Regulation Of Cyclic-amp Phosphodiesterase Of Rat Skeletal Myoblasts

The aim of the present investigation was to study the various regulatory mechanisms involved in the control of cAMP phosphodiesterases in rat skeletal myoblasts.;In rat skeletal myoblasts and adult muscle extracts, four forms of a high affinity cAMP phosphodiesterase are found in vitro. These are termed PDE I, PDE II, PDE III and PDE IV, and have approximately molecular weights of 1.5 x 10(\u276), 400,000, 120,000 and 60,000, respectively. Evidence is presented to show that there is only one primary form of phosphodiesterase in myoblasts, viz. PDE II, with the rest of the forms being derived from it.;In the presence of Bt(,2)cAMP or compounds which are able to augment in vivo concentrations of cAMP in the culture medium, the phosphodiesterase activity of skeletal myoblasts increases about 2-fold within 30 min of culture. Modification of PDE II can be demonstrated in cell-free extracts. Modification is entirely dependent on ATP and cAMP. Evidence is presented to show that during in vitro activation of phosphodiesterase, PDE II is phosphorylated.;When the myoblasts are exposed to Bt(,2)cAMP for 10-16 hours the activity of PDE III increases considerably. Spontaneous or Rous-Sarcoma virus-transformed myoblasts, however, show altered regulation of the two forms of PDE. In the presence of cAMP in the medium, unlike the nontransformed cells, the level of PDE III do not increase but the activity of PDE II rises. The altered moe of PDE regulation in transformed cells is dominant in hybrids between normal and transformed myoblasts

Mechanisms of sensitivity and resistance to CDK4/CDK6 inhibitors in hormone receptor-positive breast cancer treatment

Cell cycle dysregulation is a hallmark of cancer that promotes eccessive cell division. Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) are key molecules in the G1-to-S phase cell cycle transition and are crucial for the onset, survival, and progression of breast cancer (BC). Small-molecule CDK4/CDK6 inhibitors (CDK4/6i) block phosphorylation of tumor suppressor Rb and thus restrain susceptible BC cells in G1 phase. Three CDK4/6i are approved for the first-line treatment of patients with advanced/metastatic hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) BC in combination with endocrine therapy (ET). Though this has improved the clinical outcomes for survival of BC patients, there is no established standard next-line treatment to tackle drug resistance. Recent studies suggest that CDK4/6i can modulate other distinct effects in both BC and breast stromal compartments, which may provide new insights into aspects of their clinical activity. This review describes the biochemistry of the CDK4/6-Rb-E2F pathway in HR+ BC, then discusses how CDK4/6i can trigger other effects in BC/breast stromal compartments, and finally outlines the mechanisms of CDK4/6i resistance that have emerged in recent preclinical studies and clinical cohorts, emphasizing the impact of these findings on novel therapeutic opportunities in BC

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. Methods: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. Interpretation: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Histomorphological features of resected bladder tumors: Do energy source makes any difference

Context: The recent advent of bipolar energy in bladder tumor resection has raised many questions regarding density of current and its effect on histopathology of the resected transurethral resection of bladder tumor (TURBT) chips. Aims: The aim of this study is to evaluate the histomorphological features in resected bladder tumors comparing bipolar versus conventional (monopolar) energy. Settings and Design: Inclusion criteria were patients with primary presentation of carcinoma urinary bladder undergoing TURBT. The patients with prior resections were excluded as these could jeopardize the results of cautery artifacts. Materials and Methods: From February 2010 to December 2011, 61 patients with primary carcinoma bladder and meeting our inclusion criteria were compared. Group 1 (n = 31) underwent bipolar-TURBT (B-TURBT) and Group 2 (n = 30) monopolar-TURBT (M-TURBT). Two pathologists, who were blinded to the form of electrocautery used, examined the resected tissue. The degree of cautery artifact in each specimen was recorded. The severity of the cautery artifact was graded as absent, mild, moderate, or severe. The mean age, tumor size, and resection time were recorded in both groups. Statistical Analysis Used: Data were analyzed using SPSS 16. Data were compared in between groups using paired t-test and Pearson's Chi-square test. The significance level was set at 0.05. Results: The mean age, tumor size, and resection time were similar in between the two groups. The pathologists had no obscurity in reaching a correct diagnosis in all cases. The cautery artifacts were graded as absent in 10 (32.2%) and 8 (26.67%), mild in 12 (38.7%) and 11 (36.67%), moderate in 5 (16.1%) and 7 (23.33%) and severe in 4 (12.9%) and 5 (16.66%) cases, respectively in Group 1 and 2. There was no statistically significant histomorphogical dissimilarity between specimens according to the type of cautery used. Conclusions: Bladder tissue obtained from B-TURBT is of equivalent histomorphological feature as that of standard M-TURBT

Upgrading of gleason score on radical prostatectomy specimen compared to the pre-operative needle core biopsy: An Indian experience

Objectives : To assess the accuracy of Gleason grading/scoring on preoperative needle core biopsy (NCB) compared to the radical prostatectomy (RP) specimen. Materials and Methods : Data of NCB and RP specimens was analyzed in 193 cases. Gleason grade/scoring was done on both NCB and RP specimens. Sixteen cases were excluded for various reasons. The Gleason scores of the two sets of matched specimens were compared and also correlated with the PSA, age, and number of needle biopsy cores. The overall change was also correlated with the initial score on NCB. Results : The mean age and PSA were 63.3 ± 2(5.27) years and 18.48 ± 2(28.42) ng/ml, respectively. The average Gleason score increased from 5.51 ± 2(1.52) to 6.2 ± 2(1.42) (P < 0.02). The primary grade increased in 57 (32.2%) cases. Overall, 97 (54.8%) cases had an increase in Gleason score. Five other cases had a change from 3 + 4 = 7 to 4 + 3 = 7. Change in Gleason score was significantly more if the score on NCB was ≤6 or number of needle cores was ≤6. Besides, 28 cases had perineural invasion, 16 had capsular invasion (pT3 a ), and 4 had vascular invasion on RP specimen. Conclusions : There is a significant upgrading of Gleason score on RP specimens when compared with NCB. This trend may be correlated positively with lower initial Gleason score on preoperative biopsy and the lower number of cores taken

Pattern of metastases in renal cell carcinoma: a single institution study

Background: Increasing numbers of patients with renal cell carcinoma (RCC) are incidentally detected and can be potentially cured by surgery alone. In treating metastatic RCC, worthwhile survival rates are achieved in cases of low burden recurrences. This necessitates a rational follow up protocol, which picks up early recurrences and avoids costly surveillance for those with a favorable prognosis. Aims: We studied the patterns of metastases occurring in patients operated for localized or locally advanced renal cell carcinoma in the Indian setting and try to evolve a suitable follow up protocol. Setting and Design: Institution based, retrospective data. Method and Materials: Records of patients from January 1988 to December 2003, operated for initially localized RCC were reviewed. Follow up was performed using an established protocol. Occurrence of metastases and their patterns were studied. Statistical analysis used: Comparison of the different survival times was performed using the one-way analysis method. Multiple comparisons (post hoc test) were performed using the Bonferroni method. Result: Follow up was available on 209 patients. Mean survival was 43.75 months (SD ± 28.72). Thirty-nine patients developed 59 metastases. Lungs were the commonest site of metastases (37%), followed by bone (22%), liver (19%) and brain (8%). Relapse and survival showed significant correlation with pathological stage (p < 0.001), with higher stage being associated with greater relapses and lesser survival. There was no correlation between site of recurrence and stage of disease. Conclusions: Occurrence of metastases correlate with the pathological stage of the disease at primary presentation. Tailored, stage-based follow up protocols allow adequate surveillance for disease activity and progression without escalating the overall costs