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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↗
PubMed1992

In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. II. A common clonal origin for periarteriolar lymphoid sheath-associated foci and germinal centers.

In the genetically restricted response that follows immunization with (4-hydroxy-3-nitrophenyl)acetyl coupled to protein carriers, two distinct populations of B cells are observed in the spleens of C57BL/6 mice. By 48 h postimmunization, foci of antigen-binding B cells appear along the periphery of the periarteriolar lymphoid sheaths. These foci expand to contain large numbers of antibody-forming cells that neither bind the lectin, peanut agglutinin, nor mutate the rearranged immunoglobulin variable region loci. Germinal centers containing peanut agglutinin-positive B cells can be observed by 96-120 h after immunization. Although specific for the immunizing hapten, these B cells do not produce substantial amounts of antibody, but are the population that undergoes somatic hypermutation and affinity-driven selection. Both focus and germinal center populations are pauciclonal, founded, on average, by three or fewer B lymphocytes. Despite the highly specialized roles of the focus (early antibody production) and germinal center (higher affinity memory cells) B cell populations, analysis of VH to D to JH joins in neighboring foci and germinal centers demonstrate that these B cell populations have a common clonal origin.

Animals↗
PubMed1992

DNA adduct formation in mice following treatment with used engine oil and identification of some of the major adducts by 32P-postlabelling.

Used engine oil from a petrol-powered vehicle was fractionated by column chromatography into seven parts for which the major polycyclic aromatic hydrocarbon (PAH) components were determined by GC. Topical treatment of mice with the fractions and 32P-postlabelling of the skin DNA resulted in the detection of multiple adduct spots on TLC for some, but not all, of the fractions. The majority of the DNA binding capacity of the used engine oil was possessed by the first three fractions, (equivalent to 25, 15 and 14.5%, respectively) of the adduct forming ability of the unfractionated oil. The chromatographic mobilities of the adduct spots induced by these fractions were compared to those produced by unfractionated used engine oil. In addition, mice were also treated topically with reference PAHs, either singly or as mixtures, dissolved in unused oil at the concentrations at which they were present in the used oil. Comparisons were made between the chromatographic mobilities of the adducts formed in mouse skin DNA by synthetic mixtures with those formed by the used oil. From these data, some of the major adducts produced by treatment with used engine oil are suggested to be formed by reactive metabolites of benzo[b]naphtho[1,2-d]thiophene, benzo[c]phenanthrene, benzo[g,h,i]fluoranthene, chrysene, benzo[a]pyrene and benzo[g,h,i]perylene.

Animals↗
PubMed1992

5-Fluorouracil (5-FU) and leucovorin in platinum-refractory advanced stage ovarian carcinoma.

Twenty-nine patients with recurrent advanced stage ovarian cancer were treated with 5-fluorouracil (5-FU) and leucovorin by intravenous bolus on 5 consecutive days, repeated every 3 weeks. Twenty-one of these patients had experienced disease progression while receiving a cisplatin- or carboplatin-based regimen. There were 2 clinical complete responders and 1 partial responder to therapy (10% response rate; 95% confidence interval, 2 to 27%) and 11 individuals who experienced stable disease for periods ranging from 5 to 27 months. Of 204 cycles of therapy administered, 9 cycles were associated with hospitalization. These occurred in the more heavily pretreated members of the cohort. 5-FU and leucovorin appear to have activity in platinum-refractory ovarian cancer and form a well-tolerated regimen in most patients.

Adult↗
PubMed1992

Partial characterization of an endemic strain of a methicillin- and aminoglycoside-resistant Staphylococcus aureus (MARSA) homogeneously resistant to beta-lactam antibiotics.

Selected strains of methicillin- and aminoglycoside-resistant Staphylococcus aureus (MARSA) were subjected to a preliminary examination. They were representative of a larger group collected in a routine clinical microbiology laboratory over a period of 2 years. MARSA was endemic in the associated hospital. The characteristics investigated were antimicrobial resistance, the production of beta-lactamase, free and bound coagulase, protein A, DNA-ase, urease, lipase and pigment. The MARSA strains were generally indistinguishable, other than in their antimicrobial resistances. The resistance to methicillin was completely homogeneous. Except with imipenem, growth extended to the edge of discs containing methicillin and the other beta-lactam antibiotics tested when the strains were cultured at 37 degrees C on media without added salt. Homogeneous resistance may confer an epidemiological advantage on strains of this phenotype.

Aminoglycosides↗
PubMed1992

Comparison of two media for the isolation of thermophilic Campylobacters from waste waters of different quality.

Counts of thermophilic campylobacters from 31 different waste water samples were parallel estimated with two different cultivation media. The resulting increased isolation sale obtained with an modified Charcoal-Cefoperazone-Deoxycholat-Medium (MCCD-Medium), was statistically significant. An 15.8 fold increased isolation rate, compared with the standard medium, could be estimated with the help of the geometric mean.

Abattoirs↗
PubMed1992

The occurrence of high-level streptothricin resistance in thermotolerant campylobacters isolated from the slurry of swine and the environment.

This is the first report on the occurrence of streptothricin resistance (MIC > 400 micrograms/ml) in Campylobacter spp. The majority of resistant strains has been typed as C. coli by biotyping and SDS disc electrophoresis of bacterial whole cell proteins. The resistance to streptothricin was strongly connected with resistance to kanamycin (100%) and tetracycline (80%). As an important source of streptothricin-resistant Campylobacter strains we localized slurry of swine previously fed with feed containing streptothricins. Additionally, such strains could also be isolated from river water.

Animals↗
PubMed1992

Phase I study of taxol and granulocyte colony-stimulating factor in patients with refractory ovarian cancer.

PURPOSE: To increase the taxol dose beyond the current standard dose intensity of 175 mg/m2 per 21 days in patients with refractory ovarian cancer. PATIENTS AND METHODS: Fifteen patients who had platinum-refractory or recurrent advanced-stage ovarian cancer were treated with taxol in a phase I trial and were given granulocyte-colony stimulating factor (G-CSF). Taxol was administered at doses of 170, 200, 250, and 300 mg/m2 every 3 weeks. G-CSF was given as a daily subcutaneous injection that started 24 hours after the completion of the taxol infusion. RESULTS: Four patients required either taxol dose reduction or delay. The dose-limiting toxicity (DLT) was peripheral neuropathy, and it occurred at 300 mg/m2. This toxicity was manifested clinically as a stocking-and-glove sensory disturbance that primarily affected proprioception, and was associated with objective changes on nerve conduction studies in affected individuals. Mucositis was rarely observed. Substantial myelosuppression was observed, but was not dose-limiting. Five of 14 assessable patients experienced an objective response to therapy, with another five individuals who experienced a 30% to 45% reduction in tumor mass. CONCLUSION: Taxol can be safely administered in doses up to 250 mg/m2 with G-CSF support, which may make it possible to study taxol dose intensification.

Adult↗
PubMed1992

[The occurrence of Campylobacter in a mountain brook].

The mountain river showed fecal water pollution at all sample sites studied. The arithmetic mean values of total coliforms ranged between 28 and 196/ml. Campylobacters were isolated from all sample sites studied, with a maximum value of 1,100 Campylobacter/100 ml river water. The MCCD-medium resulted in significantly higher isolation rates of Campylobacter from water samples than the VTPRC-medium compared. Colony counts, total coliforms and Campylobacter showed numerical relations of 3831:100:1 respectively.

Campylobacter↗
PubMed1992

[The occurrence of aeromonads in a drinking water supply system].

This study concerns with the occurrence of aeromonads, coliforms and colony counts in a drinking water supply. Aeromonas contents were detected in the range of 15.0 to greater than 2,400/100 ml in the raw water samples of the man made lake. After the drinking water treatment process including fast sand filtration and chlorination aeromonads indicated in comparison to total coliforms and colony counts early and significant an after-growth of maximal 240 aeromonads/100 ml in the peripheric drinking water supply. Drinking water samples characterized by a higher water temperature resulted in the highest contents of aeromonads. The Aeromonas-Species Aeromonas sobria and Aeromonas hydrophila were isolated most frequently with 56.9 and 37.4 percent, respectively. The role of aeromonads as an indicator of after-growth in drinking water supplies is discussed.

Aeromonas↗
PubMed1991

Intraclonal generation of antibody mutants in germinal centres.

The generation and selection of somatic antibody mutants are key elements of acquired immunity, essential for the affinity maturation of antibody responses dependent on T cells. The mutants are generated through a mechanism that introduces point mutations at high rate into rearranged variable (V) region genes in the course of cell proliferation. Their appearance coincides with the generation of germinal centres, which are characterized by oligoclonal B-cell proliferation and have been suggested to be the microenvironment in which antibody mutants are generated. We report here direct evidence for this hypothesis. Rearranged V-region genes were amplified from the genomic DNA of cells picked from individual germinal centres. The sequence analysis of these genes revealed that most represent cells of distinct B-cell clones which expanded locally, generating somatic antibody mutants at high rate. By contrast, antigen-induced proliferation of B cells at another site, periarteriolar lymphocyte sheath-associated foci, was not associated with somatic hypermutation.

Amino Acid Sequence↗
PubMed1991

In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. I. The architecture and dynamics of responding cell populations.

After primary immunization with an immunogenic conjugate of (4-hydroxy-3-nitrophenyl)acetyl, two anatomically and phenotypically distinct populations of antibody-forming cells arise in the spleen. As early as 2 d after immunization, foci of antigen-binding B cells are observed along the periphery of the periarteriolar lymphoid sheaths. These foci expand, occupying as much as 1% of the splenic volume by day 8 of the response. Later, foci grow smaller and are virtually absent from the spleen by day 14. A second responding population, germinal center B cells, appear on day 8-10 and persist at least until day 16 post-immunization. Individual foci and germinal centers represent discrete pauciclonal populations that apparently undergo somatic evolution in the course of the primary response. We suggest that foci may represent regions of predominantly interclonal competition for antigen among unmutated B cells, while germinal centers are sites of intraclonal clonal competition between mutated sister lymphocytes.

Animals↗
PubMed1991

Fluorescence response in chlortetracycline-loaded neutrophils measures release of Ca2+ from intracellular membrane enclosed storage sites.

Chlortetracycline complexes with di- and trivalent cations resulting in an enhancement of its fluorescence emission intensity. Rabbit peritoneal neutrophils loaded with chlortetracycline gave a fluorescence response, even in the absence of extracellular Ca2+ and Mg2+, by a decrease in fluorescence intensity. The shift in the fluorescence emission maximum to lower wavelengths after the response suggested the response to be due to Ca2+ and not Mg2+ flux. The response was elicited by three mechanisms--a receptor-mediated mechanism by the chemotactic peptide, an ionophore-mediated one by lasalocid, and a detergent-mediated response by digitonin. These observations indicated that the response was due to transport of calcium across membranes in the intracellular compartments and may be physiologically significant. Whereas extracellular Ca2+ did not significantly affect the chemotactic peptide and lasalocid-mediated responses, Ca2+ inhibited the digitonin-mediated responses in a dose-dependent manner possibly due to extracellular Ca2+ flooding the cytosol through the digitonin-permeabilized plasma membrane and equilibrating the Ca2+ gradient across the intracellular membranes. The data collectively indicate that the fluorescence response is due to release of Ca2+ across intracellular membranes from a Ca2+ storage site into the cytosol.

Animals↗
PubMed1991

Rat liver microsomal ring- and S-oxidation of thiaarenes with central or peripheral thiophene rings.

The metabolism of the following thiaarenes has been investigated using liver microsomes of untreated, phenobarbital-, AroclorR- and 5,6-benzoflavone-pretreated rats: dibenzothiophene, naphtho[2,1-b]thiophene, benzo[b]naphtho[2,1-b]thiophene, benzo[b]naphtho[1,2-d]thiophene, benzo[b]naphtho-[2,3-d] thiophene, phenanthrol[1,2-b]thiophene, phenanthrol[4,5-bcd] thiophene, triphenyleno[1,12-bcd]-thiophene and dinaphtho[2,1-b:1',2'-d]thiophene. Thiaarenes with a central thiophene ring preferentially undergo S-oxidation and are converted into sulfoxides and sulfones, whereas those with a peripheral thiophene ring are oxidized at the carbocyclic skeleton resulting in the formation of phenols, dihydrodiols and triols. Sulfone formation seems to be inducible by phenobarbital but only little or not by 5,6-benzoflavone treatment. In most cases 5,6-benzoflavone and AroclorR treatment enhanced the rates of ring oxidation.

Animals↗
PubMed1991

[Acute corticosteroid myopathy in patient with asthma].

A patient, treated by mechanical ventilation with pancuronium or atracurium and with intravenously administered corticosteroid for status asthmaticus, presented with rhabdomyolysis (severe amyotrophy and marked of creatine kinase activity) and acute flacid and areflexic quadriplegia, involving the proximal and distal muscles but sparing the cephalic musculature. After review of the investigations (biochemistry, electromyogram, muscle biopsy), the diagnostic of acute corticosteroid myopathy following status asthmaticus was suggested, and a pancuronium neuromuscular complication or a critically ill polyneuropathy excluded. The non-inflammatory rhabdomyolysis concerned all the fiber types. Predominantly distal weakness resolved six months after the insult, in spite of the laboratory recurrence of the rhabdomyolysis at the time of a new status asthmaticus briefly treated with corticosteroid.

Acute Disease↗
PubMed1991

Measures of renal function in patients with cisplatin-related chronic renal disease.

Twenty-seven patients with advanced stage refractory ovarian cancer were studied to determine if chronic stable cisplatin-related renal dysfunction was present. Medical histories were examined to determine the types of therapy previously received as well as the total previous platinum doses received that ranged from 200 to 2,100 mg/m2. Standard assessments of renal function were made prior to administering current chemotherapy or immunotherapy to the patient, which included 24-hour creatinine clearance, serum creatinine, and blood urea nitrogen (BUN). For patients with a 24-hour creatinine clearance of less than 60 mL/minute, serum creatinine was highly variable (range: 0.9 to 2.0 mg/dL) and was not related to the degree of diminution in the 24-hour creatinine clearance value. Conversely, for patients with a serum creatinine of less than 1.5, the 24-hour creatinine clearance values varied by almost three-fold, ranging between 46 and 120 mL/minute. Two patients with serum creatinines of less than 1 had creatinine clearances of less than 50 mL per minute. Similarly, BUN measurements did not correlate with 24-hour creatinine clearance values, and the 24-hour creatinine clearance value was not related to the total cumulative platinum dose. We conclude that patients who receive substantive doses of cisplatin may experience chronic stable cisplatin-related renal dysfunction and that serum creatinine cannot be relied on to assess the degree of renal compromise. In such patients, we recommended that the 24-hour creatinine clearance value should be used when medical management is influenced by renal function.

Adult↗
PubMed1991

Confidentiality: a survey in a research hospital.

Despite the many justifications for protecting patient confidentiality, we recognize that confidentiality cannot be absolute. Our world of automated information and easy access and storage poses many threats to confidentiality. This paper has described a survey conducted at the NIH Clinical Center to assess the knowledge, attitudes, and behaviors of clinical physicians and nurses about confidentiality of patient information. The survey findings demonstrate the need for reminders and increased awareness about confidentiality in our setting. Most of the survey respondents had a good knowledge of what was expected of them, and they believed that confidentiality was important and maintaining it was their responsibility. Of interest was that in several simulated clinical situations, there was a discrepancy between what respondents indicated they should do and what they thought they would do. The biggest discrepancies appeared in situations that involved overhearing a patient conversation on the elevator, approaching an unfamiliar person who is reading a medical record in the nurses' station, and answering a patient's inquiry about the status of another patient. The findings support the speculation that this difference may be attributed to discomfort or decreased awareness, and not necessarily to lack of knowledge. Results indicate that policies and administrative expectations should be frequently communicated and enforced, and that educational programs that address issues of confidentiality should be provided. The results of this survey have been influential in guiding educational strategies and administrative activities at the clinical center. The clinical center initiated a confidentiality awareness campaign, displaying a new poster every three months in strategic locations and distributing other tangible reminders (such as pens, magnets, and buttons) containing the same confidentiality message.(ABSTRACT TRUNCATED AT 250 WORDS)

Attitude of Health Personnel↗