Pyrrole-Imidazole Polyamides - A Frontrunner in Nucleic Acid-Based Small Molecule Drugs

The remarkable success of messenger RNA vaccines against the ongoing coronavirus-2019 (COVID-19) pandemic renews attention toward nucleic acid therapeutics. While nucleic acid therapy using unmodified DNA or RNA is the primary focus in disease treatment, there is growing need to develop nucleic acid-based small molecules owing to their potential clinical benefits as drugs in terms of cost and scalability. While small molecules targeting protein-protein interactions are known to alter the transcriptional status of a cell, they can result in a transient effect and variation of bio-efficacy among patients. Small molecules targeting DNA and/or RNA are in demand in the precision medicine approach as they have consistent bioactivity among patients. This review details the progress of sequence-specific DNA-binding pyrrole-imidazole polyamides (PIPs) in modulating the transcriptional status of target gene(s) without altering the underlying DNA sequence. Here, the different versions of PIPs are listed, and also, how conjugating them with DNA alkylating agents, epigenetic modulators, and other drugs can improve their clinical utility as targeted transcription therapeutics. Owing to their specificity, functional diversity, and limited toxicity, PIP technology holds enormous promise as frontrunner in small-molecule-based nucleic acid drugs to precisely regulate therapeutically important genes on demand and treat intractable diseases.Copyright © 2023 Wiley-VCH GmbH.

Comparison of risk factors for SARS-CoV-2 infection among healthcare workers during Omicron and Delta dominance periods in Japan.

BACKGROUND: The risk factors for coronavirus disease (COVID-19) among healthcare workers (HCWs) might have changed since the emergence of the highly immune evasive Omicron variant. AIM: To compare the risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among HCWs during the Delta- and Omicron-predominant periods. METHODS: Using data from repeated serosurveys among the staff of a medical research centre in Tokyo, two cohorts were established: Delta period cohort (N = 858) and Omicron period cohort (N = 652). The potential risk factors were assessed using a questionnaire. Acute/current or past SARS-CoV-2 infection was identified by polymerase chain reaction or anti-nucleocapsid antibody tests, respectively. Poisson regression was used to calculate the risk ratio (RR) of infection risk. FINDINGS: The risk of SARS-CoV-2 infection during the early Omicron-predominant period was 3.4-fold higher than during the Delta-predominant period. Neither working in a COVID-19-related department nor having a higher degree of occupational exposure to SARS-CoV-2 was associated with an increased infection risk during both periods. During the Omicron-predominant period, infection risk was higher among those who spent ≥30 min in closed spaces, crowded spaces, and close-contact settings without wearing mask (≥3 times versus never: RR: 6.62; 95% confidence interval: 3.01-14.58), whereas no such association was found during the Delta period. CONCLUSION: Occupational exposure to COVID-19-related work was not associated with the risk of SARS-CoV-2 infection in the Delta or Omicron period, whereas high-risk behaviours were associated with an increased infection risk during the Omicron period.

Pharma PSE: a multiscale approach for reimagining pharmaceutical manufacturing

Confronted with the global challenges including COVID-19, pharmaceutical manufacturing needs to simultaneously achieve long-term efficiency and short-term resilience. Process systems engineering (PSE) can provide scientific basis here, and in fact, PSE researchers have made significant contributions to pharma in the last decade. The author, after having worked for a global pharmaceutical company, initiated research on pharmaceutical process systems engineering: Pharma PSE. The research tackles different challenges in small molecules, biopharmaceuticals, and regenerative medicine, at the scales of molecules/cells, processes, and the society. This paper first introduces the viewpoint of Pharma PSE, followed by showcasing a research example that involved a range of computer-aided analyses at different scales. The multiscale approach of Pharma PSE can provide a new horizon to “reimagine” pharmaceutical manufacturing processes and beyond, towards establishment of a sustainable healthcare society. © 2022 Elsevier B.V.

Challenges and Opportunities for Process Systems Engineering in a Changed World

Changes have always been taking place on earth. However, the latest changes related to the climate, the COVID-19 pandemic, natural resources, pollution, to name a few, have changed our world and a new normal is emerging. The energy-water-environment-food-health nexus is becoming more complex. These challenges, however, also provide opportunities to tackle them and make scientific and engineering advances. PSE is well-placed through its core and expanding domain as well as its ability to apply a systems approach to meet current and future challenges. Many opportunities exist for the PSE community to take the lead in managing this complexity. This paper will provide an overview on some of the key challenges and opportunities where PSE could make immediate as well as long lasting impacts by developing sustainable and innovative solutions. Focus will be placed on the choice of problems to solve and the solution approaches that could make an impact and help to define the new normal for future generations. © 2022 Elsevier B.V.

Clinical features of COVID-19 patients with rebound phenomenon after corticosteroid therapy

Rational: Corticosteroid therapy plays a key role in the treatment of COVID-19 patients with respiratory failure. However, a rebound phenomenon after steroid cessation rarely occurs. Here, we investigated the clinical features of patients with rebound after steroid therapy. Methods: In total, 84 patients with COVID-19 treated with corticosteroids were enrolled and analysed retrospectively. A rebound was defined as when a patient’s respiratory status deteriorated after the cessation of corticosteroid therapy, without secondary bacterial infection. Results: Subjects in the rebound group were more likely to having severe respiratory failure than those in the non-rebound group. While the duration of steroid therapy was longer in the rebound group (8 days vs 10 days, p=0.0009), the dosage of steroid and the timing of the start or termination of steroid therapy did not show any differences between the two groups (p=0.17 and 0.68, respectively). The values of soluble interleukin-2 receptor (sIL-2R) at the baseline and the values of C reactive protein (CRP) or lactate dehydrogenase (LDH) at the end of steroid therapy were significantly higher in the rebound group (937 vs 1336 U/mL;p=0.002, 0.63 vs 3.96 mg/dL;p=0.01 and 278 vs 451 IU/mL;p=0.01, respectively). No patient in the rebound group suffered from thromboses, and the causes of death were exacerbation of COVID-19, ventilator-associated pneumonia or sepsis. The prediction model using baseline features for the rebound phenomenon included four variables of age >68 years, required supplemental oxygen >5 L/min, lymphocyte counts <792 /µL and sIL-2R >1146 U/mL. The discrimination ability of this model was 0.906 (0.755–0.968). Conclusion: These findings suggest that severe respiratory failure has a higher risk for the rebound phenomenon after the cessation of corticosteroids, and the values of sIL-2R, LDH and CRP are useful to assess the probability of developing rebound. A multivariate model was developed to predict rebound risk, which showed acceptable discrimination ability.