Blood Group Antigen A Carriers Exhibit an Extended Progression-Free Survival with no more Immune-Related Adverse Events.

Extensive investigations have been conducted regarding the potential correlation between blood type and the immune system, as well as cancer risk in the Southern Chinese population. However, the prognostic value of the blood group and its genetic determinants in the context of immune checkpoint inhibitor (ICI) treatment remains unclear. Therefore, the associations between the ABO blood group and its single nucleotide polymorphisms (SNPs) were examined in relation to ICI treatment outcomes in 370 eligible patients with cancer. This approach allowed us to derive the blood group from the SNPs responsible for blood group determination. In the discovery cohort (N = 168), antigen A carriers (blood types A and AB) exhibited an extended progression-free survival (PFS; hazard ratio (HR) = 0.58, 95% confidence interval (CI) = 0.34-0.98). The association results from the SNP-derived blood were consistent with those from the measured blood group. In the validation cohort (N = 202), Cox regression analysis revealed that the antigen A carriers (rs507666 AA+GA genotype carriers) experienced significantly extended PFS compared with the non-antigen A carriers (HR = 0.61, 95% CI = 0.40-0.93). Therefore, a longer PFS was observed in antigen A carriers (P value = 0.003, HR = 0.60, 95% CI = 0.44-0.84). Furthermore, haplotype 2 carriers (rs507666 GA and rs659104 GG) demonstrated both extended PFS and improved overall survival. Notably, the presence of antigen A was not associated with the occurrence of overall immune-related adverse events (irAEs) or organ-specific toxicity. In summary, our findings revealed that antigen A carriers did not experience a higher incidence of irAEs while exhibiting better immunotherapy efficacy.

Superantigen-fused T cell engagers for tumor antigen-mediated robust T cell activation and tumor cell killing.

Inadequate T cell activation has severely limited the success of T cell engager (TCE) therapy, especially in solid tumors. Enhancing T cell activity while maintaining the tumor specificity of TCEs is the key to improving their clinical efficacy. However, currently, there needs to be more effective strategies in clinical practice. Here, we design novel superantigen-fused TCEs that display robust tumor antigen-mediated T cell activation effects. These innovative drugs are not only armed with the powerful T cell activation ability of superantigens but also retain the dependence of TCEs on tumor antigens, realizing the ingenious combination of the advantages of two existing drugs. Superantigen-fused TCEs have been preliminarily proven to have good (>30-fold more potent) and specific (>25-fold more potent) antitumor activity in vitro and in vivo. Surprisingly, they can also induce the activation of T cell chemotaxis signals, which may promote T cell infiltration and further provide an additional guarantee for improving TCE efficacy in solid tumors. Overall, this proof-of-concept provides a potential strategy for improving the clinical efficacy of TCEs.

Improving the tumor selectivity of T cell engagers by logic-gated dual tumor-targeting.

Targeting single tumor antigens makes it difficult to provide sufficient tumor selectivity for T cell engagers (TCEs), leading to undesirable toxicity and even treatment failure, which is particularly serious in solid tumors. Here, we designed novel trispecific TCEs (TriTCEs) to improve the tumor selectivity of TCEs by logic-gated dual tumor-targeting. TriTCE can effectively redirect and activate T cells to kill tumor cells (∼18 pM EC50) by inducing the aggregation of dual tumor antigens, which was ∼70- or 750- fold more effective than the single tumor-targeted isotype controls, respectively. Further in vivo experiments indicated that TriTCE has the ability to accumulate in tumor tissue and can induce circulating T cells to infiltrate into tumor sites. Hence, TriTCE showed a stronger tumor growth inhibition ability and significantly prolonged the survival time of the mice. Finally, we revealed that this concept of logic-gated dual tumor-targeted TriTCE can be applied to target different tumor antigens. Cumulatively, we reported novel dual tumor-targeted TriTCEs that can mediate a robust T cell response by simultaneous recognition of dual tumor antigens at the same cell surface. TriTCEs allow better selective T cell activity on tumor cells, resulting in safer TCE treatment.

Fermentation of rose residue by Lactiplantibacillus plantarum B7 and Bacillus subtilis natto promotes polyphenol content and beneficial bioactivity.

The present study evaluated the effect of fermentation with Lactiplantibacillus plantarum B7 and Bacillus subtilis natto on phenolic compound levels and enzyme activity, as well as antioxidant capacity of the rose residue. Results showed that the polyphenol content of rose residue was significantly increased from 16.37 ± 1.51 mg/100 mL to 41.02 ± 1.68 mg/100 mL by fermentation at 37 °C and 2.0% (v/v) inoculum size for 40 h. The flavone, soluble dietary, and protein contents were also enhanced by almost 1-fold, 3-fold, and 1-fold, respectively. Fifteen phenolic compounds were quantified in the fermented broth, among which the concentration of gallic acid, quercetin, and p-coumaric acid increased by 5-fold, 4-fold, and almost 8-fold, respectively. Chlorogenic acid was a new phenolic compound produced during fermentation. Moreover, the fermented rose residue presented higher superoxide dismutase, α-amylase, and protease activity. ABTS•+, hydroxylradical, and DPPH• scavenging activity increased by 60.93%, 57.70%, and 37.00%, respectively. This provides an effective means of transforming rose residue into a highly bioactive value-added substance.

Lasers and Intense Pulsed Light for the Treatment of Pathological Scars: A Network Meta-Analysis.

BACKGROUND: Laser and intense pulsed light (IPL) therapies have shown promising effects on pathological scars, but the comparative effectiveness of laser and IPL therapies has not yet been studied. OBJECTIVES: The aim of this study was to compare and rank the efficacy of laser and IPL therapies to determine the most effective treatment method for pathological scars. METHODS: Relevant studies published up to February 2022 were identified by searching PubMed, Web of Science, Cochrane Library, CNKI, and Wanfang databases. We defined Vancouver Scar Scale score as the primary outcome. Both frequentist and Bayesian approaches were used to perform a network meta-analysis. RESULTS: We included 25 trials with a total of 1688 participants. The rankings based on the surface under the cumulative ranking curve for the Vancouver Scar Scale score based on the Bayesian approach suggested IPL + CO2 (96.43%) > pulsed dye laser (PDL) + 1064-nm Nd:YAG (yttrium aluminum garnet) laser (86.21%) > PDL + CO2 (82.15%) > CO2 (58.97%) > 1064-nm Nd:YAG (57.03%) > PDL (52%) > 532-nm Nd:YAG (33.28%) > Er:YAG + IPL (28.38%) > Er:YAG (26.56%) > IPL (15.03%) > control (13.97%). The ranking results based on the frequentist approach were basically consistent with those based on the Bayesian approach. CONCLUSIONS: The results of the network meta-analysis showed that the combination of IPL and CO2 laser has the highest probability of being the most effective intervention. However, our conclusions must be interpreted with caution due to the relatively few evaluation indicators included in our study. Future well-designed randomized controlled trials with large sample sizes are required to confirm our conclusions.

Trends of Ten Leading Causes of Death in Head and Neck Squamous Cell Carcinoma.

OBJECTIVE: An understanding of the leading causes of death in patients with head and neck squamous cell carcinoma (HNSCC) would be helpful to inform doctors, patients, and healthcare providers on disease management. This study aimed to comprehensively study the leading causes of death in these survivors. METHODS: We investigated the trends of risk factors for major causes of death in patients with HNSCC. Causes of death in HNSCC were obtained from the Surveillance, Epidemiology, and End Results registries. We characterized trends in the 5-year cumulative mortality as well as risk factors associated with the ten leading causes of death. RESULTS: Among 48 297 deaths identified, the ten leading causes were as follows: HNSCC, heart disease, lung cancer, chronic obstructive pulmonary disease (COPD), cerebrovascular disease, pneumonia & influenza, accidents & adverse effects, esophagus cancer, chronic liver diseases, and septicemia. Non-HNSCC deaths surpassed HNSCC deaths 4 years after cancer diagnosis. There was a significant decline in the 5-year cumulative mortality from HNSCC, heart disease, lung cancer, COPD, cerebrovascular disease, and esophagus cancer. The risks of mortality from the ten leading causes varied with patient characteristics. CONCLUSION: Our findings provide a useful picture of mortality patterns in HNSCC survivors, which might help when planning personalized HNSCC care.

Correction: Effect of Physician-Pharmacist Participation in the Management of Ambulatory Cancer Pain Through a Digital Health Platform: Randomized Controlled Trial.

[This corrects the article DOI: 10.2196/24555.].

Soluble Expression of Fc-Fused T Cell Receptors Allows Yielding Novel Bispecific T Cell Engagers.

The specific recognition of T cell receptors (TCR) and peptides presented by human leukocyte antigens (pHLAs) is the core step for T cell triggering to execute anti-tumor activity. However, TCR assembly and soluble expression are challenging, which precludes the broad use of TCR in tumor therapy. Herein, we used heterodimeric Fc to assist in the correct assembly of TCRs to achieve the stable and soluble expression of several TCRs in mammalian cells, and the soluble TCRs enable us to yield novel bispecific T cell engagers (TCR/aCD3) through pairing them with an anti-CD3 antibody. The NY-ESO-1/LAGE-1 targeted TCR/aCD3 (NY-TCR/aCD3) that we generated can redirect naïve T cells to specific lysis antigen-positive tumor cells, but the potency of the NY-TCR/aCD3 was disappointing. Furthermore, we found that the activation of T cells by NY-TCR/aCD3 was mild and unabiding, and the activity of NY-TCR/aCD3 could be significantly improved when we replaced naïve T cells with pre-activated T cells. Therefore, we employed the robust T cell activation ability of staphylococcal enterotoxin C2 (SEC2) to optimize the activity of NY-TCR/aCD3. Moreover, we found that the secretions of SEC2-activated T cells can promote HLA-I expression and thus increase target levels, which may further contribute to improving the activity of NY-TCR/aCD3. Our study described novel strategies for soluble TCR expression, and the optimization of the generation and potency of TCR/aCD3 provided a representative for us to fully exploit TCRs for the precision targeting of cancers.

Effect of Physician-Pharmacist Participation in the Management of Ambulatory Cancer Pain Through a Digital Health Platform: Randomized Controlled Trial.

BACKGROUND: Self-management of ambulatory cancer pain is full of challenges. Motivated by the need for better pain management, we developed a WeChat-supported platform, Medication Housekeeper (MediHK), to enhance communication, optimize outcomes, and promote self-management in the home setting. OBJECTIVE: We conducted a randomized controlled trial to assess whether the joint physician-pharmacist team through MediHK would provide better self-management of ambulatory patients with cancer pain. METHODS: Patients were randomly assigned to either an intervention group or control group. During the 4-week study period, the pharmacist would send 24-hour pain diaries daily, adverse drug reaction (ADR) forms every 3 days, and the Brief Pain Inventory form every 15 days to patients in the intervention group via MediHK. If a patient needed a change in drug/dosage or treatment of an ADR after the comprehensive review, the pharmacist would propose pharmacological interventions to the attending physician, who was then responsible for prescribing or adjusting pain medications. If no adjustments were needed, the pharmacist provided appropriate targeted education based on knowledge deficits. Patients in the control group received conventional care and did not receive reminders to fill out the forms. However, if the control group patients filled out a form via MediHK, the pain management team would review and respond in the same way as for the intervention group. The primary outcomes included pain intensity and pain interference in daily life. Secondary outcomes included patient-reported outcome measures, medication adherence, ADRs, and rehospitalization rates. RESULTS: A total of 100 patients were included, with 51 (51%) in the intervention group and 49 (49%) in the control group. The worst pain scores, least pain scores, and average pain scores in the intervention group and the control group were statistically different, with median values of 4 (IQR 3-7) vs 7 (IQR 6-8; P=.001), 1 (IQR 0-2) vs 2 (IQR 1-3; P=.02), and 2 (IQR 2-4) vs 4 (IQR 3-5; P=.001), respectively, at the end of the study. The pain interference on patients' general activity, mood, relationships with others, and interests was reduced, but the difference was not statistically significant compared with the control group (Ps=.10-.76). The medication adherence rate increased from 43% to 63% in the intervention group, compared with an increase of 33% to 51% in the control group (P<.001). The overall number of ADRs increased at 4 weeks, and more ADRs were monitored in the intervention group (P=.003). Rehospitalization rates were similar between the 2 groups. CONCLUSIONS: The joint physician-pharmacist team operating through MediHK improved pain management. This study supports the feasibility of integrating the internet into the self-management of cancer pain. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900023075; https://www.chictr.org.cn/showproj.aspx?proj=36901.

Influencing factors of end-of-dose failure in patients with cancer pain after oral oxycodone sustained-release tablets: a retrospective, case-control study.

OBJECTIVE: Comparing the characteristics of end-of-dose failure patients and non-end-of-dose failure patients in the Chinese population and exploring the factors that may affect the occurrence of end-of-dose failure in cancer pain patients. METHODS: The outpatient with cancer pain from 2016 to 2019 were collected through hospital information system, and patients were included who met the following criteria: patients with the average numerical rating scale  ≥4 points within 3 days after taking the oxycodone sustained-release preparation, titrated to an effective therapeutic dose suitable for patients, had at least two clinical visits information of the patient with a minimum of ≥3 days between visits, the average numerical rating scale of the next visit after the treatment of occasional pain is ≥4, and were divided into end-of-dose failure group and non-end-of-dose failure group. RESULTS: Age (P < 0.05, odds ratio 0.933), diagnosis of nasopharyngeal carcinoma (P < 0.05, odds ratio 0.009), pain site is the head and neck (P < 0.05, odds ratio 0.005) and the abdomen (P < 0.01, odds ratio 0.021), and the metastatic site is the liver (P < 0.05, odds ratio 0.001) are related to the occurrence of end-of-dose failure. CONCLUSIONS: Younger patients are more likely to develop end-of-dose failure. Patients diagnosed with nasopharyngeal cancer, with pain in the head and neck and abdomen, and with liver metastases have a lower incidence of end-of-dose failure.

Trends and seasonality in cause-specific mortality among children under 15 years in Guangzhou, China, 2008-2018.

BACKGROUND: This study analyzed the trends and seasonality in mortality among children aged 0-14 years in Guangzhou, China during 2008-2018. Understanding the epidemiology of this public health problem can guide policy development for children mortality prevention. METHODS: A population-based epidemiological retrospective study was conducted. Seven thousand two hundred sixty-five individual data of children mortality were obtained from the Guangzhou Center for Disease Control and Prevention (CDC). The Poisson regression was used to quantify the annual average reduction rate and the difference in mortality rate between sex and age groups. Incidence ratio with 95% confidence interval (CI) was estimated to determine the temperaol variations in mortality by month, season, school term, day of the week and between holidays and other days. RESULTS: Between 2008 and 2018, the children mortality rate in Guangzhou decreased from 54.0 to 34.3 per 100,000 children, with an annual reduction rate of 4.6% (95% CI: 1.1%-8.1%), especially the under-5 mortality rate decreased by 8.3% (95% CI: 4.8%-11.6%) per year. Decline trends varied by causes of death, even with an upward trend for the mortality of asphyxia and neurological diseases. The risk of death among males children was 1.33 times (95% CI: 1.20-1.47) of that of females. The distribution of causes of death differed by age group. Maternal and perinatal, congenital and pneumonia were the top three causes of death in infants and cancer accounted for 17% of deaths in children aged 1-14 years. Moreover, the injury-related mortality showed significant temporal variations with higher risk during the weekend. And there was a summer peak for drowning and a winter peak for asphyxia. CONCLUSIONS: Guangzhou has made considerable progress in reducing mortality over the last decade. The findings of characteristics of children mortality would provide important information for the development and implementation of integrated interventions targeted specific age groups and causes of death.

Role of the initial degree of anaemia and treatment model in the prognosis of gastric cancer patients treated by chemotherapy: a retrospective analysis.

BACKGROUND: Anaemia is highly prevalent in gastric cancer (GC) patients. The role of initial haemoglobin levels in predicting the prognosis of GC patients treated by chemotherapy has not been well determined. Our present study aims to evaluate the relationship between the degree of anaemia and the overall survival (OS) and progression-free survival (PFS) of patients with GC. METHODS: Our retrospective study enrolled 598 patients who were treated with chemotherapy when the recurrent or metastatic GCs were unsuitable for surgical resection. Univariate and multivariate analyses were performed to identify risk factors that had the potential to affect patient prognosis. Additionally, the relationship between clinicopathological characteristics, including treatment method, and degree of cancer-related reduction in haemoglobin was further analysed. RESULTS: Our results revealed that patients with HBini level ≤ 80 g/L had a trend toward a shortened median OS and PFS (p = 0.009 and p = 0.049, respectively). Interestingly, we also found that HBdec ≥ 30 g/L was associated with a significantly shortened median OS and PFS (p = 0.039 and p = 0.001, respectively). Multivariate analysis showed that HBini levels ≤80 g/L could be used as an independent prognostic factor for recurrent and metastatic GC. More importantly, HBdec ≥ 30 g/L and treatment response were also significantly associated with OS and PFS. Furthermore, the degree of haemoglobin decrease was associated with chemotherapy including platinum and the number of chemotherapy cycles. CONCLUSION: Our study concludes that the initial degree of anaemia and a decrease in haemoglobin of ≥30 g/L can serve as biomarkers to predict prognosis in recurrent or metastatic GC patients, while chemotherapy treatment rather than red blood cell (RBC) transfusion can improve their prognosis. Additionally, platinum should not be recommended for treating severely anaemic GC patients.

Formation of new lymphatic vessels in glioma: An immunohistochemical analysis.

We investigated the distribution and formation of new lymphatic vessels in gliomas. Specimens from seven glioma cases were analyzed by immunohistochemical staining for CD34, lymphatic endothelial hyaluronic acid receptor 1 (LYVE-1), prospero-related homeobox 1 (Prox1), nestin, and hypoxia-inducible factor 1α (HIF-1α). Three types of vessels were observed in glioma specimens: LYVE-1+ lymphatic vessels, CD34+ blood vessels, and LYVE-1+ /CD34+ blood vessels. Prox1+ /LYVE-1+ cells were distributed in some lymphatic vessels as well as among vascular endothelial cells and glioma cells. Nestin+ cells were scattered throughout the gliomas, and some lymphatic cells also expressed nestin. HIF-1α+ Prox1+ cells were widely distributed within the glioma specimens. The present immunohistochemical analysis revealed upregulation of Prox1 and HIF-1α in some glioma tissues as well as the differentiation of nestin+ tumor stem cells into LYVE-1+ lymphatic vessels.

Andrographolide impairs alpha-naphthylisothiocyanate-induced cholestatic liver injury in vivo.

To investigate if andrographolide impairs cholestatic liver injury. All rats were randomly divided into six groups-(1) control (n = 6), (2) control + 200 mg/kg andrographolide (n = 6), (3) alpha-naphthylisothiocyanate (ANIT)-control (n = 6), (4) ANIT + 50 mg/kg andrographolide (n = 6), (5) ANIT + 100 mg/kg andrographolide (n = 6), and (6) ANIT + 200 mg/kg andrographolide (n = 6). We gavaged 50 mg/kg ANIT to mimic cholestatic liver injury in rats. Seven days after treatment, all the rats were killed. Serum biochemistry and hepatic histopathological assays were performed to evaluate liver injury. We observed that 200 mg/kg andrographolide significantly decreased the level of alanine transaminase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyltranspeptidase, total bilirubin, and total bile acid in the blood. It also markedly decreased hepatic interleukin-6 and tumor necrosis factor α. Furthermore, 200 mg/kg andrographolide significantly decreased malondialdehyde but increased superoxide dismutase, glutathione, and erythrocyte glutathione peroxidase. Moreover, 200 mg/kg andrographolide effectively increased the accumulation of sirtuin 1 and nuclear erythroid 2-related factor-2. It also attenuated the level of nuclear factor kappa-light-chain-enhancer of activated B and cyclooxygenase-2. These data suggest that andrographolide may impair cholestatic liver injury via anti-inflammatory and anti-oxidative stress.

In situ quantitative bioanalysis of monomethyl auristatin E-conjugated antibody-drug conjugates by flow cytometry.

Antibody-drug conjugates (ADCs) consist of cytotoxic agents covalently conjugated to monoclonal antibodies that substantially improve antitumour activity and reduce systemic toxicity. With the growing number of ADCs in clinical applications, more accurate bioanalysis data are urgently needed to facilitate the development and rational use of ADCs. Herein, we used antigen-positive cells as antigen carriers and ofatumumab (OFA-HL) and ofatumumab-based ADC (OFA-HL-MMAE) as examples to establish a new ligand-binding assay (LBA) method based on flow cytometry. We proved that the new method met the required analytical performance criteria and the lower limit of quantitation (LOQ) was 0.2 µg/mL. In addition, the LOQ of the quantitative OFA-HL flow cytometry method was reduced to 0.025 µg/mL by choosing an optimized fluorescent antibody, which indicated that the LOQ of the new method can be improved. What's more, the new method showed good stability and specificity when we used it to determine the concentrations of OFA-HL and OFA-HL-MMAE in mouse serum. During the bioanalysis of ADCs, various factors should be considered. Therefore, choosing optimal methods for ADC bioanalysis is necessary. This new method using in situ antigens not only extends the scope of application of the conventional LBA methods by avoiding the need for soluble antigens, but also improves the authenticity of ADC bioanalysis as a supplementary approach, which is valuable for developing accurate ADC assays.

CD63 inhibits the cell migration and invasion ability of tongue squamous cell carcinoma.

The present study evaluated the expression and potential role of CD63 in the migration and invasion of tongue squamous cell carcinoma (TSCC) cells. Immunohistochemistry (IHC) was used to investigate the association between the expression level of CD63 protein and the histological differentiation of samples from 40 patients with TSCC and four normal tongue tissue specimens. RNA interference (RNAi) and gene transfection technology were used to alter the expression of CD63 in TCA8113 cells. The stable silencing and overexpression of CD63 in the TCA8113 cell line was used to assess the impact of the CD63 expression level on the migratory and invasive abilities of TCA8113 cells in a wound healing assay and a Transwell invasion assay. The effect of CD63 on the expression of matrix metalloproteinase (MMP)-2 and -9 were evaluated by western blot analysis. The results of IHC revealed a positive association between the CD63 expression level and the histopathological differentiation of TSCC and a negative association between the CD63 expression level and lymph node metastasis in TSCC. Western blotting revealed that the expressions of MMP-2 and MMP-9 were clearly upregulated in CD63-silenced TCA8113 cells but reduced in CD63-overexpressing TCA8113 cells, compared with the control. The wound-healing speed and the number of cells invading Matrigel-coated filters were negatively associated with the CD63 expression level. In summary, the results of the present study revealed that CD63 may be an inhibitor of TSCC malignancy and lymph node metastasis and may have applications in the prediction of prognosis and gene therapy for patients of TSCC.

A mouse model for evaluation of efficacy and concomitant toxicity of anti-human CXCR4 therapeutics.

The development of therapeutic monoclonal antibodies through mouse immunization often originates drug candidates that are not cross-reactive to the mouse ortholog. In such cases, and particularly in oncology, drug efficacy studies are performed on human tumor xenografts or with "surrogate" anti-mouse ortholog antibodies if targeting tumor host cells. Safety assessment of drug candidate(s) is performed at a later development stage in healthy non-human primates. While the latter remains necessary before a drug advances into human subjects, it precludes evaluation of safety in disease conditions and drug de-risking during early development. Therefore, mouse models that allow concomitant evaluation of drug efficacy and safety are highly desirable. The C-X-C motif chemokine receptor 4 (CXCR4) is an attractive target for tumor-targeted and immuno-oncology therapeutics, with multiple mouse immunization-derived antibodies undergoing clinical trials. Given the pleiotropic role of CXCR4 in cancer biology, we anticipate continuous interest in this target, particularly in the testing of therapeutic combinations for immuno-oncology. Here, we describe the generation and validation of the first mouse knock-in of the whole coding region of human CXCR4. Homozygous human CXCR4 knock-in (hereafter designated as HuCXCR4KI) mice were viable and outwardly healthy, reproduced normally and nursed their young. The expression pattern of human CXCR4 in this model was similar to that of CXCR4 expression in normal human tissues. The human CXCR4 knock-in gene was expressed as a biologically active protein, thereby allowing normal animal development and adequate"homing" of leukocytes to the bone marrow. To further validate our model, we used an in vivo functional assay of leukocyte mobilization from bone marrow to peripheral blood by blocking CXCR4 signaling. Both an anti-human CXCR4 -specific blocking antibody and the small molecule CXCR4 inhibitor AMD3100 induced increased leukocyte counts in peripheral blood, whereas an anti-mouse CXCR4 -specific blocking antibody had no effect. This new mouse model is useful to evaluate efficacy and safety of anti-human CXCR4 -specific drugs as single agents or in combination therapies, particularly in the oncology, immuno-oncology, wound healing and chronic inflammation therapeutic areas.