Atezolizumab Plus PEGPH20 Versus Chemotherapy in Advanced Pancreatic Ductal Adenocarcinoma and Gastric Cancer: MORPHEUS Phase Ib/II Umbrella Randomized Study Platform.

BACKGROUND: The MORPHEUS platform comprises multiple open-label, randomized, phase Ib/II trials designed to identify early efficacy and safety signals of treatment combinations across cancers. Atezolizumab (anti-programmed cell death 1 ligand 1 [PD-L1]) was evaluated in combination with PEGylated recombinant human hyaluronidase (PEGPH20). METHODS: In 2 randomized MORPHEUS trials, eligible patients with advanced, previously treated pancreatic ductal adenocarcinoma (PDAC) or gastric cancer (GC) received atezolizumab plus PEGPH20, or control treatment (mFOLFOX6 or gemcitabine plus nab-paclitaxel [MORPHEUS-PDAC]; ramucirumab plus paclitaxel [MORPHEUS-GC]). Primary endpoints were objective response rates (ORR) per RECIST 1.1 and safety. RESULTS: In MORPHEUS-PDAC, ORRs with atezolizumab plus PEGPH20 (n = 66) were 6.1% (95% CI, 1.68%-14.80%) vs. 2.4% (95% CI, 0.06%-12.57%) with chemotherapy (n = 42). In the respective arms, 65.2% and 61.9% had grade 3/4 adverse events (AEs); 4.5% and 2.4% had grade 5 AEs. In MORPHEUS-GC, confirmed ORRs with atezolizumab plus PEGPH20 (n = 13) were 0% (95% CI, 0%-24.7%) vs. 16.7% (95% CI, 2.1%-48.4%) with control (n = 12). Grade 3/4 AEs occurred in 30.8% and 75.0% of patients, respectively; no grade 5 AEs occurred. CONCLUSION: Atezolizumab plus PEGPH20 showed limited clinical activity in patients with PDAC and none in patients with GC. The safety of atezolizumab plus PEGPH20 was consistent with each agent's known safety profile. (ClinicalTrials.gov Identifier: NCT03193190 and NCT03281369).

Adapting and pretesting the World Health Organization's Caregiver Skills Training Program for children with autism and developmental disorders or delays in Hong Kong.

The World Health Organization Caregiver Skills Training Program (WHO-CST) was developed to strengthen caregivers' skills in supporting children with developmental delays and the caregivers' well-being. The WHO-CST Hong Kong (HK) was adapted, and pre-pilot tested to support families with children suspected of having developmental delays and autism spectrum disorder and to empower the caregivers to foster their children's learning, social communication, and adaptive behavior. A sequential mixed-methods research methodology was undertaken to examine the adaptation process and initial implementation experiences. The acceptability, feasibility, and perceived benefits of the WHO-CST were assessed using stakeholders' and caregivers' qualitative and caregivers' quantitative pre- and post-intervention feedback. The data included materials generated from (1) three consultation meetings with stakeholders; (2) detailed reviews of the translated and adapted WHO-CST materials by master trainees (n = 10) trained by the WHO-CST representatives; (3) needs assessment focus group interviews with caregivers (n = 15) of children with autism spectrum disorder; and (4) pre- and post-CST program qualitative focus group interviews and quantitative evaluation. Consultation with stakeholders suggested that the program was acceptable for the local community, but the home visit and fidelity components were initially considered to be challenges towards the feasibility and sustainability of the program. Caregivers in the needs assessment focus groups gave widely diverse views about the program's uniqueness, length, delivery mode, and the inclusion of videotaping in-home visits. Post-intervention comments by caregivers about the program were mainly positive, while the MTs were critical of the content and length of the training and fidelity process. As one of the first high-income locations to adopt the WHO-CST, the evaluation findings of the WHO-CST-HK indicate that it is feasible and acceptable to implement the program in a metropolitan area where families have busy work schedules and are very conscious of privacy issues. The study results suggest that the WHO-CST program in HK and other high-income countries require scaling up and further evaluation of its implementation in real community settings. This involves systemic and contextual changes to allow task-sharing between professionals and non-specialists at the macro level. Furthermore, technology should be used to support the supervision of non-specialists. In addition, easier access to the WHO-CST materials at the micro level is required to ensure equity, equality, diversity, and inclusion of diversified families of children with developmental delays.

Acceptability and feasibility of the World Health Organization's Caregiver Skills Training Programme (WHO CST) delivered via eLearning, videoconferencing, and in-person hybrid modalities in Hong Kong.

Background: Local children with developmental disabilities were deprived of learning opportunities due to recent social and health incidents, resulting in elevating challenging behaviors and familial conflicts. This study explored the acceptability and feasibility of the World Health Organization's Caregiver Skills Training Programme (WHO CST) in alternative delivery modes under new normal and post COVID-19 period. Method: CST was delivered via eLearning (EL), videoconferencing (VC), and in-person hybrid (IP) modes to 34 parent-child dyads, being randomly assigned to modes of asynchronous non-interfering EL (n = 9), synchronous with online coaching VC (n = 7), synchronous with in-person coaching IP (n = 9) and Wait-list Control WLC (n = 9). Data from two standardized scales of General Health Questionnaire (GHQ-12) and Strengths and Difficulties Questionnaire (SDQ), and Post-session and Home Visit Feedback Form by Caregivers that included both structured and open-ended questions were collected before and after intervention. Both quantitative and qualitative approaches were used in studying the collected data. Results: High levels of acceptability and feasibility of the training programme were supported by ratings on comprehensiveness and relevance, agreement with their personal values, duration, and usefulness. IP and VC groups yielded more positive changes than EL and WLC groups with 3, 16, 13, and -3% in General Health Questionnaire (GHQ-12), -13, -15, -6 and 0% in Difficulties-total, and 36.5, 35.5, 5.8 and 2.4% in Prosocial Scale at Strengths and Difficulties Questionnaire (SDQ) for EL, VC, IP, and WLC groups respectively from baseline to 12 weeks after intervention. Results from two standardized scales echoed with qualitative observations that the programme helped improve caregivers' well-being, child's communication, and behaviors across intervention groups. Conclusions: Current findings revealed that CST delivered in three alternative modes were acceptable and feasible, and yielded positive impacts toward both caregivers and children. In-person coaching, and skill-practicing sessions were effective in mitigating child's challenging behaviors while personal interaction, either face-to-face or virtual, is a significant factor in uplifting caregivers' well-being, whereas the self-learning model was appreciated by the busy caregivers. In clinical practice, needs and goals of families and the constraints of remote interventions at the settings should be balanced.

The Resilience of Social Service Providers and Families of Children With Autism or Development Delays During the COVID-19 Pandemic-A Community Case Study in Hong Kong.

Background: Hong Kong is one of the earliest cities to have hampered by the COVID-19. When preventive public health measures are enforced, specific groups, who have already been facing inequality before the outbreak, are likely to become more overlooked and vulnerable. Aim: This community case study aims to describe the additional needs of families of children with autism spectrum disorder and other developmental issues, as well as unexpected difficulties and challenges social service professionals encountered when delivering service and their solutions toward these challenges. Methods: A focus group with 10 professionals providing the Caregiver Skills Training Program was conducted. Results: Poor families of vulnerable children were found to be challenged, more than average, in finding daily necessities during the initial stage of the outbreak. Most vulnerable children displayed additional problematic behaviors and emotional problems during the quarantine. The social service professionals addressed the family needs by providing tangible resources and offering online training, workshops, and programs to meet their needs. Several important lessons were learned. First, technology know-how on conducting online training, workshop, and program could be a challenge to some social service professionals and the parents. Second, the professionals reported that they made huge efforts to produce guidelines in protecting services users' privacy, to equip themselves with necessary skills in executing privacy-protection measures, and to keep exploring for safer alternatives. Third, providing tele-services in online mode represented a different interaction pattern between social service professionals and service users, especially in the recruitment processes and group dynamics. Conclusion: In comparison with other cities, Hong Kong has responded to the COVID-19 efficiently and effectively based on the citizen's strict adherence to behavioral advice and the innovative altruistic efforts from the multi-sectors in the community.

Synthesis and Evaluation of Camptothecin Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) that incorporate the exatecan derivative DXd in their payload are showing promising clinical results in solid tumor indications. The payload has an F-ring that also contains a second chiral center, both of which complicate its synthesis and derivatization. Here we report on new camptothecin-ADCs that do not have an F-ring in their payloads yet behave similarly to DXd-bearing conjugates in vitro and in vivo. This simplification allows easier derivatization of camptothecin A and B rings for structure-activity relationship studies and payload optimization. ADCs having different degrees of bystander killing and the ability to release hydroxyl or thiol-bearing metabolites following peptide linker cleavage were investigated.

Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice.

Expression of PD-L1, the ligand for T-cell inhibitory receptor PD-1, is one key immunosuppressive mechanism by which cancer avoids eradication by the immune system. Therapeutic use of blocking antibodies to PD-L1 or its receptor PD-1 has produced unparalleled, durable clinical responses, with highest likelihood of response seen in patients whose tumour or immune cells express PD-L1 before therapy. The significance of PD-L1 expression in each cell type has emerged as a central and controversial unknown in the clinical development of immunotherapeutics. Using genetic deletion in preclinical mouse models, here we show that PD-L1 from disparate cellular sources, including tumour cells, myeloid or other immune cells can similarly modulate the degree of cytotoxic T-cell function and activity in the tumour microenvironment. PD-L1 expression in both the host and tumour compartment contribute to immune suppression in a non-redundant fashion, suggesting that both sources could be predictive of sensitivity to therapeutic agents targeting the PD-L1/PD-1 axis.

pH- and Thiol-Responsive BODIPY-Based Photosensitizers for Targeted Photodynamic Therapy.

A diiodo distyryl boron dipyrromethene (BODIPY) core was conjugated to two ferrocenyl quenchers through acid-labile ketal and/or thiol-cleavable disulfide linkers, of which the fluorescence and photosensitizing properties were significantly quenched through a photoinduced electron-transfer process. The two symmetrical analogues that contained either the ketal or disulfide linkers could only be activated by a single stimulus, whereas the unsymmetrical analogue was responsive to dual stimuli. Upon interaction with acid and/or dithiothreitol (DTT), these linkers were cleaved selectively. The separation of the BODIPY core and the ferrocenyl moieties restored the photoactivities of the former in phosphate buffered saline and inside the MCF-7 breast cancer cells, rendering these compounds as potential activable photosensitizers for targeted photodynamic therapy. The dual activable analogue exhibited the greatest enhancement in intracellular fluorescence intensity in both an acidic environment (pH 5) and the presence of DTT (4 mm). Its photocytotoxicity against MCF-7 cells also increased by about twofold upon preincubation with 4 mm of DTT. The activation of this compound was also demonstrated in nude mice bearing a HT29 human colorectal carcinoma. A significant increase in fluorescence intensity in the tumor was observed over 9 h after intratumoral injection.

A dual activatable photosensitizer toward targeted photodynamic therapy.

An unsymmetrical bisferrocenyl silicon(IV) phthalocyanine has been prepared in which the disulfide and hydrazone linkers can be cleaved by dithiothreitol and acid, respectively. The separation of the ferrocenyl quenchers and the phthalocyanine core greatly enhances the fluorescence emission, singlet oxygen production, intracellular fluorescence intensity, and in vitro photocytotoxicity. The results have been compared with those for the two symmetrical analogues which contain either the disulfide or hydrazone linker and therefore can only be activated by one of these stimuli. For the dual activatable agent, the greatest enhancement can be attained under a slightly acidic environment (pH = 4.5-6.8) and in the presence of dithiothreitol (in millimolar range), which can roughly mimic the acidic and reducing environment of tumor tissues. This compound can also be activated in tumor-bearing nude mice. It exhibits an increase in fluorescence intensity in the tumor over the first 10 h after intratumoral injection and can effectively inhibit the growth of tumor upon illumination.

High-throughput ion exchange purification of positively charged recombinant protein in the presence of negatively charged dextran sulfate.

Product quality analyses are critical for developing cell line and bioprocess producing therapeutic proteins with desired critical product quality attributes. To facilitate these analyses, a high-throughput small-scale protein purification (SSP) is required to quickly purify many samples in parallel. Here we develop an SSP using ion exchange resins to purify a positively charged recombinant growth factor P1 in the presence of negatively charged dextran sulfate supplemented to improve the cell culture performance. The major challenge in this work is that the strong ionic interaction between P1 and dextran sulfate disrupts interaction between P1 and chromatography resins. To solve this problem, we develop a two-step SSP using Q Sepharose Fast Flow (QFF) and SP Sepharose XL (SPXL) resins to purify P1. The overall yield of this two-step SSP is 78%. Moreover, the SSP does not affect the critical product quality attributes. The SSP was critical for developing the cell line and process producing P1.

Inhibition of c-Kit is not required for reversal of hyperglycemia by imatinib in NOD mice.

AIM/HYPOTHESIS: Recent studies indicate that tyrosine kinase inhibitors, including imatinib, can reverse hyperglycemia in non-obese diabetic (NOD) mice, a model of type 1 diabetes (T1D). Imatinib inhibits c-Abl, c-Kit, and PDGFRs. Next-generation tyrosine kinase inhibitors for T1D treatment should maintain activities required for efficacy while sparing inhibition of targets that might otherwise lead to adverse events. In this study, we investigated the contribution of c-Kit inhibition by imatinib in reversal of hyperglycemia in NOD mice. METHODS: The T670I mutation in c-Kit, which confers imatinib resistance, was engineered into the mouse genome and bred onto the NOD background. Hematopoietic stem cells (HSCs) from NOD.c-Kit(T670I) mice and NOD.c-Kit(wt) littermates were expanded in the presence or absence of imatinib to verify imatinib resistance of the c-Kit(T670I) allele. Diabetic mice were treated with imatinib at the onset of hyperglycemia for three weeks, and blood glucose was monitored. RESULTS: In vitro expansion of HSCs from NOD.c-Kit(wt) mice was sensitive to imatinib, while expansion of HSCs from NOD.c-Kit(T670I) mice was insensitive to imatinib. However, in vivo treatment with imatinib lowered blood glucose levels in both strains of mice. CONCLUSIONS/INTERPRETATION: The HSC experiment confirmed that, in NOD.c-Kit(T670I) mice, c-Kit is resistant to imatinib. As both NOD.c-Kit(T670I) and NOD.c-Kit(wt) mice responded comparably to imatinib, c-Kit inhibition does not substantially contribute to the efficacy of imatinib in T1D. Thus, we conclude that inhibition of c-Kit is not required in next-generation tyrosine kinase inhibitors for T1D treatment, and may be selected against to improve the safety profile.

IL-2 immunotherapy reveals potential for innate beta cell regeneration in the non-obese diabetic mouse model of autoimmune diabetes.

Type-1 diabetes (T1D) is an autoimmune disease targeting insulin-producing beta cells, resulting in dependence on exogenous insulin. To date, significant efforts have been invested to develop immune-modulatory therapies for T1D treatment. Previously, IL-2 immunotherapy was demonstrated to prevent and reverse T1D at onset in the non-obese diabetic (NOD) mouse model, revealing potential as a therapy in early disease stage in humans. In the NOD model, IL-2 deficiency contributes to a loss of regulatory T cell function. This deficiency can be augmented with IL-2 or antibody bound to IL-2 (Ab/IL-2) therapy, resulting in regulatory T cell expansion and potentiation. However, an understanding of the mechanism by which reconstituted regulatory T cell function allows for reversal of diabetes after onset is not clearly understood. Here, we describe that Ab/IL-2 immunotherapy treatment, given at the time of diabetes onset in NOD mice, not only correlated with reversal of diabetes and expansion of Treg cells, but also demonstrated the ability to significantly increase beta cell proliferation. Proliferation appeared specific to Ab/IL-2 immunotherapy, as anti-CD3 therapy did not have a similar effect. Furthermore, to assess the effect of Ab/IL-2 immunotherapy well after the development of diabetes, we tested the effect of delaying treatment for 4 weeks after diabetes onset, when beta cells were virtually absent. At this late stage after diabetes onset, Ab/IL-2 treatment was not sufficient to reverse hyperglycemia. However, it did promote survival in the absence of exogenous insulin. Proliferation of beta cells could not account for this improvement as few beta cells remained. Rather, abnormal insulin and glucagon dual-expressing cells were the only insulin-expressing cells observed in islets from mice with established disease. Thus, these data suggest that in diabetic NOD mice, beta cells have an innate capacity for regeneration both early and late in disease, which is revealed through IL-2 immunotherapy.

A disulfide-linked conjugate of ferrocenyl chalcone and silicon(IV) phthalocyanine as an activatable photosensitiser.

A novel bis(ferrocenyl chalcone) silicon(IV) phthalocyanine has been prepared in which the disulfide linker can be cleaved by dithiothreitol. The separation of the ferrocenyl quencher and the phthalocyanine core greatly enhances the fluorescence emission, singlet oxygen production and in vitro photocytotoxicity.

A zinc(II) phthalocyanine conjugated with an oxaliplatin derivative for dual chemo- and photodynamic therapy.

A novel zinc(II) phthalocyanine substituted with an oxaliplatin derivative via a triethylene glycol linker has been synthesized. The two components work in a cooperative manner in the antitumor action. The conjugate shows a cytotoxic effect in the dark due to the cytostatic oxaliplatin moiety and an enhanced cytotoxicity upon illumination due to the photosensitizing phthalocyanine unit against the HT29 human colon adenocarcinoma cells. The IC(50) value of the conjugate is as low as 0.11 µM, which is 5-fold lower than that of the reference compound without the platinum complex. The high photodynamic activity of the conjugate can be attributed to its high cellular uptake and efficiency in generating intracellular reactive oxygen species. The conjugate also shows preferential localization in the lysosomes of the cells and induces cell death mainly through apoptosis.

Formation and photoinduced processes of a self-assembled subphthalocyanine-porphyrin-phthalocyanine supramolecular complex.

We report herein the formation and excitation energy transfer property of a ternary supramolecular complex of subphthalocyanine-porphyrin-phthalocyanine held by host-guest interactions.

Photocytotoxicity and magnetic relaxivity responses of dual-porous γ-Fe2O3@meso-SiO2 microspheres.

Novel high magnetization microspheres with porous γ-Fe(2)O(3) core and porous SiO(2) shell were synthesized using a templating method, whereas the size of the magnetic core and the thickness of the porous shell can be controlled by tuning the experimental parameters. By way of an example, as-prepared γ-Fe(2)O(3)@meso-SiO(2) microspheres (170 nm) display excellent water-dispersity and show photonic characteristics under externally applied a magnetic field. The magnetic property of the γ-Fe(2)O(3) porous core enables the microspheres to be used as a contrast agent in magnetic resonance imaging with a high r(2) (76.5 s(-1) mM(-1) Fe) relaxivity. The biocompatible composites possess a large BET surface area (222.3 m(2)/g), demonstrating that they can be used as a bifunctional agent for both MRI and drug carrier. Because of the high substrate loading of the magnetic, dual-porous materials, only a low dosage of the substrate will be acquired for potential practical applications. Hydrophobic zinc(II) phthalocyanine (ZnPC) photosensitizing molecules have been encapsulated into the dual-porous microspheres to form γ-Fe(2)O(3)@meso-SiO(2)-ZnPC microspheres. Biosafety, cellular uptake in HT29 cells, and in vitro MRI of these nanoparticles have been demonstrated. Photocytotoxicity (λ > 610 nm) of the HT29 cells uptaken with γ-Fe(2)O(3)@meso-SiO(2)-ZnPC microspheres has been demonstrated for 20 min illumination.

Switching the photoinduced processes in host-guest complexes of ß-cyclodextrin-substituted silicon(IV) phthalocyanines and a tetrasulfonated porphyrin.

Porphyrins and phthalocyanines are two attractive classes of functional dyes for the construction of artificial light harvesting and charge separation molecular systems. The assembly of these components by supramolecular approach is of particular interest as this provides a facile route to build multi-chromophoric arrays with various architectures and tuneable photophysical properties. We report herein a series of host-guest complexes formed between a tetrasulfonated porphyrin and several silicon(IV) phthalocyanines substituted axially with two permethylated ß-cyclodextrin units via different spacers. As shown by electronic absorption and fluorescence spectroscopic methods, the two components bind spontaneously in a 1:1 manner in water with large binding constants in the range of 1.1 × 10(7) to 3.5 × 10(8) M(-1). The photophysical properties of the resulting supramolecular complexes have also been studied in detail using steady-state and time-resolved optical spectroscopic methods. It has been found that two major photoinduced processes, namely fluorescence resonance energy transfer and charge transfer are involved which are controlled by the spacer between the ß-cyclodextrin units and the silicon centre of phthalocyanine. Despite the fact that charge transfer is a thermodynamically favourable process for all the complexes, only the ones with a tetraethylene glycol or oxo linker exhibit an efficient charge transfer from the excited phthalocyanine to the porphyrin entity. The lifetimes of the corresponding charge-separated states have been determined to be 200 and 70 ps by picosecond pump-probe experiments.

Unsymmetrical ß-cyclodextrin-conjugated silicon(IV) phthalocyanines as highly potent photosensitisers for photodynamic therapy.

A series of unsymmetrical silicon(IV) phthalocyanines with a permethylated ß-cyclodextrin unit and a sugar or a diamino moiety as the axial substituents have been prepared. These compounds are highly photocytotoxic with IC(50) values as low as 21 nM, which is ca. sevenfold lower than those of the symmetrical bis(cyclodextrin) analogue.

Preparation and photodynamic activities of silicon(IV) phthalocyanines substituted with permethylated ß-cyclodextrins.

A series of silicon(IV) phthalocyanines linked to two permethylated ß-cyclodextrin moieties through different spacers at the axial positions have been synthesized and characterized. The effects of these spacers on the photophysical properties and in vitro photodynamic activities have also been examined. Having two bulky hydrophilic substituents, all of these compounds are soluble and essentially nonaggregated in DMF and even in aqueous media. The fluorescence and singlet oxygen quantum yields in DMF are lower for the analogue with the shortest separation between the amino group in the spacer and the phthalocyanine ring. The fluorescence quantum yield of this compound increases in water probably due to protonation of the amino group, which inhibits the reductive quenching process. This series of compounds also exhibit photocytotoxicity toward HT29 human colon adenocarcinoma and HepG2 human hepatocarcinoma cells with IC(50) values in the range of 0.04-1.32 µM. The analogue with an α,ω-aminohydroxypentyl linker shows the highest potency, which can be ascribed to its high cellular uptake and high efficiency in generating intracellular reactive oxygen species. This compound also shows preferential localization in the lysosome, induces cell death mainly through apoptosis, and inhibits the growth of tumor in vivo. The results suggest that it is a promising photosensitizer for photodynamic therapy.

Primary cilia regulate Gli/Hedgehog activation in pancreas.

Previous studies have suggested that defects in pancreatic epithelium caused by activation of the Hedgehog (Hh) signaling pathway are secondary to changes in the differentiation state of the surrounding mesenchyme. However, recent results describe a role of the pathway in pancreatic epithelium, both during development and in adult tissue during neoplastic transformation. To determine the consequences of epithelial Hh activation during pancreas development, we employed a transgenic mouse model in which an activated version of GLI2, a transcriptional mediator of the pathway, is overexpressed specifically in the pancreatic epithelium. Surprisingly, efficient Hh activation was not observed in these transgenic mice, indicating the presence of physiological mechanisms within pancreas epithelium that prevent full Hh activation. Additional studies revealed that primary cilia regulate the level of Hh activation, and that ablation of these cellular organelles is sufficient to cause significant up-regulation of the Hh pathway in pancreata of mice overexpressing GLI2. As a consequence of overt Hh activation, we observe profound morphological changes in both the exocrine and endocrine pancreas. Increased Hh activity also induced the expansion of an undifferentiated cell population expressing progenitor markers. Thus, our findings suggest that Hh signaling plays a critical role in regulating pancreatic epithelial plasticity.