Thiazole, a unique heterocycle containing sulphur and nitrogen atoms, occupies an important place in medicinal chemistry. It is an essential core scaffold present in many natural (Vitamin B1- ...Thiamine) and synthetic medicinally important compounds. The versatility of thiazole nucleus demonstrated by the fact that it is an essential part of penicillin nucleus and some of its derivatives which have shown antimicrobial (sulfazole), antiretroviral (ritonavir), antifungal (abafungin), antihistaminic and antithyroid activities. The synthetic importance of thiazole derivatives, its reduced forms and condensed derivatives have been increased much by their recent applications as anticancer (tiazofurin), anthelmintic, vulcanising accelerators (mercaptobenzothiazole) and photographic sensitizers. Thiazole chemistry has developed steadily after the pioneering work of Hofmann and Hantsch. Bogert and co-workers made significant contribution to expand this field. Mills established the importance of thiazole ring in cyanine dyes which is used as photographic sensitizer. Benzothiazole, a fused derivative of thiazole have also proved its commercial value. Present review describes chemical and biological importance of thiazole and its condensed derivatives with an emphasis on recent developments.
We have used in vitro and mouse xenograft models to examine the interaction between breast cancer stem cells (CSC) and bone marrow-derived mesenchymal stem cells (MSC). We show that both of these ...cell populations are organized in a cellular hierarchy in which primitive aldehyde dehydrogenase expressing mesenchymal cells regulate breast CSCs through cytokine loops involving IL6 and CXCL7. In NOD/SCID mice, labeled MSCs introduced into the tibia traffic to sites of growing breast tumor xenografts where they accelerated tumor growth by increasing the breast CSC population. With immunochemistry, we identified MSC-CSC niches in these tumor xenografts as well as in frozen sections from primary human breast cancers. Bone marrow-derived MSCs may accelerate human breast tumor growth by generating cytokine networks that regulate the CSC population.
The installation of gem-difluoromethylene groups into organic structures remains a daunting synthetic challenge despite their attractive structural, physical, and biochemical properties. A very ...efficient retrosynthetic approach would be the functionalization of a single C–F bond from a trifluoromethyl group. Recent advances in this line of attack have enabled the C–F activation of trifluoromethylarenes, but limit the accessible motifs to only benzylic gem-difluorinated scaffolds. In contrast, the C–F activation of trifluoroacetates would enable their use as a bifunctional gem-difluoromethylene synthon. Herein, we report a photochemically mediated method for the defluorinative alkylation of a commodity feedstock: ethyl trifluoroacetate. A novel mechanistic approach was identified using our previously developed diaryl ketone HAT catalyst to enable the hydroalkylation of a diverse suite of alkenes. Furthermore, electrochemical studies revealed that more challenging radical precursors, namely trifluoroacetamides, could also be functionalized via synergistic Lewis acid/photochemical activation. Finally, this method enabled a concise synthetic approach to novel gem-difluoro analogs of FDA-approved pharmaceutical compounds.
IMPORTANCE: Pregnant women are at increased risk of morbidity and mortality from COVID-19 but have been excluded from the phase 3 COVID-19 vaccine trials. Data on vaccine safety and immunogenicity in ...these populations are therefore limited. OBJECTIVE: To evaluate the immunogenicity of COVID-19 messenger RNA (mRNA) vaccines in pregnant and lactating women, including against emerging SARS-CoV-2 variants of concern. DESIGN, SETTING, AND PARTICIPANTS: An exploratory, descriptive, prospective cohort study enrolled 103 women who received a COVID-19 vaccine from December 2020 through March 2021 and 28 women who had confirmed SARS-CoV-2 infection from April 2020 through March 2021 (the last follow-up date was March 26, 2021). This study enrolled 30 pregnant, 16 lactating, and 57 neither pregnant nor lactating women who received either the mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) COVID-19 vaccines and 22 pregnant and 6 nonpregnant unvaccinated women with SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES: SARS-CoV-2 receptor binding domain binding, neutralizing, and functional nonneutralizing antibody responses from pregnant, lactating, and nonpregnant women were assessed following vaccination. Spike-specific T-cell responses were evaluated using IFN-γ enzyme-linked immunospot and multiparameter intracellular cytokine–staining assays. Humoral and cellular immune responses were determined against the original SARS-CoV-2 USA-WA1/2020 strain as well as against the B.1.1.7 and B.1.351 variants. RESULTS: This study enrolled 103 women aged 18 to 45 years (66% non-Hispanic White) who received a COVID-19 mRNA vaccine. After the second vaccine dose, fever was reported in 4 pregnant women (14%; SD, 6%), 7 lactating women (44%; SD, 12%), and 27 nonpregnant women (52%; SD, 7%). Binding, neutralizing, and functional nonneutralizing antibody responses as well as CD4 and CD8 T-cell responses were present in pregnant, lactating, and nonpregnant women following vaccination. Binding and neutralizing antibodies were also observed in infant cord blood and breast milk. Binding and neutralizing antibody titers against the SARS-CoV-2 B.1.1.7 and B.1.351 variants of concern were reduced, but T-cell responses were preserved against viral variants. CONCLUSION AND RELEVANCE: In this exploratory analysis of a convenience sample, receipt of a COVID-19 mRNA vaccine was immunogenic in pregnant women, and vaccine-elicited antibodies were transported to infant cord blood and breast milk. Pregnant and nonpregnant women who were vaccinated developed cross-reactive antibody responses and T-cell responses against SARS-CoV-2 variants of concern.
Coronavirus disease 2019 (COVID-19) testing is a critical component of public health surveillance and pandemic control, especially among the unvaccinated, as the nation resumes in-person activities. ...This study examined the relationships between COVID-19 testing rates, testing positivity rates, and vaccination coverage across US counties.
Data from the Health and Human Services' Community Profile Report and 2016-2020 American Community Survey 5-Year Estimates were used. A total of 3114 US counties were analyzed from January through September 2021. Associations among the testing metrics and vaccination coverage were estimated using multiple linear regression models with fixed effects for states and adjusted for county demographics. COVID-19 testing rates (polymerase chain reaction PCR testing per 1000), testing positivity (percentage of all PCR tests that were positive), and vaccination coverage (percentage of county population that was fully vaccinated) were determined.
Nationally, median daily COVID-19 testing rates were highest in January and September (35.5 and 34.6 tests per capita, respectively) and lowest in July (13.2 tests per capita). Monthly testing positivity was between 0.03 and 0.12 percentage points lower for each percentage points of vaccination coverage, and monthly testing rates were between 0.08 and 0.22 tests per capita higher for each percentage point of vaccination coverage.
The quantity of COVID-19 testing was associated with vaccination coverage, implying counties having populations with relatively lower protection against the virus are conducting less testing than counties with relatively more protection. Monitoring testing practices in relation to vaccination coverage may be used to monitor the sufficiency of COVID-19 testing based on population susceptibility to the virus.
Longstanding racial disparities in heart failure (HF) outcomes exist in the United States, in part, due to social determinants of health. We examined whether neighborhood environment modifies the ...disparity in 30-day HF readmissions and mortality between Black and White patients in the Southeastern United States.
We created a geocoded retrospective cohort of patients hospitalized for acute HF within Emory Healthcare from 2010 to 2018. Quartiles of the Social Deprivation Index characterized neighborhood deprivation at the census tract level. We estimated the relative risk of 30-day readmission and 30-day mortality following an index hospitalization for acute HF. Excess readmissions and mortality were estimated as the absolute risk difference between Black and White patients within each Social Deprivation Index quartile, adjusted for geographic clustering, demographic, clinical, and hospital characteristics.
The cohort included 30 630 patients, mean age 66 years, 48% female, 53% Black. Compared with White patients, Black patients were more likely to reside in deprived census tracts and have higher comorbidity scores. From 2010 to 2018, 29.4% of Black and 23.0% of White patients experienced either a 30-day HF readmission or 30-day death (
<0.001). Excess in composite 30-day HF readmissions and mortality for Black patients ranged from 3.9% (95% CI, 1.5%-6.3%;
=0.0002) to 6.8% (95% CI, 4.1%-9.5%;
<0.0001) across Social Deprivation Index quartiles. Accounting for traditional risk factors did not eliminate the Black excess in combined 30-day HF readmissions or mortality in any of the neighborhood quartiles.
Excess 30-day HF readmissions and mortality are present among Black patients in every neighborhood strata and increase with progressive neighborhood socioeconomic deprivation.
Impressive decreases in cardiovascular mortality have been achieved through risk factor reduction and clinical intervention, yet cardiovascular disease remains a leading cause of death nationally.
To ...estimate up-to-date preventable fractions of cardiovascular mortality associated with elimination and reduction of 5 leading risk factors nationally and by state in the United States.
Cross-sectional and cohort studies.
Nationally representative and state-representative samples of the U.S. population.
Adults aged 45 to 79 years.
Self-reported risk factor status in the BRFSS (Behavioral Risk Factor Surveillance System) 2009-2010 was corrected to approximate clinical definitions. The relative hazards of cardiovascular death (International Classification of Diseases, 10th Revision, codes I00 to I99) associated with risk factors were estimated using data from NHANES (National Health and Nutrition Examination Survey) (1988-1994 and 1999-2004, followed through 2006).
The preventable fraction of cardiovascular mortality associated with complete elimination of elevated cholesterol levels, diabetes, hypertension, obesity, and smoking was 54.0% for men and 49.6% for women in 2009 to 2010. When the more feasible target of reducing risk factors to the best achieved levels in the states was considered, diabetes (1.7% and 4.1%), hypertension (3.8% and 7.3%), and smoking (5.1% and 4.4%) were independently associated with the largest preventable fractions among men and women, respectively. With both targets, southern states had the largest preventable fractions, and western states had the smallest.
Self-reported state data; mortality hazards relied on baseline risk factor status.
Major modifiable cardiovascular risk factors collectively accounted for half of cardiovascular deaths in U.S. adults aged 45 to 79 years in 2009 to 2010. Fewer than 10% of cardiovascular deaths nationally could be prevented if all states were to achieve risk factor levels observed in the best-performing states.
Robert Wood Johnson Foundation.
The topic of neonatal cardiovascular care in neonatal-perinatal medicine (NPM) fellowship training has continued to transform due to increased complexity of patients, development of specialized ...units, continued Accreditation Council for Graduate Medical Education requirements, and clinical practice variation across centers that care for neonates with congenital heart disease (CHD).
We developed a neonatal cardiac curriculum comprised of eight interactive sessions with novel active learning concepts specific to our NPM fellows. A self-assessment survey in comfort in managing infants with CHD and perceived competency in neonatal cardiology topics was performed by all neonatology fellows at baseline and after completion of the curriculum. The American Board of Pediatrics Subspecialty In-training Exam (SITE) scores for fellows were compared to that of the national average.
The average comfort score (0-100) of the first-year fellows increased from 33 to 76, and that of the second and third-year fellows increased from 72 to 86, and 75 to 86, respectively. The first-year fellows improved their competency score by 44 points (3 standard deviations), the second-year fellows improved their score by about 26 points (one standard deviation), and there was an overall 9-point increase in the competency score of all fellows (one standard deviation). The average local SITE score was lower than the national average before the initiation of this curriculum, became nearly equal to the national average score at the end of the first year the curriculum was implemented, and has progressively become higher since then.
Due to the variable clinical exposure and differing practice models of managing CHD a neonatal cardiac curriculum may be beneficial to NPM trainees.
Circulating tumor cells (CTC) seed cancer metastases; however, the underlying cellular and molecular mechanisms remain unclear. CTC clusters were less frequently detected but more metastatic than ...single CTCs of patients with triple-negative breast cancer and representative patient-derived xenograft models. Using intravital multiphoton microscopic imaging, we found that clustered tumor cells in migration and circulation resulted from aggregation of individual tumor cells rather than collective migration and cohesive shedding. Aggregated tumor cells exhibited enriched expression of the breast cancer stem cell marker CD44 and promoted tumorigenesis and polyclonal metastasis. Depletion of CD44 effectively prevented tumor cell aggregation and decreased PAK2 levels. The intercellular CD44-CD44 homophilic interactions directed multicellular aggregation, requiring its N-terminal domain, and initiated CD44-PAK2 interactions for further activation of FAK signaling. Our studies highlight that CD44
CTC clusters, whose presence is correlated with a poor prognosis of patients with breast cancer, can serve as novel therapeutic targets of polyclonal metastasis. SIGNIFICANCE: CTCs not only serve as important biomarkers for liquid biopsies, but also mediate devastating metastases. CD44 homophilic interactions and subsequent CD44-PAK2 interactions mediate tumor cluster aggregation. This will lead to innovative biomarker applications to predict prognosis, facilitate development of new targeting strategies to block polyclonal metastasis, and improve clinical outcomes.
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Cancer cells possess a high metabolic demand for their rapid proliferation, survival, and progression and thus create an acidic and hypoxic tumor microenvironment (TME) deprived of nutrients. ...Moreover, acidity within the TME is the central regulator of tumor immunity that influences the metabolism of the immune cells and orchestrates the local and systemic immunity, thus, the TME has a major impact on tumor progression and resistance to anti-cancer therapy. Specifically, myeloid cells, which include myeloid-derived suppressor cells (MDSC), dendritic cells, and tumor-associated macrophages (TAMs), often reprogram their energy metabolism, resulting in stimulating the angiogenesis and immunosuppression of tumors. This review summarizes the recent findings of glucose, amino acids, and fatty acid metabolism changes of the tumor-associated macrophages (TAMs), and how the altered metabolism shapes the TME and anti-tumor immunity. Multiple proton pumps/transporters are involved in maintaining the alkaline intracellular pH which is necessary for the glycolytic metabolism of the myeloid cells and acidic TME. We highlighted the roles of these proteins in modulating the cellular metabolism of TAMs and their potential as therapeutic targets for improving immune checkpoint therapy.
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