RESULTS: Sub-Tenon's anaesthesia using articaine 2% resulted in a more rapid onset of motor block compared with a bupivacaine/lidocaine (P=0.0076). Ocular movement scores were significantly lower from 2 min after injection until the end of surgery (P=0.031 ANOVA). CONCLUSION: Articaine 2% is safe and effective for sub-Tenon's anaesthesia and is a suitable alternative to the traditional bupivacaine 0.5%/lidocaine 2% mixture.

Adult↗
PubMed2004

Hyperammonemia with citrullinemia.

Two cases of hyperammonemia with elevated citrulline are reported, one resulting from a deficiency of pyruvate carboxylase and the other from a partial deficiency of argininosuccinate synthetase. Diagnosis was based on clinical, biochemical and amino acid profiles. The utility of amino acid determinations in hyperammonemia suspected to underlie an inborn error of metabolism is emphasized.

Adolescent↗
PubMed2004

Variability in the extent of sensory deficit after sural nerve biopsy.

BACKGROUND: Sural nerve biopsy (SNBx) is associated with multiple complications such as paresthesia, pain, or numbness in the sural nerve distribution at the site of biopsy and wound infection. An accurate idea of these adverse events would be useful while taking informed consent from patients. AIMS: We conducted a prospective study to determine the extent of sensory deficits after SNBx. SETTINGS AND DESIGN: It is a prospective, hospital-based (tertiary teaching hospital) study. MATERIALS AND METHODS: All the patients who had SNBx between May 2003 and March 2004 were eligible for inclusion. However, patients with sensory impairment in sural nerve territory or abnormal sural nerve conduction studies prior to the procedure were excluded. SNBx was performed in the ankle region under local anesthesia, and a 3 cm nerve segment was excised. Touch, pain, temperature, vibration and joint position were tested after the nerve biopsy. The extent of sensory deficit was determined. Any other complications, when present were also noted. Follow-up assessment was performed at three months or later. RESULTS: Fifty patients (26 women) fulfilled the inclusion and exclusion criteria. The mean age was 37.4 (16-63) years. One-two weeks after the SNBx, 46 (92%) patients had sensory deficit along the lateral aspect of the foot at the site of the biopsy, and 48 (96%) patients had sensory impairment extending beyond the outer aspect of the fifth toe. At follow-up, sensory deficit was present in 89% patients and paresthesia in 39%. CONCLUSIONS: The majority of the patients undergoing SNBx develop persistent sensory deficits, which often extend beyond the typical sural nerve territory.

Adolescent↗
PubMed2003

Delayed type hypersensitivity-associated disruption of splenic periarteriolar lymphatic sheaths coincides with temporary loss of IFN-gamma production and impaired eradication of bacteria in Brucella abortus-infected mice.

A major problem of infections with facultative intracellular bacteria is their chronic course. We comprehensively evaluated the host response in murine brucellosis to study mechanisms contributing to bacterial persistence in the presence of an established immune response. Evidence is presented that the decrease in eradication kinetics, reproducibly occurring 18 d after infection of mice with Brucella abortus S19, is related to a state of downregulation of defense mechanisms. This is not due to a Th1 to Th2 switch or prostaglandin-mediated suppression by macrophages but is most probably caused by a severe disruption of spleen morphology at the height of Brucella-induced delayed type hypersensitivity. This results in a profound depletion of both CD4(+) and CD8(+) T cells in periarteriolar lymphatic sheaths, a consecutive deleterious shift in the relation of permissive macrophages and protective lymphocytes and an impaired capacity of splenocytes to produce IFN-gamma in response to soluble Brucella antigen.

Animals↗
PubMed2003

Hepatic arterial infusion using pirarubicin combined with systemic chemotherapy: a phase II study in patients with nonresectable liver metastases from colorectal cancer.

BACKGROUND: A prospective phase II study was performed to determine the feasibility, efficacy and safety of arterial hepatic infusion (HAI) using pirarubicin combined with intravenous chemotherapy. PATIENTS AND METHODS: From December 1991 to April 1994, 75 patients with unresectable colorectal metastases confined to the liver were included in this multicenter study to receive intra-arterial hepatic pirarubicin and a systemic monthly regimen of 5-fluorouracil (5-FU) and folinic acid. Sixty-four patients were analyzed in the intention-to-treat analysis and 61 in the per-protocol analysis. RESULTS: Tolerance of this regimen was rather good; however, functional catheter problems were observed in 29 patients (45%) resulting in failure of HAI in 21 cases (33%) after a median of three cycles; vomiting grade 3 was present in 12.5% of patients, neutropenia grade 4 in 23% and alopecia grade 3 in 19%. The overall response rate was 31.9% in intention-to-treat analysis, and 39.3% in per-protocol analysis. Extrahepatic progression was reported in only 21.7% of patients. Time to hepatic progression and extra-hepatic progression was 8.3 and 15 months, respectively, in intention-to-treat analysis, and 11 and 18 months, respectively, in per-protocol analysis. Median survival was 19 and 20 months in intention-to-treat analysis and per-protocol, respectively. CONCLUSIONS: In our study, the combination of intra-arterial pirarubicin and intravenous chemotherapy demonstrated some efficacy and good tolerance in the treatment of isolated colorectal liver metastases. This treatment seems to prevent extra-hepatic spread and prolong survival time. The results of this study have to be confirmed by new trials using more active systemic chemotherapy.

Adolescent↗
PubMed2003

The clinicopathological spectrum of Rosenthal fibre encephalopathy and Alexander's disease: a case report and review of the literature.

Alexander's disease is a leucodystrophy that usually presents in early childhood, but can infrequently arise in adults. It is characterised pathologically by megalencephaly, demyelination, and the presence of numerous Rosenthal fibres. Most cases have been shown to be due to mutations in the gene encoding glial fibrillary acidic protein. In rare instances, numerous Rosenthal fibres have been found at autopsy in patients who have suffered protracted debilitating systemic illnesses, some with associated brain stem signs, and in very rare instances in patients with no apparent neurological abnormality. The term "Rosenthal fibre encephalopathy" is used to distinguish these cases from those of Alexander's disease. We report the first case of Rosenthal fibre encephalopathy in a young man with AIDS, and review the literature.

AIDS Dementia Complex↗
PubMed2002

Significance of a prenatally diagnosed del(10)(q23).

Structural chromosome mosaicism is rare. We report a case of prenatal mosaicism for a deletion of chromosome 10(q23). To our knowledge, there are only three reports of prenatally diagnosed cases of del(10)(q23). Two of these cases were due to an inherited fragile site. In the present case amniocentesis revealed 46,XY,del(10)(q23)[9]/46,XY[45]. Follow-up chromosome analysis of peripheral blood and placental tissue from a phenotypically normal liveborn male revealed the del(10)(q23) in only 3/100 blood cells grown in low-folate medium. It appears that prenatally diagnosed deleted (10q) mosaicism represents culture artifact and is not clinically significant.

Adult↗