PubMed Health⌕ Search

Biomedical subjects

A Jakobovits

Publications and source records attributed to A Jakobovits.

At least 19 recordsLinked to original sources
PubMed2001

[Term pregnancy with fetus papyraceus].

The authors describe a case of dichorionic-diamniotic twin gestation diagnosed in the first trimester. One of the twins perished during the 2nd trimester and became compressed against the uterine wall (stuck twin phenomenon). The surviving sibling weighing 3400 g was delivered by cesarean section at term in good condition along with the placenta. A much smaller, pale second placenta was extracted thereafter together with a hardly recognizable fetus papyraceus.

Adult↗
PubMed2001

Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia.

We identified TMPRSS2 as a gene that is down-regulated in androgen-independent prostate cancer xenograft tissue derived from a bone metastasis. Using specific monoclonal antibodies, we show that the TMPRSS2-encoded serine protease is expressed as a Mr 70,000 full-length form and a cleaved Mr 32,000 protease domain. Mutation of Ser-441 in the catalytic triad shows that the proteolytic cleavage is dependent on catalytic activity, suggesting that it occurs as a result of autocleavage. Mutational analysis reveals the cleavage site to be at Arg-255. A consequence of autocatalytic cleavage is the secretion of the protease domain into the media by TMPRSS2-expressing prostate cancer cells and into the sera of prostate tumor-bearing mice. Immunohistochemical analysis of clinical specimens demonstrates the highest expression of TMPRSS2 at the apical side of prostate and prostate cancer secretory epithelia and within the lumen of the glands. Similar luminal staining was detected in colon cancer samples. Expression was also seen in colon and pancreas, with little to no expression detected in seven additional normal tissues. These data demonstrate that TMPRSS2 is a secreted protease that is highly expressed in prostate and prostate cancer, making it a potential target for cancer therapy and diagnosis.

Androgens↗
PubMed2001

Anti-PSCA mAbs inhibit tumor growth and metastasis formation and prolong the survival of mice bearing human prostate cancer xenografts.

Prostate stem-cell antigen (PSCA) is a cell-surface antigen expressed in normal prostate and overexpressed in prostate cancer tissues. PSCA expression is detected in over 80% of patients with local disease, and elevated levels of PSCA are correlated with increased tumor stage, grade, and androgen independence, including high expression in bone metastases. We evaluated the therapeutic efficacy of anti-PSCA mAbs in human prostate cancer xenograft mouse models by using the androgen-dependent LAPC-9 xenograft and the androgen-independent recombinant cell line PC3-PSCA. Two different anti-PSCA mAbs, 1G8 (IgG1kappa) and 3C5 (IgG2akappa), inhibited formation of s.c. and orthotopic xenograft tumors in a dose-dependent manner. Furthermore, administration of anti-PSCA mAbs led to retardation of established orthotopic tumor growth and inhibition of metastasis to distant sites, resulting in a significant prolongation in the survival of tumor-bearing mice. These studies suggest PSCA as an attractive target for immunotherapy and demonstrate the therapeutic potential of anti-PSCA mAbs for the treatment of local and metastatic prostate cancer.

Animals↗
PubMed2000

[Recent recurrence of a Biblical case of complicated twin birth].

The authors present a case which appears to resemble the child-birth of Thamar described in the Bible. The arm of one of the sons of Thamar prolapsed during the process of delivery. The same complication occurred in a patient of the authors, involving laid a head the arm of a male fetus. In both instances, the other twin child was born first, in the case of Thamar by the vaginal route, in that of the authors, by cesarean section. The description of this birthing event in the Bible permits the conclusion that complication observed in contemporary obstetric practice already occurred 7000 years ago.

Adult↗
PubMed2000

The human immunoglobulin loci introduced into mice: V (D) and J gene segment usage similar to that of adult humans.

Variable gene segments of the human immunoglobulin loci are represented in the human peripheral repertoire at different frequencies. XenoMouse strains contain approximately 2 megabases of the human immunoglobulin heavy and kappa light chain loci that functionally recapitulate the human humoral immune system. Analysis of human antibody transcripts from XenoMouse spleens and lymph nodes revealed that V, D and J gene segment utilization from these unimmunized animals were nearly identical to the gene segment utilization reported for humans with extensive antigenic histories.

Adult↗
PubMed1999

STEAP: a prostate-specific cell-surface antigen highly expressed in human prostate tumors.

In search of novel genes expressed in metastatic prostate cancer, we subtracted cDNA isolated from benign prostatic hypertrophic tissue from cDNA isolated from a prostate cancer xenograft model that mimics advanced disease. One novel gene that is highly expressed in advanced prostate cancer encodes a 339-amino acid protein with six potential membrane-spanning regions flanked by hydrophilic amino- and carboxyl-terminal domains. This structure suggests a potential function as a channel or transporter protein. This gene, named STEAP for six-transmembrane epithelial antigen of the prostate, is expressed predominantly in human prostate tissue and is up-regulated in multiple cancer cell lines, including prostate, bladder, colon, ovarian, and Ewing sarcoma. Immunohistochemical analysis of clinical specimens demonstrates significant STEAP expression at the cell-cell junctions of the secretory epithelium of prostate and prostate cancer cells. Little to no staining was detected at the plasma membranes of normal, nonprostate human tissues, except for bladder tissue, which expressed low levels of STEAP at the cell membrane. Protein analysis located STEAP at the cell surface of prostate-cancer cell lines. Our results support STEAP as a cell-surface tumor-antigen target for prostate cancer therapy and diagnostic imaging.

Amino Acid Sequence↗
PubMed1999

Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy.

A fully human IgG2kappa monoclonal antibody (MAb), E7.6.3, specific to the human epidermal growth factor (EGF) receptor (EGFr) was generated from human antibody-producing XenoMouse strains engineered to be deficient in mouse antibody production and to contain the majority of the human antibody gene repertoire on megabase-sized fragments from the human heavy and kappa light chain loci. The E7.6.3 MAb exhibits high affinity (KD = 5 x 10(-11) M) to the receptor, blocks completely the binding of both EGF and transforming growth factor alpha (TGF-a) to various EGFr-expressing human carcinoma cell lines, and abolishes EGF-dependent cell activation, including EGFr tyrosine phosphorylation, increased extracellular acidification rate, and cell proliferation. The antibody (0.2 mg i.p. twice a week for 3 weeks) prevents completely the formation of human epidermoid carcinoma A431 xenografts in athymic mice. More importantly, the administration of E7.6.3 without concomitant chemotherapy results in complete eradication of established tumors as large as 1.2 cm3. Tumor eradication of A431 xenografts was achieved in nearly all of the mice treated with total E7.6.3 doses as low as 3 mg, administered over the course of 3 weeks, and a total dose of 0.6 mg led to tumor elimination in 65% of the mice. No tumor recurrence was observed for more than 8 months after the last antibody injection, which further indicated complete tumor cell elimination by the antibody. The potency of E7.6.3 in eradicating well-established tumors without concomitant chemotherapy indicates its potential as a monotherapeutic agent for the treatment of multiple EGFr-expressing human solid tumors, including those for which no effective chemotherapy is available. Being a fully human antibody, E7.6.3 is expected to exhibit minimal immunogenicity and a longer half-life as compared with mouse or mouse-derivatized MAbs, thus allowing repeated antibody administration, including in immunocompetent patients. These results suggest E7.6.3 as a good candidate for assessing the full therapeutic potential of anti-EGFr antibody in the therapy of multiple patient populations with EGFr-expressing solid tumors.

Animals↗
PubMed1999

Target antigens for prostate cancer immunotherapy.

The detection and treatment of prostate cancer has been markedly improved by the use of Prostate-Specific Antigen (PSA) as a serological biomarker for disease. However, even after surgical intervention and hormone ablation therapy, a significant proportion of patients progress to advanced metastatic disease, for which there is no cure. An important goal has become the identification of antigens in advanced stage prostate cancer that represent targets for therapy. Recently, great progress has been made to utilize immunological therapies to treat cancer. Monoclonal antibody therapy has been successfully approved for the treatment of breast cancer and B-cell lymphoma, and multiple clinical trails are currently in progress in a variety of cancers, including prostate cancer. Pre-clinical and clinical studies are also underway to evaluate cancer vaccine approaches directed against antigens that are highly expressed in prostate and other cancers. This article describes several target antigens expressed in prostate cancer and immunological approaches directed against them that may be effective for treating prostate cancer patients.

Acid Phosphatase↗
PubMed1998

[Fetal ethology].

The author summarises the main aspects of fetal activity and behavior. Fetal activity provides information about early stages of the neurodevelopmental processes. Fetal behavior offers an opportunity for the study of motor, sensory, and cognitive functions in the fetus and, thus, of fetal wellbeing. In high risk pregnancies, studies of fetal behavior may help to establish the optimal time for the delivery of the fetus.

Delivery, Obstetric↗
PubMed1998

[Single live-birth after twin conception].

The authors discuss the pregnancy outcome following the demise of one or more embryos or fetuses of the set of a multiple pregnancy. The consequences depend, to great extent, upon the time of the intrauterine demise. Sonographic examination identifies the empty chorionic sacs when death of embryos occurred during the first trimester. Circulatory disturbance at the time of early embryogenesis led to the formation of a fetus acardius amorphus. One fetus died during the second trimester and careful sonographic search revealed laterally displaced fetus papyraceous. An other growth retarded, dead, small fetus was found closely attachd to the uterine wall (stuck twin). All these complications caused spontaneous fetal reduction in multiple gestations.

Abnormalities, Multiple↗
PubMed1998

Regulation of B cell development by variable gene complexity in mice reconstituted with human immunoglobulin yeast artificial chromosomes.

The relationship between variable (V) gene complexity and the efficiency of B cell development was studied in strains of mice deficient in mouse antibody production and engineered with yeast artificial chromosomes (YACs) containing different sized fragments of the human heavy (H) chain and kappa light (L) chain loci. Each of the two H and the two kappa chain fragments encompasses, in germline configuration, the same core variable and constant regions but contains different numbers of unique VH (5 versus 66) or Vkappa genes (3 versus 32). Although each of these YACs was able to substitute for its respective inactivated murine counterpart to induce B cell development and to support production of human immunoglobulins (Igs), major differences in the efficiency of B cell development were detected. Whereas the YACs with great V gene complexity restored efficient development throughout all the different recombination and expression stages, the YACs with limited V gene repertoire exhibited inefficient differentiation with significant blocks at critical stages of B cell development in the bone marrow and peripheral lymphoid tissues. Our analysis identified four key checkpoints regulated by VH and Vkappa gene complexity: (a) production of functional mu chains at the transition from the pre B-I to the pre B-II stage; (b) productive VkappaJkappa recombination at the small pre B-II stage; (c) formation of surface Ig molecules through pairing of mu chains with L chains; and (d) maturation of B cells. These findings demonstrate that V gene complexity is essential not only for production of a diverse repertoire of antigen-specific antibodies but also for efficient development of the B cell lineage.

Animals↗
PubMed1998

Production and selection of antigen-specific fully human monoclonal antibodies from mice engineered with human Ig loci.

The ability to produce highly specific fully human monoclonal antibodies to human antigens has potential significant applications to human therapy. This review describes the creation of novel mouse strains engineered to produce a diverse repertoire of fully human antibodies in the absence of mouse antibodies. These mouse strains have been generated by introducing megabase-sized human immunoglobulin loci, containing the majority of the human antibody gene repertoire, in nearly germline configuration, into mice deficient in mouse antibody production. The mice produce high levels of human IgMkappa and IgGkappa antibodies with a diverse adult-like repertoire. Upon immunization with multiple human antigens the mice generate high affinity, antigen-specific fully human monoclonal antibodies with neutralization activity. Comparison of these mice to other strains containing limited human antibody gene repertoire underscores the importance of the large number of variable genes for faithful reproduction of functional and diverse human antibody response in mice.

Journal Article↗
PubMed1998

[Notching of the bilateral uterine artery flow velocity wave-forms in the third trimester and perinatal complications].

Pulsatile color duplex Doppler ultrasonography system was used to study blood flow velocity waveforms in the uterine arteries of 492 pregnant women in the third trimester. In 38 (7.7%) patients unilateral and in 42 (8.5%) bilateral postsystolic notches were observed. Those with bilateral early diastolic notches experienced poor perinatal outcome in 40 (95.2%) instances. The same occurred in 16 (42.1%) others with unilateral notches and in 13 (3.2%) without notches but with evidence of increased impedance (pulsatility index > 1.20, resistance index > 0.58 and systolic/diastolic ratio > 2.6). The presence of bilateral postsystolic notches in the uterine artery flow velocity waveforms appears to be a reliable predictor of poor pregnancy outcome.

Adult↗
PubMed1998

The long-awaited magic bullets: therapeutic human monoclonal antibodies from transgenic mice.

The ability to produce a diverse repertoire of fully human monoclonal antibodies (mAbs) may have significant applications to human therapy. This update describes the creation of a novel tool for the production of therapeutic human mAbs: a mouse strain engineered to produce a large range of human antibodies in the absence of mouse antibodies. This strain, XenoMouse, has been generated by the introduction of large segments of human immunoglobulin loci, containing the majority of the human antibody gene repertoire, into mice deficient in mouse antibody production. The mice produce a diverse array of authentic fully human IgGkappa antibodies. Upon immunisation with multiple human antigens the mice generate large panels of high affinity, antigen-specific fully human mAbs with therapeutic activities. XenoMouse-derived hybridomas were shown to be stable, producing significant levels of human mAbs. XenoMouse technology represents an efficient and reliable tool for the production of therapeutic human mAbs, which can accelerate the evaluation and validation of antibody therapy in human disease.

Journal Article↗
PubMed1997

Inactivation of the mouse HPRT locus by a 203-bp retroposon insertion and a 55-kb gene-targeted deletion: establishment of new HPRT-deficient mouse embryonic stem cell lines.

To obtain useful hypoxanthine phosphoribosyl-transferase (HPRT)-deficient mouse ES cell lines, two different methods were employed: (i) selection of spontaneous 6-TG-resistant mutants and (ii) gene targeting of the HPRT locus. The first approach resulted in the establishment of E14.1TG3B1, a spontaneous HPRT-deficient cell line with an insertional mutation of 203 bp in the third exon of the HPRT gene. The insert is highly homologous to the B2 mouse repetitive element and has all the expected retroposon characteristics, thus providing an example of gene inactivation by retroposon insertion. This clone exhibited stable 6-TG resistance and high germ-line transmission frequency. Thus E14.1TG3B1 is a useful ES cell line for modifying the mouse genome using the HPRT gene as a selection marker and for transmission at a high frequency into the mouse germ line. The second approach resulted in a 55-kb deletion of the mouse HPRT locus, demonstrating the feasibility of replacement-targeting vectors to generate large genomic DNA deletions.

Animals↗
PubMed1997

Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice.

We constructed two megabase-sized YACs containing large contiguous fragments of the human heavy and kappa (kappa) light chain immunoglobulin (Ig) loci in nearly germline configuration, including approximately 66 VH and 32 V kappa genes. We introduced these YACs into Ig-inactivated mice and observed human antibody production which closely resembled that seen in humans in all respects, including gene rearrangement, assembly, and repertoire. Diverse Ig gene usage together with somatic hypermutation enables the mice to generate high affinity fully human antibodies to multiple antigens, including human proteins. Our results underscore the importance of the large Ig fragments with multiple V genes for restoration of a normal humoral immune response. These mice are likely to be a valuable tool for the generation of therapeutic antibodies.

Amino Acid Sequence↗