Aim Up‐to‐date epidemiological studies on the global burden of severe periodontitis is scarce. This study aimed to present the latest estimates for prevalence of severe periodontitis from 1990 to 2019, by region, age, and level of socio‐demographic development. Materials and Methods Estimates from the Global Burden of Disease study 2019 were used to investigate burden and trends of prevalence of severe periodontitis and its association with socio‐demographic development at global, regional, and national level. Decomposition analysis was performed to explore the contribution of demographic and epidemiological factors to the evolving burden of severe periodontitis. Results In 2019, there were 1.1 billion (95% uncertainty interval: 0.8–1.4 billion) prevalent cases of severe periodontitis globally. From 1990 to 2019, age‐standardized prevalence rate of severe periodontitis increased by 8.44% (6.62%–10.59%) worldwide. Prevalence of severe periodontitis is higher among less developed countries/regions. Global population growth accounted for 67.9% of the increase in the number of prevalent cases of severe periodontitis from 1990 to 2019. Conclusions The global burden of severe periodontitis has been substantial and increasing over the past three decades. Upstream policy changes are urgently needed to address the global public health challenge of severe periodontitis.

Signaling pathways intersecting with the p21-activated kinases (PAKs) play important roles in tumorigenesis and cancer progression. By recognizing that the limitations of FRAX1036 (1) were chiefly associated with the highly basic amine it contained, we devised a mitigation strategy to address several issues such as hERG activity. The 5-amino-1,3-dioxanyl moiety was identified as an effective means of reducing pK a and logP simultaneously. When positioned properly within the scaffold, this group conferred several benefits including potency, pharmacokinetics, and selectivity. Mouse xenograft PK/PD studies were carried out using an advanced compound, G-5555 (12), derived from this approach. These studies concluded that dose-dependent pathway modulation was achievable and paves the way for further in vivo investigations of PAK1 function in cancer and other diseases.

Activated Wnt/β-catenin signaling is frequently associated with colorectal cancer. Wnt inhibitors, including tankyrase inhibitors, are being explored as potential anticancer agents. Wnt signaling is also critical for intestinal tissue homeostasis, and Wnt inhibitors have been shown to cause intestinal toxicity in mice by affecting intestinal stem cells. This study sought to characterize the intestinal toxicity of tankyrase inhibitors, including reversibility, and to assess their therapeutic index. Novel tankyrase inhibitor G-631 caused dose-dependent intestinal toxicity with a therapeutic index < 1 after 14 days of dosing in mice. At a tolerated subtherapeutic dose level, the intestinal toxicity was composed of enteritis characterized by villus blunting, epithelial degeneration, and inflammation, which fully reversed after 14 days of recovery. Doubled exposure showed weak antitumor activity in a xenograft colorectal cancer model but also caused more severe intestinal toxicity characterized by multifocal-regionally extensive necrotizing and ulcerative enteritis leading to morbidity or moribundity in some animals. This toxicity was only partially reversed after 14 days of recovery, with evidence of crypt and villus regeneration, mildly blunted villi, and/or scarring in association with chronic inflammation of the submucosa. Therefore, the clinical utility of tankyrase inhibitors is likely limited by the on-target intestinal toxicity and a therapeutic index < 1 in mice.

Taken together, Angptl4 modulates vascular permeability, angiogenesis, inflammatory signaling, and associated diseases. The use of Angptl4-modulating agents such as certain drugs, food constituents (such as fatty acids), nuclear factor (such as PPARα), and bacteria may treat associated diseases such as tumor metastasis, ischemic-reperfusion injury, inflammation, and chronic low-grade inflammation. However, the diverse physiological functions of Angptl4 in different tissues can lead to potentially deleterious side effects when used as a therapeutic target. In this regard, a better understanding of the underlying mechanisms for Angptl4 in different tissues is necessary.

p21-activated kinase 1 (PAK1) has an important role in transducing signals in several oncogenic pathways. The concept of inhibiting this kinase has garnered significant interest over the past decade, particularly for targeting cancers associated with PAK1 amplification. Animal studies with the selective group I PAK (pan-PAK1, 2, 3) inhibitor G-5555 from the pyrido[2,3-d]pyrimidin-7-one class uncovered acute toxicity with a narrow therapeutic window. To attempt mitigating the toxicity, we introduced significant structural changes, culminating in the discovery of the potent pyridone side chain analogue G-9791. Mouse tolerability studies with this compound, other members of this series, and compounds from two structurally distinct classes revealed persistent toxicity and a correlation of minimum toxic concentrations and PAK1/2 mediated cellular potencies. Broad screening of selected PAK inhibitors revealed PAK1, 2, and 3 as the only overlapping targets. Our data suggest acute cardiovascular toxicity resulting from the inhibition of PAK2, which may be enhanced by PAK1 inhibition, and cautions against continued pursuit of pan-group I PAK inhibitors in drug discovery.

Previous studies on the global burden of caries primarily focused on simple descriptive statistics. We aimed to characterize the burden, trends, and inequalities of untreated caries of permanent and deciduous teeth from 1990 to 2019 at the global, regional, and national levels through an array of analytic approaches. Estimates of caries burden were extracted from the Global Burden of Disease Study 2019. Decomposition analysis was performed to examine the contribution of demographic and epidemiologic factors to the evolving number of prevalent caries cases. In portfolio analysis, the caries epidemiologic profile of each country was categorized by terciles of age-standardized prevalence in 2019 and average annual percentage change from 1990 to 2019. Sociodemographic attribution analysis was performed to reveal the scale of inequality in burden of caries. Age-standardized prevalence of caries in permanent and deciduous teeth decreased 3.6% (95% uncertainty interval, 2.6% to 4.5%) and 3.0% (1.3% to 4.9%), respectively. Population growth was the key driver of the changes in the number of caries cases, especially in sub-Saharan Africa (percentage contribution: 126.6%, permanent teeth; 103.0%, deciduous teeth). Caries prevalence in the permanent dentition was lower in more developed countries, whereas a reverse trend was noted in the deciduous dentition, except for the highest sociodemographic quintile where caries prevalence was the lowest. Globally, 64.6 million (95% CI, 64.4 to 64.9 million) and 62.9 million (62.8 to 63.1 million) prevalent cases of caries in permanent and deciduous teeth were attributable to sociodemographic inequality in 2019. This amounted to 3.2% (3.2% to 3.2%) and 12.1% (12.1% to 12.1%) of the global number of prevalent cases of caries in permanent and deciduous teeth. Burden of dental caries remains a global public health challenge. A systemwide reform of the global oral health care system is needed to tackle the causes of the burden and inequality of dental caries.

Psoriasis is one of the most common chronic inflammatory skin diseases, affecting ~2% of the population. The lack of characterization of the pathogenesis of psoriasis has hindered efficient clinical treatment of the disease. In our study, we observed that expression of complement component 5a receptor 1(C5aR1) was significantly increased in skin lesions of both imiquimod (IMQ) and IL23-induced psoriatic mice and patients with psoriasis. C5aR1 deficiency or treatment with C5a receptor 1 antagonist (C5aR1a) in mice significantly attenuated psoriasis-like skin lesions and expression of inflammatory cytokines and chemokines. Moreover, C5aR1 deficiency significantly decreased IMQ-induced infiltration of plasmacytoid dendritic cells (pDCs), monocytes and neutrophils in psoriatic skin lesions and functions of pDCs, evidenced by the remarkable reduction in the IMQ-induced production of interferon-α (IFN-α) and tumor necrosis factor α (TNF-α), and FMS-like tyrosine kinase 3 ligand (FLT3L)-dependent pDCs differentiation. Accordingly, in vitro treatment with recombinant C5a accelerated pDCs migration and the differentiation of bone marrow cells into pDCs. Furthermore, biopsies of psoriatic patients showed a dramatic increase of C5aR1 + pDCs infiltration in psoriatic skin lesions, compared to healthy subjects. Our results provide direct evidence that C5a/C5aR1 signaling plays a critical role in the pathogenesis of psoriasis. Inhibition of C5a/C5aR1 pathway is expected to be beneficial in the treatment of patients with psoriasis.

Background: Although lung cancer incidence and mortality have been declining since the 1990s, the extent to which such progress has been made is unequal across population segments. Updated epidemiologic data on trends and patterns of disparities are lacking. Methods: Data on lung cancer cases and deaths during 1974 to 2015 were extracted from the Surveillance, Epidemiology, and End Results program. Age-standardized lung cancer incidence and mortality and their annual percent changes were calculated by histologic types, demographic variables, and tumor characteristics. Results: Lung cancer incidence decreased since 1990 (1990 to 2007: annual percent change, −0.9 [95% CI, −1.0%, −0.8%]; 2007 to 2015: −2.6 [−2.9%, −2.2%]). Among adults aged between 20 and 39 years, a higher incidence was observed among females during 1995 to 2011, after which a faster decline in female lung cancer incidence (males: −2.5% [−2.8%, −2.2%]; females: −3.1% [−4.7%, −1.5%]) resulted in a lower incidence among females. The white population had a higher incidence than the Black population for small cell carcinoma since 1987. Black females were the only group whose adenocarcinoma incidence plateaued since 2012 (−5.0% [−13.0%, 3.7%]). A higher incidence for squamous cell carcinoma was observed among Black males and females than among white males and females during 1974 to 2015. After circa 2005, octogenarians and older patients constituted the group with the highest lung cancer incidence. Incidence for localized and AJCC/TNM stage I lung cancer among octogenarians and older patients plateaued since 2009, while mortality continued to rise (localized: 1.4% [0.6%, 2.1%]; stage I: 6.7% [4.5%, 9.0%]). Conclusions: Lung cancer disparities prevail across population segments. Our findings inform effective approaches to eliminate lung cancer disparities by targeting at-risk populations.