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BackgroundSubstance use disorder (SUD) is a major health issue in Indonesia, where several barriers to treatment exist, including inaccessibility to treatment services, stigma, and criminalization of drug issues. Peer involvement and the use of telemedicine to deliver psychotherapy are promising approaches to overcome these barriers. ObjectiveThis study aims (1) to describe the development of a new group psychotherapy coprovided by a health care worker and a peer and (2) to evaluate the acceptability, practicality, and preliminary outcomes of the program delivered via videoconferencing in Indonesia. MethodsBuilding upon an established relapse prevention therapy in Japan, we developed a 3-month weekly group therapy module in the Indonesian language. Adjustments were made via focus group discussions with local stakeholders in terms of substance types, understandability, inclusive language, and cultural relevance. A pilot study was conducted to test the new module provided by a peer and a psychiatrist via videoconferencing, termed tele-Indonesia Drug Addiction Relapse Prevention Program (tele-Indo-DARPP), with a pre- and postcontrolled design. We analyzed data from semistructured feedback interviews and outcome measurements, including the number of days using substances and quality of life, and compared the intervention (tele-Indo-DARPP added to treatment as usual [TAU]) and control (TAU only) arms. ResultsIn total, 8 people diagnosed with SUD participated in the pilot study with a mean age of 37 (SD 12.8) years. All were men, and 7 (88%) used sedatives as the primary substance. Collectively, they attended 44 of the 48 tele-Indo-DARPP sessions. A total of 3 out of 4 (75%) preferred telemedicine rather than in-person therapy. Positive acceptability and practicality were shown from qualitative feedback, in which the participants who joined the tele-Indo-DARPP reported that they liked the convenience of joining from home and that they were able to open up about personal matters, received helpful advice from peers, and received support from other participants. Providers reported that they feel the module was provider-friendly, and the session was convenient to join without diminishing rapport-building. Meanwhile, troubles with the internet connection and difficulty in comprehending some terminology in the workbook were reported. The intervention arm showed better improvements in psychological health and anxiety symptoms. ConclusionsGroup psychotherapy via videoconferencing coprovided by health care workers and peers was acceptable and practical for participants with SUD and service providers in this study. A large-scale study is warranted to examine the effectiveness of the newly developed module in Indonesia.

Background Substance use disorder (SUD) is a leading contributor to the global burden of disease. In Indonesia, the availability of formal treatment for SUD falls short of the targeted coverage. A standardised therapeutic option for SUD with potential for widespread implementation is required, yet evidence-based data in the country are scarce. In this study, we developed a cognitive behavioural therapy (CBT)-based group telemedicine model and will investigate effectiveness and implementability in a multicentre randomised controlled trial.Methods A total of 220 participants will be recruited from the social networks of eight sites in Indonesia: three hospitals, two primary healthcare centres and three rehabilitation centres. The intervention arm will participate in a relapse prevention programme called the Indonesia Drug Addiction Relapse Prevention Programme (Indo-DARPP), a newly developed 12-week module based on CBT and motivational interviewing constructed in the Indonesian context. The programme will be delivered by a healthcare provider and a peer counsellor in a group therapy setting via video-conferencing, as a supplement to participants’ usual treatments. The control arm will continue treatment as usual. The primary outcome will be the percentage increase in days of abstinence from the primarily used substance in the past 28 days. Secondary outcomes will include addiction severity, quality of life, motivation to change, psychiatric symptoms, cognitive function, coping, and internalised stigma. Assessments will be performed at baseline (week 0), post-treatment (week 13), and 3 and 12 months post-treatment completion (weeks 24 and 60). Retention, participant satisfaction, and cost-effectiveness will be assessed as the implementation outcomes.Ethics and dissemination The study protocol was reviewed and approved by the Ethics Committees of Universitas Indonesia and Kyoto University. The results will be disseminated via academic journals and international conferences. Depending on trial outcomes, the treatment programme will be advocated for adoption as a formal healthcare-based approach for SUD.Trial registration number UMIN000042186.

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14 , AZD4747, a clinical development candidate for the treatment of KRAS G12C -positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRAS G12C with an anticipated low clearance and high oral bioavailability profile in humans.

AZD4625 is a potent, selective, and orally bioavailable inhibitor of oncogenic KRASG12C as demonstrated in cellular assays and in vivo in preclinical cell line-derived and patient-derived xenograft models. In vitro and cellular assays have shown selective binding and inhibition of the KRASG12C mutant isoform, which carries a glycine to cysteine mutation at residue 12, with no binding and inhibition of wild-type RAS or isoforms carrying non-KRASG12C mutations. The pharmacology of AZD4625 shows that it has the potential to provide therapeutic benefit to patients with KRASG12C mutant cancer as either a monotherapy treatment or in combination with other targeted drug agents., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: The Regulatory T cell (Treg) lineage is defined by the transcription factor FOXP3, which controls immune-suppressive gene expression profiles. Tregs are often recruited in high frequencies to the tumor microenvironment where they can suppress antitumor immunity. We hypothesized that pharmacological inhibition of FOXP3 by systemically delivered, unformulated constrained ethyl-modified antisense oligonucleotides could modulate the activity of Tregs and augment antitumor immunity providing therapeutic benefit in cancer models and potentially in man., Methods: We have identified murine Foxp3 antisense oligonucleotides (ASOs) and clinical candidate human FOXP3 ASO AZD8701. Pharmacology and biological effects of FOXP3 inhibitors on Treg function and antitumor immunity were tested in cultured Tregs and mouse syngeneic tumor models. Experiments were controlled by vehicle and non-targeting control ASO groups as well as by use of multiple independent FOXP3 ASOs. Statistical significance of biological effects was evaluated by one or two-way analysis of variance with multiple comparisons., Results: AZD8701 demonstrated a dose-dependent knockdown of FOXP3 in primary Tregs, reduction of suppressive function and efficient target downregulation in humanized mice at clinically relevant doses. Surrogate murine FOXP3 ASO, which efficiently downregulated Foxp3 messenger RNA and protein levels in primary Tregs, reduced Treg suppressive function in immune suppression assays in vitro. FOXP3 ASO promoted more than 70% reduction in FOXP3 levels in Tregs in vitro and in vivo, strongly modulated Treg effector molecules (eg, ICOS, CTLA-4, CD25 and 4-1BB), and augmented CD8 + T cell activation and produced antitumor activity in syngeneic tumor models. The combination of FOXP3 ASOs with immune checkpoint blockade further enhanced antitumor efficacy., Conclusions: Antisense inhibitors of FOXP3 offer a promising novel cancer immunotherapy approach. AZD8701 is being developed clinically as a first-in-class FOXP3 inhibitor for the treatment of cancer currently in Ph1a/b clinical trial (NCT04504669)., Competing Interests: Competing interests: The authors are paid employees of AstraZeneca or Ionis Pharmaceuticals, as indicated by their affiliations., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)