Vaccine-induced protective T cell immunity is necessary for HIV-1 functional cure. We previously reported that rhesus PD1-Gag-based DNA vaccination sustained simian-human immunodeficiency virus ...(SHIV) suppression by inducing effector-memory CD8
T cells. Here, we investigated a human PD1-Gag-based DNA vaccine, namely, ICVAX, for clinical translation. PD1-based dendritic cell targeting and mosaic antigenic designs were combined to generate the ICVAX by fusing the human soluble PD1 domain with a bivalent HIV-1 Gag-p41 mosaic antigen. The mosaic antigen was cross-reactive with patients infected with B, CRF07/08_BC, and CRF01_AE variants. In mice, ICVAX elicited stronger, broader, and more polyfunctional T cell responses than mosaic Gag-p41 alone, and suppressed EcoHIV infection more efficiently. In macaques, ICVAX elicited polyfunctional effector-memory T cell responses that targeted multiple nonoverlapping epitopes of the Gag-p41 antigen. Furthermore, ICVAX manufactured following good manufacturing practices proved potent immunogenicity in macaques after biannual homologous vaccination, warranting clinical evaluation of ICVAX as an immunotherapy against HIV-1.
This study presents that ICVAX, a PD1-based DNA vaccine against HIV-1, could induce broad and polyfunctional T cell responses against different HIV-1 subtypes. ICVAX encodes a recombinant antigen consisting of the human soluble PD1 domain fused with two mosaic Gag-p41 antigens. The mosaic antigens cover more than 500 HIV-1 strains circulating in China including the subtypes B/B', CRF01_AE, and CRF07/08_BC. In mice, ICVAX elicited stronger, broader, and more polyfunctional T cell responses, with better EcoHIV suppression than the nontargeting mosaic Gag-p41 DNA vaccine. Moreover, both lab-generated and GMP-grade ICVAX also elicited strong polyfunctional effector-memory T cell responses in rhesus macaques with good immunogenicity against multiple nonoverlapping epitopes of the Gag-p41 antigen. This study therefore highlights the great potential to translate the PD1-based DNA vaccine approach into clinical use, and opens up new avenues for alternative HIV-1 vaccine design for HIV-1 preventive and functional cure.
Oxidative phosphorylation is an indispensable resource of ATP in tissues with high requirement of energy. If the ATP demand is not met, studies suggest that this will lead to senescence and cell ...death in the affected tissue. The term reserve respiratory capacity or spare respiratory capacity is used to describe the amount of extra ATP that can be produced by oxidative phosphorylation in case of a sudden increase in energy demand. Depletion of the reserve respiratory capacity has been related to a range of pathologies affecting high energy requiring tissues. During aging of an organism, and as a result of mitochondrial dysfunctions, the efficiency of oxidative phosphorylation declines. Based on examples from the energy requiring tissues such as brain, heart, and skeletal muscle, we propose that the age-related decline of oxidative phosphorylation decreases the reserve respiratory capacity of the affected tissue, sensitizes the cells to surges in ATP demand, and increases the risk of resulting pathologies.
For patients with a past medical history of diabetes, acute coronary syndrome, chronic kidney disease, 10-year atherosclerotic cardiovascular disease risk higher than 10% and the elderly people, ...pharmacotherapy is recommended for patients with systolic blood pressure (SBP) greater than or equal to130 mm Hg; lifestyle modification is recommended for patients in this group with SBP greater than or equal to120 mm Hg or for secondary stroke prevention.3 This lower threshold for the definition of hypertension allows early identification of at-risk individuals and thus earlier intervention before hypertension becomes irreversible or results in further complications.4 The application of the 2017 ACC/AHA guideline is controversial in Hong Kong, because of the increased burden on the healthcare system. Implications for local clinical practice and research The prevalence of hypertension is likely to increase in Hong Kong, owing to the ageing population. ...a more forward-looking approach to the management of hypertension should be adopted in Hong Kong, with more focus on epidemiological issues. The characteristics of patients labelled “stage 1 hypertension” are mostly younger, male, and obese.12 At the early stage, hypertension is easily manageable via lifestyle modifications, particularly in younger patients. ...blood pressure control rates are generally better in younger patients and do not require pharmacological treatment.13 This reduces the risk of serious adverse events such as hypotension or electrolyte disturbances. Considering these factors, further studies are needed to ascertain the appropriate hypertension threshold that is applicable for Hong Kong population. ...the hypertension guideline should be constantly reviewed in the future according to advancements in research findings.
This post-hoc analysis retrospectively assessed data from two recent studies of antiemetic regimens for chemotherapy-induced nausea and vomiting (CINV). The primary objective was to compare ...olanzapine-based versus netupitant/palonosetron (NEPA)-based regimens in terms of controlling CINV during cycle 1 of doxorubicin/cyclophosphamide (AC) chemotherapy; secondary objectives were to assess quality of life (QOL) and emesis outcomes over four cycles of AC.
This study included 120 Chinese patients with early-stage breast cancer who were receiving AC; 60 patients received the olanzapine-based antiemetic regimen, whereas 60 patients received the NEPA-based antiemetic regimen. The olanzapine-based regimen comprised aprepitant, ondansetron, dexamethasone, and olanzapine; the NEPA-based regimen comprised NEPA and dexamethasone. Patient outcomes were compared in terms of emesis control and QOL.
During cycle 1 of AC, the olanzapine group exhibited a higher rate of 'no use of rescue therapy' in the acute phase (olanzapine vs NEPA: 96.7% vs 85.0%, P=0.0225). No parameters differed between groups in the delayed phase. The olanzapine group had significantly higher rates of 'no use of rescue therapy' (91.7% vs 76.7%, P=0.0244) and 'no significant nausea' (91.7% vs 78.3%, P=0.0408) in the overall phase. There were no differences in QOL between groups. Multiple cycle assessment revealed that the NEPA group had higher rates of total control in the acute phase (cycles 2 and 4) and the overall phase (cycles 3 and 4).
These results do not conclusively support the superiority of either regimen for patients with breast cancer who are receiving AC.
Nausea and vomiting are common in cancer patients. The most common cause of nausea and vomiting is the administration of cytotoxic chemotherapy. Apart from chemotherapy-induced nausea and vomiting ...(CINV), biological agents may also cause these symptoms. In this review, discussion will be focused on management of nausea and vomiting due to antineoplastic therapies. The cornerstone of effective management of nausea and vomiting secondary to these antineoplastic drugs is the prevention with the use of appropriate guideline-directed combination antiemetic regimen. Type 3 serotonin receptor antagonists (5HT3RAs), neurokinin-1 receptor antagonists (NK1RAs), and dexamethasone are the backbone antiemetic drugs. In recent years, newer drugs and preparations have been introduced for clinical use and include second-generation 5HT3RA, palonosetron; granisetron transdermal patch; the recently introduced NK1RA rolapitant; and the novel oral combined drug NEPA (netupitant plus palonosetron); and last but not least, the atypical antipsychotic olanzapine.
Paraneoplastic neurological syndromes are independent of metastasis, direct tumour infiltration, or known indirect mechanisms such as toxicity, ectopic hormone secretion, or induced coagulopathies.1 ...Paraneoplastic neurological syndromes may affect any part of the nervous system, and are believed to result when an immunologic response is directed against shared antigens that are ectopically expressed by the tumour, but otherwise predominantly expressed by the nervous system (onconeural antigens).1 Antibodies can be detected in the serum or cerebrospinal fluid of many, but not all, patients with PNS.2 Diagnosing PNS requires identification of the type of neurological syndrome based on neurological signs and symptoms, the detection of well-characterised onconeural antibodies, and the presence of a cancer.3 Paraneoplastic neurological syndromes are rare in patients with solid tumours, and probably even rarer among patients with lymphomas.4 The predominant types of PNS in lymphomas are paraneoplastic cerebellar degeneration in Hodgkin's lymphoma, and dermatomyositis/polymyositis in both Hodgkin's lymphoma and non-Hodgkin's lymphoma. Traditionally considered a variant of multiple sclerosis, presence of the disease-specific aquaporin-4 antibody, which plays a direct role in the pathogenesis of NMOSD, distinguishes the two entities.5 Recently, NMOSD is increasingly recognised as a paraneoplastic disorder especially in men or in patients who present in older age.6 Paraneoplastic NMOSD has been reported in a wide variety of tumour histological types but mostly in solid tumours.6 We recently encountered a definite case of PNS in a patient who was diagnosed with mantle cell lymphoma (MCL) and shortly afterwards developed neurological symptoms due to NMOSD. Early recognition of a neurological syndrome as paraneoplastic often leads to the discovery and treatment of the underlying tumour, which is a crucial step in the management of the PNS.1 2 Author contributions All authors have made substantial contributions to the concept or design; acquisition of data; analysis or interpretation of data; drafting of the article; and critical revision for important intellectual content.
There has been a substantial research effort worldwide to develop non-noble metal catalysts in electrolyzers for H2 production from renewable energy sources. Pt catalysts are found to display the ...highest hydrogen evolution reaction (HER) activity under typical experimental conditions with relatively low acidity and overpotentials. However, it is noted that catalytic activity is highly dependent on acidity and applied potential used. In real practice of a high workload electrolyzer, high acidity and large negative potentials are required to optimize the HER activity. We hereby report that inexpensive silver catalysts, particularly the cubic form of silver nanoparticles, can clearly exhibit superior HER activity over Pt with a different rate-determining step in an electrolyzer when such conditions are reached. This is attributed to the weaker Ag–H bond at the surface than Pt–H which is more favorable for H recombination to form H2. It is thus believed that this study provides new insights into designing economical and highly efficient catalysts that can replace the expensive noble metal analogues in a working electrolyzer.
Chemotherapy-induced nausea and vomiting (CINV) are highly distressing symptoms for cancer patients undergoing cytotoxic chemotherapy. This dataset was obtained from a homogenous group of Chinese ...breast cancer patients who were uniformly planned to receive a highly emetogenic (neo)adjuvant chemotherapy regimen, consisting of doxorubicin and cyclophosphamide (commonly known as AC). Patients were being randomized to one of the two antiemetic regimens: aprepitant, ondansetron and dexamethasone with (the Olanzapine arm) or without olanzapine (the Standard arm). Patients underwent self-reported diaries and questionnaires to record their nausea and vomiting symptoms, use of rescue medication as well as their quality of life (QOL). The primary and secondary endpoints have focused on efficacy analysis during the first cycle of AC chemotherapy; the results have been reported in The Breast 1. In this Data in Brief article, we provide outcome of the analysis of data collected during multiple cycles of chemotherapy. The data reported here include the proportion of patients with “Complete Response”, “Complete Protection” and “Total Control” of emesis in the acute (0–24 h), delayed (24–120 h) and overall periods (0–120 h), as well as QOL data during all the 4 cycles of AC.
Chemotherapy-induced nausea and vomiting (CINV) are distressing symptoms. This randomized study evaluated the antiemetic efficacies of standard antiemetic regimen with/without olanzapine.
Eligible ...patients were chemotherapy-naive Chinese breast cancer patients who were planned for (neo)adjuvant doxorubicin/cyclophosphamide. Antiemetic regimen for all studied population included aprepitant, ondansetron and dexamethasone; patients were randomized to Olanzapine (with olanzapine) or Standard arms (without olanzapine). Patients filled in self-reported diaries and completed visual analogue scales for nausea, as well as Functional Living Index-Emesis questionnaires. Blood profiles including fasting glucose and lipids were monitored.
120 patients were randomized. In Cycle 1 doxorubicin/cyclophosphamide, the Olanzapine arm had significantly higher rates of “Complete Response” than the Standard arm: 65.0% vs 38.3% in the overall period (p = 0.0035), 70.0% vs 51.7% in the acute period (p = 0.0397) and 92.9% vs 74.2% in the delayed period (p = 0.0254). Olanzapine arm also had significantly higher rates of “No significant nausea” and “No nausea” during all 3 time-frames and better QOL. Similar findings were also revealed throughout multiple cycles. Pre-study abnormalities in glucose and lipids occurred in 39.7% and 34.2% of the studied population respectively; there were no differences in these parameters between the two arms at end-of-study assessment.
The addition of olanzapine to standard aprepitant-based antiemetic regimen provides clinically meaningful improvement in controlling CINV. This was associated with a positive impact on QOL and tolerable toxicity profiles among Chinese breast cancer patients receiving doxorubicin/cyclophosphamide chemotherapy. Further studies on metabolic profiles of breast cancer patients are warranted.
•Olanzapine is reported to reduce nausea and vomiting after highly emetogenic chemotherapy.•Reported studies are limited by heterogeneous populations receiving diverse cytotoxic regimes.•This study enrolled Chinese breast cancer patients undergoing doxorubicin/cyclophosphamide.•Adding olanzapine to aprepitant/ondansetron/dexamethasone is superior in controlling nausea and vomiting.•Baseline investigations shows a surprisingly high rate of glucose and lipids abnormalities.
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