A systematic review of exercise studies for individuals hospitalized with an acute exacerbation of chronic obstructive pulmonary disease: Focus on the principles of exercise training.

BACKGROUND: For exercise interventions to be effectively reproduced or applied in a "real world" clinical setting, clinical trials must thoroughly document all components of the exercise prescription and ensure that participants adhere to each component. However, previous reviews have not critically examined the quality of exercise prescription of inpatient Pulmonary Rehabilitation (PR) programs. OBJECTIVE: The objectives of this review were to evaluate the (a) application of the principles of exercise training, (b) reporting of the frequency, intensity, time and type (FITT) components of exercise prescription, and (c) reporting of patient's adherence to the FITT components in intervention studies for patients admitted to hospital for an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: Relevant scientific databases were searched for randomized controlled trials (RCTs) that compared in-hospital PR with usual care for people hospitalized with AECOPD. Title and abstract followed by full-text screening were conducted independently by two reviewers. Data were extracted and synthesized to evaluate the application of the principles of exercise training and the reporting/adherence of the FITT components. RESULTS: Twenty-seven RCTs were included. Only two applied all principles of exercise training. Specificity was applied by 70%, progression by 48%, overload by 37%, initial values by 89% and diminishing returns and reversibility by 37% of trials. Ten trials adequately reported all FITT components. Frequency and type were the components most reported (85% and 81%, respectively), while intensity was less frequently reported (52%). Only three trials reported on the patient's adherence to all four components. CONCLUSIONS: Studies have not adequately reported the exercise prescription in accordance with the principles of exercise training nor reported all the FITT components of the exercise prescription and patient's adherence to them. Therefore, interpretation of the current literature is limited and information for developing exercise prescriptions to individuals hospitalized with an AECOPD is lacking.

CD6-targeted antibody-drug conjugate as a new therapeutic agent for T cell lymphoma.

T cell lymphomas (TCL) are heterogeneous, aggressive, and have few available targeted therapeutics. In this study, we determined that CD6, an established T cell marker, was expressed at high levels on almost all examined TCL patient specimens, suggesting that CD6 could be a new therapeutic target for this life-threatening blood cancer. We prepared a CD6-targeted antibody-drug conjugate (CD6-ADC) by conjugating monomethyl auristatin E (MMAE), an FDA-approved mitotic toxin, to a high-affinity anti-human CD6 monoclonal antibody (mAb). In contrast to both the unconjugated anti-CD6 mAb, and the non-binding control ADC, CD6-ADC potently and selectively killed TCL cells in vitro in both time- and concentration-dependent manners. It also prevented the development of tumors in vivo in a preclinical model of TCL. More importantly, systemic or local administration of the CD6-ADC or its humanized version, but not the controls, significantly shrank established tumors in the preclinical mouse model of TCL. These results suggest that CD6 is a novel therapeutic target in TCLs and provide a strong rationale for the further development of CD6-ADC as a promising therapy for patients with these potentially fatal lymphoid neoplasms.

Safety and Efficacy of Inpatient Pulmonary Rehabilitation for Patients Hospitalized with an Acute Exacerbation of Chronic Obstructive Pulmonary Disease: Systematic Review and Meta-analyses.

Rationale: Pulmonary rehabilitation (PR) during hospitalization for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) occurs during a period of disease instability for the patient, and the safety and efficacy of PR, specifically during the hospitalization period, have not been established. Objective: The purpose of this review is to determine the safety and efficacy of PR during the hospitalization phase for individuals with AECOPD. Methods: Scientific databases were searched up to August 2022 for randomized controlled trials that compared in-hospital PR with usual care. PR programs commenced during the hospitalization and included a minimum of two sessions. Titles and abstracts followed by full-text screening and data extraction were conducted independently by two reviewers. The intervention effect estimates were calculated through meta-analysis using a random-effect model. Results: A total of 27 studies were included (n = 1,317). The meta-analysis showed that inpatient PR improved the 6-minute-walk distance by 105 m (P < 0.001). Inpatient PR improved the performance on the five-repetition sit-to-stand test by -7.02 seconds (P = 0.03). Quality of life (QOL), as measured by the 5-level EuroQoL Group-5 dimension version (EQ-ED-5L) and the St. George's Respiratory Questionnaire, was significantly improved by the intervention. Inpatient PR increased lower limb muscle strength by 33.35 N (P < 0.001). There was no change in the length of stay. Only one serious adverse event related to the intervention was reported. Conclusions: This review suggests that it is safe and effective to provide PR during hospitalization for individuals with AECOPD. In-hospital PR improves functional exercise capacity, QOL, and lower limb strength without prolonging the hospital length of stay.

Lessons on Drug Development: A Literature Review of Challenges Faced in Nonalcoholic Fatty Liver Disease (NAFLD) Clinical Trials.

NAFLD is the most common chronic liver disease worldwide, occurring in both obese and lean patients. It can lead to life-threatening liver diseases and nonhepatic complications, such as cirrhosis and cardiovascular diseases, that burden public health and the health care system. Current care is weight loss through diet and exercise, which is a challenging goal to achieve. However, there are no FDA-approved pharmacotherapies for NAFLD. This review thoroughly examines the clinical trial findings from 22 drugs (Phase 2 and above) and evaluates the future direction that trials should take for further drug development. These trialed drugs can broadly be categorized into five groups-hypoglycemic, lipid-lowering, bile-pathway, anti-inflammatory, and others, which include nutraceuticals. The multitude of challenges faced in these yet-to-be-approved NAFLD drug trials provided insight into a few areas of improvement worth considering. These include drug repurposing, combinations, noninvasive outcomes, standardization, adverse event alleviation, and the need for precision medicine with more extensive consideration of NAFLD heterogenicity in drug trials. Understandably, every evolution of the drug development landscape lies with its own set of challenges. However, this paper believes in the importance of always learning from lessons of the past, with each potential improvement pushing clinical trials an additional step forward toward discovering appropriate drugs for effective NAFLD management.

Safety and efficacy of inpatient pulmonary rehabilitation for patients hospitalised with an acute exacerbation of chronic obstructive pulmonary disease: a systematic review protocol.

INTRODUCTION: Pulmonary rehabilitation (PR) following an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) reduces the risk of hospital admissions, and improves physical function and health-related quality of life. However, the safety and efficacy of in-hospital PR during the most acute phase of an AECOPD is not well established. This paper describes the protocol for a systematic review with meta-analysis to determine the safety and efficacy of inpatient acute care PR during the hospitalisation phase. METHODS AND ANALYSIS: Medical literature databases and registries MEDLINE, EMBASE, Physiotherapy Evidence Database, Cumulative Index to Nursing and Allied Health Literature, Canadian Agency for Drugs and Technologies in Health, CENTRAL, Allied and Complementary Medicine Database, WHO trials portal and ClinicalTrials.gov will be searched for articles from inception to June 2021 using a prespecified search strategy. We will identify randomised controlled trials that have a comparison of in-hospital PR with usual care. PR programmes had to commence during the hospitalisation and include a minimum of two sessions. Title and abstract followed by full-text screening will be conducted independently by two reviewers. A meta-analysis will be performed if there is sufficient homogeneity across selected studies or groups of studies. The Population, Intervention, Comparator, Outcomes and Study characteristics framework will be used to standardise the data collection process. The quality of the cumulative evidence will be assessed using the Grading of Recommendations, Assessment, Development and Evaluations framework. ETHICS AND DISSEMINATION: AECOPD results in physical limitations which are amenable to PR. This review will assess the safety and efficacy of in-hospital PR for AECOPD. The results will be presented in a peer-reviewed publication and at research conferences. Ethical review is not required for this study.

A pilot clinical trial of oral tetrahydrouridine/decitabine for noncytotoxic epigenetic therapy of chemoresistant lymphoid malignancies.

One mechanism by which lymphoid malignancies resist standard apoptosis-intending (cytotoxic) treatments is genetic attenuation of the p53/p16-CDKN2A apoptosis axis. Depletion of the epigenetic protein DNA methyltransferase 1 (DNMT1) using the deoxycytidine analog decitabine is a validated approach to cytoreduce malignancy independent of p53/p16. In vivo decitabine activity, however, is restricted by rapid catabolism by cytidine deaminase (CDA). We, therefore, combined decitabine with the CDA-inhibitor tetrahydrouridine and conducted a pilot clinical trial in patients with relapsed lymphoid malignancies: the doses of tetrahydrouridine/decitabine used (∼10/0.2 mg/kg orally (PO) 2×/week) were selected for the molecular pharmacodynamic objective of non-cytotoxic, S-phase dependent, DNMT1-depletion, guided by previous Phase 1 studies. Patients with relapsed/refractory B- or T-cell malignancies (n = 7) were treated for up to 18 weeks. Neutropenia without concurrent thrombocytopenia is an expected toxicity of DNMT1-depletion and occurred in all patients (Grade 3/4). Subjective and objective clinical improvements occurred in 4 of 7 patients, but these responses were lost upon treatment interruptions and reductions to manage neutropenia. We thus performed parallel experiments in a preclinical in vivo model of lymphoma to identify regimen refinements that might sustain DNMT1-targeting in malignant cells but limit neutropenia. We found that timed-alternation of decitabine with the related molecule 5-azacytidine, and combination with inhibitors of CDA and de novo pyrimidine synthesis could leverage feedback responses of pyrimidine metabolism to substantially increase lymphoma cytoreduction but with less neutropenia. In sum, regimen innovations beyond incorporation of a CDA-inhibitor are needed to sustain decitabine DNMT1-targeting and efficacy against chemo-resistant lymphoid malignancy. Such potential solutions were explored in preclinical in vivo studies.

2,3-Diaryl-3H-imidazo[4,5-b]pyridine derivatives as potential anticancer and anti-inflammatory agents.

In this study we examined the suitability of the 3H-imidazo[4,5-b]pyridine ring system in developing novel anticancer and anti-inflammatory agents incorporating a diaryl pharmacophore. Eight 2,3-diaryl-3H-imidazo[4,5-b]pyridine derivatives retrieved from our in-house database were evaluated for their cytotoxic activity against nine cancer cell lines. The results indicated that the compounds showed moderate cytotoxic activity against MCF-7, MDA-MB-468, K562 and SaOS2 cells, with K562 being the most sensitive among the four cancer cell lines. The eight 2,3-diaryl-3H-imidazo[4,5-b]pyridine derivatives were also evaluated for their COX-1 and COX-2 inhibitory activity in vitro. The results showed that compound 3f exhibited 2-fold selectivity with IC50 values of 9.2 and 21.8 µmol/L against COX-2 and COX-1, respectively. Molecular docking studies on the most active compound 3f revealed a binding mode similar to that of celecoxib in the active site of the COX-2 enzyme.

Pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinolines: Novel compounds that reverse ABCG2-mediated resistance in cancer cells.

Overexpression of ATP-binding cassette transporter (ABC) subfamily G2 in cancer cells is known to elicit a MDR phenotype, ultimately resulting in cancer chemotherapy failure. Here, we report, for the first time, the effect of eight novel pyrimido[1″,2″:1,5]pyrazolo[3,4-b]quinoline (IND) derivatives that inhibit ABCG2 transporter restoring cancer cell chemosensitivity. IND -4, -5, -6, -7, and -8, at 10 µM, and nilotinib at 5 µM, significantly potentiated (8-10 fold) the cytotoxicity of the ABCG2 substrates mitoxantrone (MX) and doxorubicin in HEK293 cells overexpressing ABCG2 transporter, MX (~14 fold) in MX-resistant NCI-H460/MX-20 small cell lung cancer, and of topotecan (~7 fold) in S1-M1-80 colon cancer cells which all stably expressing ABCG2. In contrast, cytotoxicity of cisplatin, which is not an ABCG2 substrate, was not altered. IND-5,-6,-7, and -8 significantly increased the accumulation of rhodamine-123 in multidrug resistant NCI-H460/MX-20 cells overexpressing ABCG2. Both IND-7 and -8, the most potent ABCG2 inhibitors, had the highest affinities for the binding sites of ABCG2 in modeling studies. In conclusion, the beneficial actions of new class of agents warrant further development as potential MDR reversal agents for clinical anticancer agents that suffer from ABCG2-mediated MDR insensitivity.