Peptide drug development has made great progress in the last decade thanks to new production, modification, and analytic technologies. Peptides have been produced and modified using both chemical and biological methods, together with novel design and delivery strategies, which have helped to overcome the inherent drawbacks of peptides and have allowed the continued advancement of this field. A wide variety of natural and modified peptides have been obtained and studied, covering multiple therapeutic areas. This review summarizes the efforts and achievements in peptide drug discovery, production, and modification, and their current applications. We also discuss the value and challenges associated with future developments in therapeutic peptides.

MCL-1 is an essential BCL-2 family member that promotes the survival of multiple cellular lineages, but its role in cardiac muscle has remained unclear. Here, we report that cardiac-specific ablation of Mcl-1 results in a rapidly fatal, dilated cardiomyopathy manifested by a loss of cardiac contractility, abnormal mitochondria ultrastructure, and defective mitochondrial respiration. Strikingly, genetic ablation of both proapoptotic effectors (Bax and Bak) could largely rescue the lethality and impaired cardiac function induced by Mcl-1 deletion. However, while the overt consequences of Mcl-1 loss were obviated by combining with the loss of Bax and Bak, mitochondria from the Mcl-1-, Bax-, and Bak-deficient hearts still revealed mitochondrial ultrastructural abnormalities and displayed deficient mitochondrial respiration. Together, these data indicate that merely blocking cell death is insufficient to completely overcome the need for MCL-1 function in cardiomyocytes and suggest that in cardiac muscle, MCL-1 also facilitates normal mitochondrial function. These findings are important, as specific MCL-1-inhibiting therapeutics are being proposed to treat cancer cells and may result in unexpected cardiac toxicity.

BackgroundTo explore the retinal vascular density changes in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) patients using optical coherence tomography angiography (OCTA).MethodsWe recruit 62 AD patients, 47 MCI patients, and 49 cognitively healthy controls (HC) in this study. All participants in the study received a comprehensive ophthalmological and neurological evaluation, including global cognitive screening, as well as the Mini-Mental State Examination (MMSE), and completed the following eye examinations: visual acuity (VA), intraocular pressure (IOP), examination with slit-lamp, fundus photography (Version 1.5.0.0, NIDEK CO, LTD) and Optical coherence tomography imaging (software ReVue version 2017.1.0.155, Optovue Inc., Fremont, CA, United States). The visual rating scales for atrophy and white matter lesion in MRI was evaluated for all the patients with AD and MCI.ResultsIn the AD patient group, the superficial vascular density in the superior, inferior and whole retina was 44.64 ± 3.34, 44.65 ± 3.55, and 44.66 ± 3.36, respectively. These values were 44.24 ± 3.15, 43.72 ± 3.16, and 44 ± 3.07, respectively, in the MCI patient group. After multivariate analysis of the generalized linear model, adjustments for the confounding factors of sex, age, hypertension, diabetes and the quality index of OCTA image, the superficial vascular density in the AD and MCI patient groups was significantly lower than that in the HC group (P < 0.05): 46.94 ± 2.04, 46.67 ± 2.26, and 46.82 ± 2.08, respectively. No difference in the area of the FAZ among the three groups was observed (AD group: 0.34 ± 0.11 mm2; MCI group: 0.36 ± 0.12 mm2; control group: 0.33 ± 0.12 mm2, p > 0.05). The ganglion cell complex (GCC) thickness, inner parafovea thickness, and peripapillary retinal nerve fiber layer (p-RNFL) thickness were associated with the superficial vascular density. We found no significant correlation between the global cognition (MMSE scores) or between the Fazekas score and retinal OCT angiogram flow density.ConclusionThe superficial vascular density in the AD and MCI patient groups was significantly lower than that in the HC group. Our findings suggest the retinal microvascular dysfunction occurred in MCI and AD.

The humanized bone marrow-liver-thymus (BLT) mouse model harbors a nearly complete human immune system, therefore providing a powerful tool to study human immunology and immunotherapy. However, its application is greatly limited by the restricted supply of human CD34+ hematopoietic stem cells and fetal thymus tissues that are needed to generate these mice. The restriction is especially significant for the study of human immune systems with special genetic traits, such as certain human leukocyte antigen (HLA) haplotypes or monogene deficiencies. To circumvent this critical limitation, we have developed a method to quickly propagate established BLT mice. Through secondary transfer of bone marrow cells and human thymus implants from BLT mice into NSG (NOD/SCID/IL-2Rg -/-) recipient mice, we were able to expand one primary BLT mouse into a colony of 4-5 proBLT (propagated BLT) mice in 6-8 weeks. These proBLT mice reconstituted human immune cells, including T cells, at levels comparable to those of their primary BLT donor mouse. They also faithfully inherited the human immune cell genetic traits from their donor BLT mouse, such as the HLA-A2 haplotype that is of special interest for studying HLA-A2-restricted human T cell immunotherapies. Moreover, an EGFP reporter gene engineered into the human immune system was stably passed from BLT to proBLT mice, making proBLT mice suitable for studying human immune cell gene therapy. This method provides an opportunity to overcome a critical hurdle to utilizing the BLT humanized mouse model and enables its more widespread use as a valuable preclinical research tool.

Severe combined immunodeficiency (SCID), a rare type of genetic associated immune disorder, is poorly characterized in mainland China. We retrospectively reviewed 44 patients with SCID who received treatment from 2004 to 2011 in Shanghai, China, and herein summarize their clinical manifestations and immunological and preliminary genetic features. The male-to-female ratio was 10:1. Twenty five patients presented with X-SCID symptoms. Only one patient was diagnosed before the onset of symptoms due to positive family history. The mean time of delay in the diagnosis of X-SCID was 2.69 months (range, 0.5-8.67). Thirty-seven of the 44 patients died by the end of 2011 with the mean age of death being 7.87 months (range, 1.33-31). Six patients received hematopoietic stem cell transplantation (HSCT); only one of them survived, who was transplanted twice. The time between onset and death was shorter in the HSCT-treated group compared with the untreated group (2.87 ± 1.28 and 3.34 ± 0.59 months, respectively), probably due to active infections during transplantation. Bacillus Calmette-Guérin (BCG) complications occurred in 14 of the 34 patients who received BCG vaccination. Transfusion-induced graft-versus-host disease occurred in 5 patients. Total 20 mutations in interleukin-2 receptor subunit gamma (IL2RG) were identified in 22 patients, including 11 novel mutations. Most patients were misdiagnosed before referred to our SCID Center. Therefore, establishing more diagnostic centers dedicated to the care of PID and accessible by primary immunodeficiency patients will facilitate early, correct diagnosis and better care of SCID in China.

Recent developments in stereotactic technique and deep brain stimulation (DBS) may make stereotactic neurosurgery a viable and reversible treatment for drug addiction.

ObjectivesTo describe the prevalence of modifiable risk factors for upper digestive tract cancer (UDTC) and its coprevalence, and investigate relevant influencing factors of modifiable UDTC risk factors coprevalence among residents aged 40–69 years in Yangzhong city, China.DesignCross-sectional study.ParticipantsA total of 21 175 participants aged 40–69 years were enrolled in the study. 1962 subjects were excluded due to missing age, marital status or some other selected information. Eventually, 19 213 participants were available for the present analysis.Main outcomes measuresPrevalence and coprevalence of eight modifiable UDTC risk factors (overweight or obesity, current smoking, excessive alcohol consumption, insufficient vegetables intake, insufficient fruit intake and the consumption of pickled, fried and hot food) were analysed.ResultsThe prevalence of overweight/obesity, current smoking, excessive alcohol consumption, insufficient vegetables intake, insufficient fruit intake and the consumption of pickled, fried and hot food in this study was 45.3%, 24.1%, 16.2%, 66.1%, 94.5%, 68.1%, 36.0% and 88.4%, respectively. Nearly all (99.9%) participants showed one or more UDTC risk factors, 98.6% of the participants showed at least two risk factors, 92.2% of the participants had at least three risk factors and 69.7% of the participants had four or more risk factors. Multivariate logistic regression analysis revealed that men, younger age, single, higher education, higher annual family income and smaller household size were more likely to present modifiable UDTC risk factors coprevalence.ConclusionsThe prevalence and coprevalence of modifiable UDTC risk factors are high among participants in Yangzhong city. Extra attention must be paid to these groups who are susceptible to risk factors coprevalence during screening progress. Relative departments also need to make significant public health programmes that aim to decrease modifiable UDTC risk factors coprevalence among residents aged 40–69 years from high-risk areas of UDTC.

Introduction: A challenge in Electronic Nicotine Delivery System (ENDS) research is how to refer to these devices in ways that are meaningful to current or potential users. The objectives of this study were to: (1) describe the frequency of ENDS terms in a web-based smoking cessation intervention; and (2) determine whether terms vary by US geographic region and date. Methods: Data were drawn from public posts between 2008-2015 on http://BecomeAnEX.org and limited to US users. We conducted "exact" and "fuzzy" searches to find posts containing ENDS keywords using custom Python scripts, and extracted geocoding data and date for each post. We examined counts and frequencies of ENDS terms by unique user, by unique user and region, and by unique user and date. Results: We identified 1023 unique US website users who had written a post containing one or more ENDS keywords. Posters were majority female (79%), educated (78% attended at least some college), and had a median age of 47 years. Overall, 92% of ENDS posters employed the term "e-cigarette" or a derivation. Derivations of "vape" became increasingly popular in 2013, whereas "NJoy" and "blu" were employed by fewer than 2% of posters. We found no variation in frequency of ENDS terms by US region. Conclusions: Researchers may have confidence that "e-cigarette" and "vape" are recognizable terms among US treatment-seeking smokers. Conversely, terms such as "ENDS, " commonly employed by researchers and public health advocates, are not used by smokers and may be an impediment to tobacco control research. Implications: Researchers may have confidence that "e-cigarette, " and, to a lesser extent, "vape" are recognizable terms among US adult smokers referring to ENDS (including accessories, brand names, and actions). Conversely, terms such as "electronic nicotine delivery systems, " commonly employed by researchers and public health advocates, are not used by US smokers and may be an impediment to tobacco control research and practice.