Iridium(III) carbene complexes as potent girdin inhibitors against metastatic cancers.

Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 µM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.

A Phase 1, Randomized, Double-Blinded, Placebo-Controlled and Dose-Escalation Study to Evaluate the Safety and Immunogenicity of the Intranasal DelNS1-nCoV-RBD LAIV for COVID-19 in Healthy Adults.

An intranasal COVID-19 vaccine, DelNS1-based RBD vaccines composed of H1N1 subtype (DelNS1-nCoV-RBD LAIV) was developed to evaluate the safety and immunogenicity in healthy adults. We conducted a phase 1 randomized, double-blinded, placebo-controlled study on healthy participants, age 18-55 and COVID-19 vaccines naïve, between March and September 2021. Participants were enrolled and randomly assigned (2:2:1) into the low and high dose DelNS1-nCoV-RBD LAIV manufactured in chicken embryonated eggs or placebo groups. The low and high-dose vaccine were composed of 1 × 107 EID50/ dose and 1 × 107.7 EID50/ dose in 0.2 mL respectively. The placebo vaccine was composed of inert excipients/dose in 0.2 mL. Recruited participants were administered the vaccine intranasally on day 0 and day 28. The primary end-point was the safety of the vaccine. The secondary endpoints included cellular, humoral, and mucosal immune responses post-vaccination at pre-specified time-points. The cellular response was measured by the T-cell ELISpot assay. The humoral response was measured by the serum anti-RBD IgG and live-virus neutralizing antibody against SARS-CoV-2. The saliva total Ig antibody responses in mucosal secretion against SARS-CoV-2 RBD was also assessed. Twenty-nine healthy Chinese participants were vaccinated (low-dose: 11; high-dose: 12 and placebo: 6). The median age was 26 years. Twenty participants (69%) were male. No participant was discontinued due to an adverse event or COVID-19 infection during the clinical trial. There was no significant difference in the incidence of adverse events (p = 0.620). For the T-cell response elicited after full vaccination, the positive PBMC in the high-dose group increased to 12.5 SFU/106 PMBC (day 42) from 0 (baseline), while it increased to 5 SFU/106 PBMC (day 42) from 2.5 SFU/106 PBMC (baseline) in the placebo group. The high-dose group showed a slightly higher level of mucosal Ig than the control group after receiving two doses of the vaccine (day 31, 0.24 vs. 0.21, p = 0.046; day 56 0.31 vs. 0.15, p = 0.45). There was no difference in the T-cell and saliva Ig response between the low-dose and placebo groups. The serum anti-RBD IgG and live virus neutralizing antibody against SARS-CoV-2 were undetectable in all samples. The high-dose intranasal DelNS1-nCoV-RBD LAIV is safe with moderate mucosal immunogenicity. A phase-2 booster trial with a two-dose regimen of the high-dose intranasal DelNS1-nCoV-RBD LAIV is warranted.

Dosimetric benefits of adaptive radiation therapy for patients with stage III non-small cell lung cancer.

BACKGROUND: Daily adaptive radiation therapy (ART) of patients with non-small cell lung cancer (NSCLC) lowers organs at risk exposure while maintaining the planning target volume (PTV) coverage. Thus, ART allows an isotoxic approach with increased doses to the PTV that could improve local tumor control. Herein we evaluate daily online ART strategies regarding their impact on relevant dose-volume metrics. METHODS: Daily cone-beam CTs (1 × n = 28, 1 × n = 29, 11 × n = 30) of 13 stage III NSCLC patients were converted into synthetic CTs (sCTs). Treatment plans (TPs) were created retrospectively on the first-fraction sCTs (sCT1) and subsequently transferred unaltered to the sCTs of the remaining fractions of each patient (sCT2-n) (IGRT scenario). Two additional TPs were generated on sCT2-n: one minimizing the lung-dose while preserving the D95%(PTV) (isoeffective scenario), the other escalating the D95%(PTV) with a constant V20Gy(lungipsilateral) (isotoxic scenario). RESULTS: Compared to the original TPs predicted dose, the median D95%(PTV) in the IGRT scenario decreased by 1.6 Gy ± 4.2 Gy while the V20Gy(lungipsilateral) increased in median by 1.1% ± 4.4%. The isoeffective scenario preserved the PTV coverage and reduced the median V20Gy(lungipsilateral) by 3.1% ± 3.6%. Furthermore, the median V5%(heart) decreased by 2.9% ± 6.4%. With an isotoxic prescription, a median dose-escalation to the gross target volume of 10.0 Gy ± 8.1 Gy without increasing the V20Gy(lungipsilateral) and V5%(heart) was feasible. CONCLUSIONS: We demonstrated that even without reducing safety margins, ART can reduce lung-doses, while still reaching adequate target coverage or escalate target doses without increasing ipsilateral lung exposure. Clinical benefits by means of toxicity and local control of both strategies should be evaluated in prospective clinical trials.

Inducing gene expression by targeting promoter sequences using small activating RNAs.

Vector-based systems comprised of exogenous nucleic acid sequences remain the standard for ectopic expression of a particular gene. Such systems offer robust overexpression, but have inherent drawbacks such as the tedious process of construction, excluding sequences (e.g. introns and untranslated regions) important for gene function and potential insertional mutagenesis of host genome associated with the use of viral vectors. We and others have recently reported that short double-stranded RNAs (dsRNAs) can induce endogenous gene expression by targeting promoter sequences in a phenomenon referred to as RNA activation (RNAa) and such dsRNAs are termed small activating RNAs (saRNAs). To date, RNAa has been successfully utilized to induce the expression of different genes such as tumor suppressor genes. Here, we describe a detailed protocol for target selection and dsRNA design with associated experiments to facilitate RNAa in cultured cells. This technique may be applied to selectively activate endogenous gene expression for studying gene function, interrogating molecular pathways and reprogramming cell fate.

The link between enthesitis and arthritis in psoriatic arthritis: a switch to a vascular phenotype at insertions may play a role in arthritis development.

OBJECTIVE: Subclinical enthesopathy is recognised in both psoriasis and psoriatic arthritis (PsA). This study used ultrasonography with power Doppler (PD) to test the hypothesis that subclinical enthesopathy in PsA was associated with an 'inflammatory' or vascular phenotype compared to that seen in psoriasis. METHODS: 100 patients with a mean age of 46.3 years (SD 15) (42 with psoriasis and 58 with PsA) and 23 matched healthy controls (HC) from two centres were included. 1230 lower limb entheses were scanned by ultrasonographers blinded to clinical details. Both inflammatory and chronic features of enthesopathy were scored. RESULTS: Psoriasis patients (with or without arthritis) were more likely to express a vascular phenotype, with higher inflammation-related enthesopathy scores than HC (for inflammation p<0.0001, for chronicity p=0.02, for total ultrasound scores p<0.0001). The PsA patients had higher ultrasound enthesopathy scores than psoriasis patients (inflammation p=0.04, chronicity p=0.02) and HC (inflammation p<0.0001, chronicity p=0.003). When symptomatic entheses were excluded, PsA patients still had higher PD scores than psoriasis patients (p=0.003). Doppler positivity in at least one entheseal site was observed more frequently in PsA (21/58, 36.2%) versus psoriasis (4/42, 9.5%; p=0.002). CONCLUSIONS: This study shows that the ultrasound appearances of subclinical enthesitis in psoriasis differ from the subclinical enthesitis in PsA, with PsA patients having more PD. This is suggestive of a more inflammatory or vascular process in PsA, and offers potentially novel insights into the progression from skin to joint disease in psoriasis.

Psoriasis patients with nail disease have a greater magnitude of underlying systemic subclinical enthesopathy than those with normal nails.

OBJECTIVE: Enthesopathy is a major feature of psoriatic arthritis (PsA), which is supported by imaging studies. Given that nail disease often predates PsA and that the nail is directly anchored to entheses, the authors asked whether nail involvement in psoriasis equates with a systemic enthesopathy. METHODS: Forty-six patients with psoriasis (31 with nail disease) and 21 matched healthy controls (HC) were recruited. 804 entheses of upper and lower limbs were scanned by an ultrasonographer blinded to clinical details. RESULTS: Psoriasis patients had higher enthesitis scores than HC (median (range) 21 (0-65) vs 11 (3-39), p=0.005). Enthesopathy scores were higher in patients with nail disease (23 (0-65)) than in patients without nail disease (15 (5-26), p=0.02) and HC (11 (3-39), p=0.003). Inflammation scores of patients with nail disease (13 (0-34)) were higher than patients without nail disease (8 (2-15), p=0.02) and HC (5 (0-19), p<0.001). Modified nail psoriasis severity index scores were correlated to both inflammation (r(2)=0.45, p=0.005) and chronicity scores (r(2)=0.35, p=0.04). No link between the psoriasis area and severity index and enthesitis was evident. CONCLUSION: The link between nail disease and contemporaneous subclinical enthesopathy offers a novel anatomical basis for the predictive value of nail psoriasis for PsA evolution.

Oral versus intravenous administration of cyclophosphamide: a case report.

BACKGROUND: Cyclophosphamide, an alkylating agent, has been used as an immunosuppressant in the treatment of various autoimmune disorders and malignancies. It is highly capable of reducing T and B lymphocytes. CASE PRESENTATION: Regular blood tests are important to detect bone marrow suppression. The risk of opportunistic infection such as pneumonia secondary to pneumocystic carinii increases drastically with lymphopaenia. Hence, prophylactic co-trimoxazole is frequently prescribed as long as patients are on cyclophosphamide. CONCLUSION: The benefits and toxicity risks of intravenous versus oral administration of cyclophosphamide are described in this article.

The role of fear-avoidance beliefs in patients with neck pain: relationships with current and future disability and work capacity.

OBJECTIVES: To investigate the relationship between fear-avoidance beliefs and future disability and work capacity in patients with neck pain. DESIGN: A prospective observational study. SETTING: Physiotherapy outpatient departments. PATIENTS: One hundred and twenty patients with neck pain intensity sufficient to affect their work capacity. INTERVENTIONS: Patients participated in either six-week conventional physiotherapy or an exercise training programme to test whether the type of treatment received by the patients together with other outcome measures affected the predictive power of fear-avoidance beliefs. MAIN OUTCOME MEASURES: Patients underwent examination of the active neck range of movements and neck muscle strength and completed the Fear-Avoidance Beliefs Questionnaire, the Northwick Park Neck Pain Questionnaire, the Medical Outcomes 36-Item Short-Form Health Survey and the 11-point pain numerical rating scale. These were assessed at the beginning and at week 6 of the rehabilitation programme. Patients' work capacity was assessed at week 6 and three months after the six-week rehabilitation programme. RESULTS: Spearman's correlation coefficients between fear-avoidance beliefs and initial and week 6 disability levels were 0.47 and 0.48, respectively. Regression analysis showed that the fear-avoidance beliefs significantly improved the goodness of fit of the model for predicting week 6 disability levels and return to complete work capacity at week 6 and three months after the rehabilitation programme, even after controlling for the physical impairments, the health status, the pain intensity and the type of treatment received. CONCLUSIONS: The fear-avoidance beliefs factor is an important biopsychosocial variable in predicting future disability level and return to complete work capacity in patients with neck pain.

Long-term outcome of the Hong Kong vascularized, pedicled temporalis fascia flap in reconstruction of mastoid cavity.

OBJECTIVES: The vascularized, pedicled temporalis fascia flap (Hong Kong flap) is an established procedure in the reconstruction of the mastoid cavity. The long-term outcome and complications have not been studied. We set out to appraise this procedure in our study. STUDY DESIGN: The clinical records of 302 ears that had the Hong Kong flap procedure from 1987 to 2006 were retrospectively studied. The study reviewed the otologic complaints leading to Hong Kong flap, the number and findings of the second or more looks, analysis of procedures year by year, time to achieve a dry ear, and the complications. RESULTS: The main otologic complaint leading to use of the Hong Kong flap is otorrhoea. The number of Hong Kong flap procedures has decreased in recent years. Twenty-one percent had second or more looks after the procedure. Forty percent of the mastoid cavities at the second look were found to have residual or recurrent cholesteatoma. It takes a median of 2 months to achieve a dry ear after the procedure. CONCLUSIONS: We conclude that the Hong Kong flap procedure is simple and desirable for mastoid reconstruction to achieve a safe and dry cavity with few complications.

Psychometric properties of the Fear-Avoidance Beliefs Questionnaire in patients with neck pain.

OBJECTIVES: To translate the Fear-Avoidance Beliefs Questionnaire and investigate the validity and reliability of the Chinese version of the questionnaire in patients with neck pain. DESIGN: Observational cross-sectional and prospective study. SETTING: Physiotherapy outpatient departments. SUBJECTS: Four samples with 476 consecutive adult patients with neck pain from four physiotherapy centres. METHODS: The original questionnaire was translated into Chinese by forward and backward translation and reviewed by a panel of experts. The subjects completed the Chinese version of the fear-avoidance questionnaire, Northwick Park Neck Pain Questionnaire, Medical Outcomes 36-Item Short-Form Health Survey and their pain intensity was measured using an 11-point pain numerical rating scale. They were observed and measured at the beginning of physiotherapy, at week 3 and at week 6 after treatment began. RESULTS: The questionnaire had very good content validity and test-retest reliability with an intraclass correlation coefficient of 0.81 and Cronbach's alpha coefficient of 0.90. Spearman's correlation coefficients between fear-avoidance and the neck pain questionnaire, the health survey (physical), health survey (mental) and pain scale were 0.56, 0.45, 0.36 and 0.34, respectively. The standard response mean and effect size at week 6 were 0.38 and 0.32, respectively. Factor analysis yielded three factors which accounted for 61.6% of the total variance of the questionnaire. CONCLUSION: The Fear-Avoidance Beliefs Questionnaire is a valid and reliable tool for patients with neck pain. It has been shown to demonstrate very good content validity, a high degree of test-retest reliability and internal consistency, good construct validity and medium responsiveness.

Correlation between generic health status and region-specific functional measures on patients with neck pain.

This is a cross-sectional and prospective study to examine the correlation between the Northwick Park Neck Pain Questionnaire and the Medical Outcomes 36-Item Short-Form Health Survey on patients with neck pain in the course of physiotherapy. A total of 359 consecutive adult patients with neck pain, from three physiotherapy outpatient departments, who completed the Northwick Park Neck Pain Questionnaire and Medical Outcomes 36-Item Short-Form Health Survey, were observed and measured at different intervals - at the beginning of physiotherapy, at week 3, week 6 and upon discharge from physiotherapy. The results showed that both the Northwick Park Neck Pain Questionnaire and the Medical Outcomes 36-Item Short-Form Health Survey were able to differentiate patients with neck pain in health and diseased states. The Spearman's correlation coefficients between the Northwick Park Neck Pain Questionnaire and the 36-Item Short-Form Health Survey physical and mental component summary scores at entry of physiotherapy were -0.64 with the physical component summary score and -0.44 with the mental component summary score, and, at discharge from physiotherapy, were -0.75 with the physical component summary score and -0.46 with the mental component summary score. The Northwick Park Neck Pain Questionnaire has psychometric properties with both physical and mental dimensions of measurement of pain in patients with neck pain.