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At least 19 recordsLinked to original sources
PubMed2025

Evolutionary and Functional Analysis of Caspase-8 and ASC Interactions to Drive Lytic Cell Death, PANoptosis.

Caspases are evolutionarily conserved proteins essential for driving cell death in development and host defense. Caspase-8, a key member of the caspase family, is implicated in nonlytic apoptosis, as well as lytic forms of cell death. Recently, caspase-8 has been identified as an integral component of PANoptosomes, multiprotein complexes formed in response to innate immune sensor activation. Several innate immune sensors can nucleate caspase-8-containing PANoptosome complexes to drive inflammatory lytic cell death, PANoptosis. However, how the evolutionarily conserved and diverse functions of caspase-8 drive PANoptosis remains unclear. To address this, we performed evolutionary, sequence, structural, and functional analyses to decode caspase-8's complex-forming abilities and its interaction with the PANoptosome adaptor ASC. Our study distinguished distinct subgroups within the death domain superfamily based on their evolutionary and functional relationships, identified homotypic traits among subfamily members, and captured key events in caspase evolution. We also identified critical residues defining the heterotypic interaction between caspase-8's death effector domain and ASC's pyrin domain, validated through cross-species analyses, dynamic simulations, and in vitro experiments. Overall, our study elucidated recent evolutionary adaptations of caspase-8 that allowed it to interact with ASC, improving our understanding of critical molecular associations in PANoptosome complex formation and the underlying PANoptotic responses in host defense and inflammation. These findings have implications for understanding mammalian immune responses and developing new therapeutic strategies for inflammatory diseases.

Caspase 8↗
PubMed2025

Genomic Alterations in Multiple Myeloma: A Comprehensive Landscape.

UNLABELLED: Multiple myeloma (MM) is a biologically heterogeneous plasma cell malignancy in which cytogenetic abnormalities play a key role in disease prognosis. This study evaluates the spectrum of genomic aberrations in newly diagnosed multiple myeloma (NDMM) patients, with a focus on high-risk cytogenetic profiles, including double-hit (DHMM), and triple-hit multiple myeloma (THMM). This is a retrospective analysis of NDMM patients, reviewing clinical and laboratory data for baseline characteristics, cytogenetics, therapy, and outcomes. Patients were categorized based on the cytogenetic abnormalities. Double-hit MM was defined by the coexistence of two high-risk abnormalities and triple-hit MM was defined by coexistence of three or more high-risk abnormalities. Survival outcomes were assessed using Kaplan-Meier analysis and Cox regression models using SigmaPlot (version 15). A total of 314 NDMM cases (205 Male: 109 Female; median age 58 years) enrolled between 2014 and 2021 were evaluated. Using the Revised International Staging System (R2-ISS), most patients were in stage 2 (41.1%) and stage 3 (38.2%). Cytogenetic analysis revealed one or more high-risk abnormalities in 43% of cases. Among the high-risk group, one, two and three or more high-risk abnormalities were observed in 89 (28%), 35 (11%), and 11 (4%) patients, respectively. THMM cases exhibited the poorest outcomes [median overall survival (OS):7 months], in comparison to DHMM (OS: 33 months), SHMM (OS: 40 months), and patients without high-risk features (OS: 60 months). Cox regression analysis confirmed that THMM patients had a 3.6-fold increased risk of death (HR: 3.677; 95% CI: 2.219-7.915; p&#x2009;<&#x2009;0.001) and 4-fold increased risk of progression (HR: 4.191; 95% CI: 1.897-7.126; p&#x2009;<&#x2009;0.001) compared to patients without any high-risk abnormalities. Among 67 patients undergoing autologous stem cell transplant (ASCT), high risk abnormalities were significantly associated with shorter OS (HR: 2.409; 95% CI: 1.094-5.291; p&#x2009;=&#x2009;0.029, 111 months for ASCT without high-risk vs. 78 months for ASCT with high- risk abnormalities) and shortened PFS (HR: 2.379; 95% CI: 1.285-4.403; p&#x2009;=&#x2009;0.006, 85 months for ASCT without high-risk vs. 34 months with high-risk abnormalities). Double and triple-hit MM constitute 14.6% of NDMM cases, indicating poor survival and early disease progression. Comprehensive cytogenetic profiling at diagnosis and post-ASCT has the potential to improve risk stratification and guide individualized treatment strategies for high-risk MM patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s12288-025-02284-5.

Cytogenetic↗
PubMed1977

Leukaemia in benzene workers.

Workers occupationally exposed to benzene in 1940-49 were followed for vital status up to 1975. In comparison with two control populations, a significant (P less than 0-002) excess of leukaemia was observed. A five-old excessive risk of all leukaemias and a ten-fold excess of deaths from myeloid and monocytic leukaemias combined are demonstrated in the study population compared with controls. These figures under-estimate the true leukaemia risk to benzene-exposed workers, because follow-up is only 75% complete and the untraced 25% of the study population were all regarded, in the statistical analysis, as being alive at the end of the study period. The environment of the workers in the study population was not contaminated with solvents other than benzene, and existing records indicate that the benzene levels themselves were generally below the limits recommended at the time of their measurement.

Adult↗
PubMed1979

A pilot program of multiple cadaver organ and tissue retrieval.

A one year pilot project conducted at a 2,000 bed medical center involved a unique approach to the retrieval from cadavers of multiple viable organs and tissues. Aspects of the program included a special unit for sterile evaluation and storage of tissue, a computerized registry of potential donors, a nurse to coordinate and expedite retrieval, and a retrospective chart review to define the incidence and location of potential cadaver donors. There were requests for 121 tissues by 39 investigators. Eleven different tissues were needed within 4 hours of death. Forty-two percent of individuals contacted directly enlisted in the donor registry, three of whom were identified on the computer at the time of death. A five-fold increase in cadaver donor evaluation referrals occurred, and one third of referrals resulted in viable tissue retrieval. A review of 728 deaths indicated that 45% could have been potential eye donors, 27% pancreas donors and 2.5% kidney donors. A coordinated program to retrieve multiple viable organs and tissues for transplantation and research appeared to be effective in this initial pilot study.

Cadaver↗
PubMed2025

Genomic Epidemiology of Resurgent Hepatitis A in Florida, 2018-2022.

During 2018-2022, a resurgence of hepatitis A occurred in Florida, with 5491 cases reported. Genotyping was performed on a convenience sample of cases through amplification and sequencing of the hepatitis A virus VP1-P2B junction region. Virus isolates from 1190 cases (22%) were genotyped; 69% were subgenotype IB, 30% were subgenotype IA, and 1% were subgenotype IIIA. Subgenotype IB was more common among patients reporting recent drug use or homelessness, whereas IA was more common among those reporting recent international travel and among men who have sex with men. Genotype IB infection was associated with a more than 4-fold greater odds of death compared to IA infection. A network analysis revealed 11 genomic clusters of &#x2265;10 cases, with distinct temporal and spatial distributions. Case reports in 2023 decreased to below pre-2018 numbers, likely due to high population immunity following natural infection and extensive vaccination activities in the highest-risk groups.

Humans↗
PubMed2025

Psychometric Properties and Prognostic Value of the UCSD Shortness of Breath Questionnaire in Hypersensitivity Pneumonitis: A Prospective Cohort Study.

RATIONALE: Dyspnea is a prominent symptom of hypersensitivity pneumonitis (HP), limiting patients' activity and impairing their quality of life. The University of California San Diego Shortness of Breath questionnaire (UCSD) is a 24-item instrument used to assess dyspnea severity in patients with various respiratory conditions. OBJECTIVE: To examine the psychometric properties of the UCSD and assess the validity of its scores as measures of dyspnea severity and prognostic value in a prospective cohort with HP. METHODS: We evaluated the reliability, validity, and responsiveness of UCSD scores and assessed the association between score change and survival in a cohort of patients with HP who completed the UCSD and other HP severity metrics at baseline, 6 and 12 months. We introduce the reliable change index (RCI) and the likely change index (LCI) as ways to assess the statistical significance of within-individual change in UCSD scores and conducted analyses to provide context. RESULTS: At baseline, internal consistency (Cronbach's coefficient alpha) was 0.97; there were significant, moderately strong correlations between UCSD scores and percent predicted forced vital capacity (FVC%) r = -0.39, percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%) r = -0.33), and Borg dyspnea scores (0.55). UCSD scores were significantly different between the lowest and highest FVC%, 64.9 &#xb1; 18.9 vs. 36.2 &#xb1; 22.9. A 10-point worsening in the UCSD score was associated with a nearly 15-fold increase in time-to-death over the follow-up period. CONCLUSION: The UCSD has acceptable psychometric properties for assessing dyspnea severity in patients with HP. Worsening dyspnea is associated with shortened survival.

Journal Article↗
PubMed1978

[Purification and properties of plasminogen activator from human blood plasma after sudden death].

Plasminogen activator from human blood plasma after sudden death was isolated and purified 60-90-fold by precipitation with ammonium sulfate, ZnSO4 and ethanol as well as by chromatography on DEAE-Sephadex A-50 and gel--filtration through Sephadex G-200. The resulting enzyme had specific activity of 110-210 units per mg of protein. The enzyme prepartion possessed no plasmin activity; total content of carbohydrates was 2.4-2.5%; that of syalic acids--1.2-1.3%. The enzyme was found heterogeneous during disc electrophoresis in 7.0% polyacrylamide gel and corresponded in its mobility to beta-globulins of blood plasma. Molecular weight of enzyme as determined by gel-filtration through Sephadex G-200 is 70000. The isoelectric point lies at pH 6.2.

Death, Sudden↗
PubMedDate not supplied

[Comparative study of the biological activity and toxic effect of 1alpha-hydroxycholecalciferol and ergocalciferol in rats].

Single administration of 0.25 microgram of sunthetic Ialpha-hydroxycholecalciferol (IalphaOHD3) into nephrectomized rats, maintained at D-avitaminous diet, improved the active transport of calcium ions against the concentration gradient in small intestine of these animals, whereas ergocalciferol was biologically inactive under the same conditions. Administration of IalphaOHD3 during 5 days at a dose 0.025 microgram normalized calcium content in blood serum of rats with D-avitaminosis, Increased doses of IalphaOHD3, administered into intact animals, caused transient hyperphosphatemia, hypercalcemia, calcinosis of internal tissues (kidney heart, aorta) as well as death of some animals. IalphaOHD3 exceeded 400-fold the hypercalcemic and calcinose effects of ergocalciferol. LD50 for IalphaOHD3 was equal to 100 microgram/kg, if it was administered during 5 days per os. Tissue calcinosis was developed after administration of a daily dose 10 microgram/kg, moderate hypercalcemia was caused by a daily dose 1 microgram/kg or 0.25 microgram per an animal; this amount is only 10-fold higher as compared with the physiologic requirement. Ergocalciferol caused hypercalcemia and metastatic calcification only at a dose 4000 microgram/kg. Clinical use of IalphaOHD3 at doses, exceeding the physiologic requirements, has to be prohibited due to high activity of the preparation and to toxicity of its increased doses.

Animals↗
PubMed1978

DNA synthesis and proliferation of human lymphocytes in vitro. I. Cell kinetics of response to phytohemagglutinin.

The response of human lymphocytes to phytohemagglutinin (PHA) stimulation was assessed in detailed kinetic studies, in order to define conditions permitting and regulating proliferation. By utilizing live and dead cell counts, cell cycle characterizations, and calculations of rates of entry into S phase and mitosis, it was demonstrated that dilute culture conditions (2 X 10(5) cells/ml) enable lymphocytes to proliferate for a period of 5 or 6 days. Although cell division occurs in concentrated cultures (2 X 10(6) cells/ml), net proliferation is not demonstrable due to extensive cell death and earlier decay in the proliferative response. It is projected that without cell death the cell count would rise more than 6-fold in a dilute culture and 2-fold in a concentrated culture under these growth conditions. The kinetic analyses did not demonstrate separate PHA dose thresholds for blastogenesis and entry into S phase. High doses of PHA stimulated a suboptimal response by causing excessive cell death without reducing initial entry into the cell cycle. These results provide a kinetic explanation for the frequent observation of little net proliferation despite substantial 3H-thymidine incorporation in PHA-stimulated lymphocyte cultures. Cell death is identified as a parameter that must be considered in the interpretation of in vitro lymphocyte stimulation studies, and methods for quantifying the role of cell death are demonstrated.

Blood Cell Count↗
PubMed1979

[Production and study of the immunogenic properties of a bivalent inactivated vaccine against mucosal disease (bovine viral diarrhea and infectious rhinotracheitis)].

Bivalent inactivated vaccine against mucous disease (MD) and infectious rhinotracheitis (IR) in cattle was produced from cell cultural MD and IR virus suspensions. The vaccine was concentrated on aluminium hydroxide, inactivated by ethanol and is without residual virus. Saponine in final 1:1500 dilution is added as supplementary adjuvant. Immunogeneity of the vaccine was tested on 10-month-old calves, which had shown full resistance against experimental infection with virulent strains of both viruses. Testing on calves for harmlessness by use of a five-fold higher vaccine dose indicated complete tolerance of the vaccine. The prophylactic effect of the vaccine applied in practical work to directly threatened with immediate MD and IR infection cows, including pregnant ones, consisted in reduced number of cases of abortion, of inborn malformations, in lower neonatal calf death-rate, etc. No disturbances were observed following two-fold vaccination of the animals, a fact proving its harmlessness. The positive results of the studied vaccine allow its further application in the combined prophylaxis of MD and IR in calf fattening and breeding complexes.

Animals↗
PubMed1979

Underlying disorders responsible for the neonatal deaths associated with low Apgar Scores.

Data from a large study were used to determine the frequency of fatal disorders associated with low Apgar scores. 5-min scores had the best correlation with mortality rates. Death rates were more than ten times greater with abnormal than with normal 5-min scores. This difference was only 3-fold for 1-min values. Amniotic fluid infections were responsible for nearly half of the deaths in preterm and 24% of the deaths in term neonates with 5-min Apgar scores 0--6. The respective values for disorders that cause antenatal hypoxia were 25 and 24% and for major congenital anomalies, 7 and 28%.

Abruptio Placentae↗
PubMed1979

Pertussis vaccine--an analysis of benefits, risks and costs.

Using decision analysis, we estimated the benefits, risks and costs of routine childhood immunization against pertussis. Without an immunization program, we predict that there would be a 71-fold increase in cases and an almost fourfold increase in deaths (2.0 to 7.6) per cohort of one million children. With a vaccination program, we predict 0.1 case of encephalitis associated with pertussis and five cases of post-vaccination encephalitis; without a program, there would be only 2.3 cases of encephalitis associated with pertussis. Community vaccination would reduce by 61 per cent the costs related to pertussis. Our analysis supports continuation of vaccination in routine childhood immunization programs, but suggests the need for more reliable data on complications from the vaccine, further study of the epidemiology of pertussis and development of a less toxic vaccine.

Child↗
PubMed1978

Cultural and environmental factors affecting the longevity of Escherichia coli in Histosols.

The survival of Escherichia coli in organic soils (Histosols) was examined. The death rate of this organism in Pahokee muck was less than that observed in Pompano fine sand. The number of viable E. coli cells found in the muck was approximately threefold greater than that found in the sand following 8 days of incubation. The initial population of the coliform affected the death rate. The rate of loss of viability varied 100-fold when the population size decreased from 2.5 x 10(7) to 3.4 x 10(4). Other factors affecting the viability of E. coli in muck were aerobic versus anaerobic growth of the organism and moist versus flooded conditions in the soil. The greatest survival of the coliform was noted with anaerobically grown cells amended to flooded soil. That the observed decrease in E. coli viability in soil was the result of biotic factors was demonstrated with amendment of sterile soil with E. coli. When 1.1 x 10(5) bacteria per g of soil were added to sterile muck, a population of 3.0 x 10(7) organisms per g of soil developed over a 10-day period. The role of the protozoa in eradication of the coliform from the muck was indicated by a sixfold increase in the protozoan population in natural soil amended with E. coli. Higher organic matter content in a Histosol compared with a mineral soil resulted in an increased survival of the fecal coliforms. Biotic factors are instrumental in the decline in coliform populations, but the potential for growth of the coliform in the organic soil could extend the survival of the organism.

Aerobiosis↗
PubMedDate not supplied

[Model of eradication of tuberculosis in children in an area with high epidemiological potential].

In the territory of the Drajna TB dispensary, in the Prahova County, a series of complex measures have been experimented in the course of the second trimester of 1972, intending to prevent and to eliminate tuberculosis in children. Of the 31,731 children aged between 1 and 14 years, 29,496 have been tested with 2 units of PPD-IC65 (93 percent). A proportion of 12,6 percent of those tested presented reactions of more than 10 mm in diameter and 22,779 were vaccinated with BCG (Pasteur-Paris strain). The radiological pulmonary control of the reactors allowed for the detection of 24 cases of tuberculosis all of them new and asymptomatic. The efficiency of the detection was of 0,8 new cases per 1,000 tuberculin tested children or of 0,4 new cases per 100 of reactors that had been x-ray examined. This prophylactic action was repeated in 1973 in 2,219 children aged between 1 and 2-1/2 years that had been ommited in the preceding year and 4 new cases of tuberculosis were detected. In the medical districts in which there was a high prevalence of the children infection total radiophotographic case finding of the adult population was carried out. The result was a doubling of the TB incidence in children in 1972 followed by a 5-fold reduction of the indicators in 1973. The severe forms and death through tuberculosis in children have disappeared. The risk to develop the disease in BCG vaccinated children was reduced to 4,4 0/0000 per year. It is estimated that a generalization over the whole of the county of these prophylactic measures, as applied in the Drajna territory, under the form of a mass campaign, will allow for an improvement of the epidemiometric indicators in children in a relatively short time.

Adolescent↗
PubMed1976

[Chemotherapy of acute malaria attacks in patients returning from tropical and subtropical countries (author's transl)].

The number of primary malaria attacks caused by imported infections notified in the Federal Republic of Germany during the period of 1963 through 1975 has increased five fold from 30 to 154 per year. The total number of deaths in the same period was 55. This gave rise to outline again the established methods of chemotherapy and their parasitological basis. The chloroquine resistance of P. falciparum strains is discussed. No causal relationship exists between drug resistance and the fatalities by imported malaria. The need for early diagnosis and treatment in falciparum malaria is emphasized. In order to avoid diagnostic difficulties in medical practice it is suggested to have blood films for parasitological diagnosis sent to a specialized laboratory, and to start chloroquine treatment immediately without awaiting confirmation or rejection of the diagnosis. This procedure would minimize the risk for the patient and would cause no harm if malaria should not be confirmed.

Antimalarials↗
PubMed1976

A measles epizootic with 5 deaths in newly-imported rhesus monkeys (Macaca mulatta).

Of 21 newly-imported rhesus monkeys, 11 showed a typical macular rash and 13 developed a 4-fold or greater rise in antibody titre to measles. 5 animals died, 4 of them with extensive pneumonia, pleurisy and pericarditis. Although measles was involved in each case, there were contributory causes of death, namely Diplococcus pneumoniae and Staphylococcus aureus infection, and infestation with Oesophagostomum (nodular worm) larvae.

Animals↗
PubMed1977

Causes of death among construction machinery operators.

Causes of death among 2,190 deceased operating engineers identified from the 1967 International Union of Operating Engineers death benefit listing were analyzed to determine if there were conditions occurring with unusual frequency that might be indicative of hazardous conditions in the work environment. The most striking finding was a three-fold excess of fatal accidents occurring at places other than the home or resident institution. The increased risk was evident in each of four regions of the country and at all ages under 65. Significant excesses in deaths from lung cancer and intestinal cancer were seen also. Comparative mortality from lung cancer was directly related to age, with the greatest increase (two-fold) occurring after age 75. There was no evidence of a greater than expected frequency of deaths from non-malignant respiratory disease among operating engineers.

Accidents↗