Traditional development of small protein scaffolds has relied on display technologies and mutation-based engineering, which limit sequence and functional diversity, thereby constraining their therapeutic and application potential. Protein design tools have significantly advanced the creation of novel protein sequences, structures, and functions. However, further improvements in design strategies are still needed to more efficiently optimize the functional performance of protein-based drugs and enhance their druggability. Here, we extended an evolution-based design protocol to create a novel minibinder, BindHer, against the human epidermal growth factor receptor 2 (HER2). It not only exhibits super stability and binding selectivity but also demonstrates remarkable properties in tissue specificity. Radiolabeling experiments with ^99mTc, ⁶⁸Ga, and ¹⁸F revealed that BindHer efficiently targets tumors in HER2-positive breast cancer mouse models, with minimal nonspecific liver absorption, outperforming scaffolds designed through traditional engineering. These findings highlight a new rational approach to automated protein design, offering significant potential for large-scale applications in therapeutic mini-protein development.

Objective:To analyze and compare the short-term efficacy and safety of sintilimab and tislelizumab in neoadjuvant therapy for advanced esophageal squamous cell carcinoma.Methods:The clinical data of 95 patients with esophageal squamous cell carcinoma who received neoadjuvant chemotherapy (paclitaxel + nedaplatin) combined with immunotherapy in the Department of Thoracic Surgery of the Affiliated Hospital of North Sichuan Medical College from January 2021 to October 2022 were collected. According to the different use of immune drugs, they were divided into the sintilimab group ( n=58) and the tislelizumab group ( n=37). The objective remission rate (ORR), adverse reactions, R0 resection rate, pathological complete response (pCR) rate, etc. were analyzed and compared between the two groups after neoadjuvant therapy. Results:After 2 cycles of neoadjuvant therapy, the sintilimab group and the tislelizumab group had a similar ORR [72.4% (42/58) vs. 56.8% (21/37), χ2=2.48, P=0.115]. The main adverse reactions of the two groups of patients included gastrointestinal reactions (nausea, vomiting, diarrhea), hematological toxicity, hypothyroidism, alopecia, liver and kidney dysfunction, pneumonia, etc. The incidence of grade 3 adverse reactions was less than 15%, with no grade 4 adverse reactions. The incidence of hypothyroidism in the sintilimab group was significantly higher than that in the tislelizumab group [56.9% (33/58) vs. 16.2% (6/37) ], with a statistically significant difference ( χ2=15.45, P<0.001) ; There was no statistically significant difference in surgical resection ( χ2=1.26, P=0.661) and pCR rate [31.0% (18/58) vs. 32.4% (12/37), χ2=0.02, P=0.886] between the two groups of patients. In terms of postoperative complications, both groups of patients experienced partial pulmonary infections and anastomotic fistulas, but the incidence was relatively low [19.0% (11/58) vs. 24.3% (9/37), 3.4% (2/58) vs. 2.7% (1/37) ], with no statistically significant difference ( χ2=0.39, P=0.532; χ2<0.01, P>0.999) . Conclusion:For preoperative neoadjuvant therapy of advanced esophageal squamous cell carcinoma, the use of either sintilimab or tislelizumab in addition to chemotherapy has good short-term efficacy and safety. Thyroid function should be monitored carefully when using sintilimab.

With the rapid development of social economy， the number of patients with nervous system diseases has increased， and the incidence of the population has a trend of younger， which has a serious impact on life health and social economy. Artemisinin is an active antimalarial component extracted and isolated from Artemisia annua， a Chinese medicinal material. Artemisinin and its derivatives， in addition to the antimalarial effect， also have anti-parasitic， anti-fungal， anti-viral， hypoglycemic， hypolipidemic， anti-tumor， and anti-inflammatory effects， showing a wide range of pharmacological activities. In the past five years， research on the new pharmacological effects of artemisinin and its derivatives has been deepening， and the efficacy of artemisinin and its derivatives in nervous system diseases has attracted much attention， including anti-neuroinflammation， anti-oxidative stress， maintaining the stability of the blood-brain barrier， regulating the release of neurotransmitters， repairing neuronal damage， and promoting neuronal regeneration. These pharmacological effects indicate that artemisinin and its derivatives are potentially capable of neuroprotection. By sorting out literature on the pharmacological activity of artemisinin and its derivatives in nervous system during 2019－2024， this paper systematically summarized the protective effects of artemisinin and its derivatives against nervous system diseases such as stroke， neurodegenerative diseases， neuroimmunological diseases， neuralgia， and nervous system tumors. This review is expected to provide clues and evidence for new indication expansion of artemisinin drugs， innovative drug development， and clinical treatment of nervous system diseases.

The impact of air pollution on human health has always been a research hotspot in the global health field. Outdoor air pollutants composed of multiple components can enter the human body through various pathways. Cardiovascular diseases are a group of diseases caused by outdoor air pollutants. Studies have shown that the incidence of cardiovascular diseases， including hypertension， arrhythmia， and heart failure， is significantly increased among people exposed to air pollution environments. Air pollutants such as fine particulate matter， nitrogen dioxide， ozone， carbon monoxide， and sulfur dioxide are closely related to the occurrence of cardiovascular diseases， and short-term and long-term exposure causes different cardiovascular risks. By reviewing the relevant research reports from 2019 to 2024， this article summarizes the epidemiological evidence of cardiovascular diseases caused by different air pollutants. It generalizes the pathways through which air pollutants accelerate the progression of cardiovascular diseases. These pathways include oxidative stress， inflammatory response， thrombosis， extracellular vesicle release， endoplasmic reticulum stress， apoptosis， endothelial dysfunction， autonomic nervous system imbalance， and their interactions. Based on the different mechanisms of air pollution on cardiovascular diseases， the article analyzes the main progress in drug intervention and summarizes the roles of various active ingredients and compound prescriptions of traditional Chinese medicine in treating air pollution-related cardiovascular diseases， providing reference for the research on the mechanisms and drug interventions of air pollution-related cardiovascular diseases.

The complex pathophysiological mechanisms between diabetes mellitus and cardiovascular diseases have not yet been fully elucidated， becoming one of the challenges in clinical care. Glucagon-like peptide-1 receptor agonist （GLP1-RA） and sodium glucose cotransporter-2 inhibitors （SGLT2） are clinically used to reduce the cardiovascular risk of patients with diabetes mellitus. Traditional Chinese medicine has diverse biological activities and unique advantages in the treatment of chronic complex diseases due to its multi-component and multi-target effects. Based on recent reports， this paper reviewed the common risk factors of diabetes mellitus and cardiovascular diseases （e.g.， hyperglycemia， insulin resistance， and inflammation）， related targets such as apolipoprotein C-Ⅲ （APOC3）， S100 calcium-binding protein A8/A9 （S100A8/A9）， growth/differentiation factor-15 （GDF-15）， and NACHT， LRR， and PYD domains-containing protein 3 （NLRP3）， advanced glycation end products， insulin resistance， endothelial dysfunction， endoplasmic reticulum stress， mitochondrial dysfunction， and intestinal flora disorder. In addition， this paper summarized the research progress in the treatment of cardiovascular diseases in diabetes mellitus with the active ingredients （e.g.， baicalein， puerarin， curcumin， notoginsenoside， and tanshinone Ⅱ_A）， single herbal medicines （e.g.， Astragali Radix， Ginseng Radix et Rhizoma， Sophorae Flavescentis Radix， Cinnamomi Cortex， and Corni Fructus）， and compound formulas （e.g.， Buzang Tongluo Fang， Yiqi Yangyin Huoxue Fang， Shenqi Fang， Huangqisan， Danggui Buxue Tang， and Liuwei Dihuang Wan） of traditional Chinese medicine. Traditional Chinese medicine mainly treats cardiovascular diseases in diabetes mellitus by reducing inflammation and oxidative stress， ameliorating dyslipidemia and insulin resistance， protecting islet β cell function， repairing endothelial damage， inhibiting smooth muscle cell proliferation， foam cell formation， macrophage polarization， and cardiac hypertrophy and fibrosis， and regulating intestinal flora disorder. These processes involve insulin receptor substrate/ phosphatidylinositol 3-kinase/protein kinase B （IRS/PI3K/Akt）， peroxisome proliferator-activated receptor α/γ （PPAR α/γ）， nuclear factor-kappa B （NF-κB）， adenosine 5′-monophosphate （AMP）-activated protein kinase （AMPK）， hypoxia-inducible factor-1-BCH domain-containing protein （HIF-1-BNIP）， vascular endothelial growth factor/hypoxia-inducible factor-1α （VEGF/HIF-1α） and other signaling pathways. This review is expected to provide a theoretical basis and reference for the treatment of cardiovascular diseases in diabetes mellitus with traditional Chinese medicine.

Oral submucous fibrosis (OSF) can cause various oral dysfunctions in patients and can turn into oral cancer. The causes and processes of OSF malignant transformation involve betel nut chewing, vascular atrophy, tissue hypoxia, cell cycle changes, aging, autophagy, and changes in cancer/cancer suppressor genes and microRNAs. It is of great significance to study the causes and process of OSF malignant transformation for the treatment and prevention of OSF malignant transformation.

Forkhead box protein O1 (FOXO1) has been extensively studied as a tumor suppressor. In oral squamous cell carcinoma, studies have demonstrated that FOXO1 can inhibit tumor cell oxidative stress, stemness and epithelial-mesenchymal transition, and promote tumor cell autophagy and apoptosis. FOXO1 may serve as a potential target for the treatment of oral squamous cell carcinoma.

Objective:To analyze the clinical characteristics and the risk factors for poor prognosis of patients with bloodstream infection (BSI) caused by carbapenem-resistant Klebsiella pneumoniae (CRKP), and to guide clinical treatment. Methods:The clinical characteristics, co-infection sites, comorbidities, laboratory tests, and antimicrobial drug exposure of adult patients with CRKP BSI admitted to The First Affiliated Hospital of Anhui Medical University from August 2015 to August 2020 were retrospectively analyzed. The patients were divided into good prognosis group and poor prognosis group. The clinical data of the two groups were compared. Statistical analysis was performed using Mann-Whitney U test and chi-square test. Binary logistic regression was used to analyze the risk factors for poor prognosis in patients with CRKP BSI. Results:Among the 106 CRKP BSI patients, 47 were in the good prognosis group and 59 were in the poor prognosis group. The length of hospital stay (39(22, 89) d vs 21(15, 38) d), the ratio of history of admission within 90 days (17.0%(8/47) vs 35.6%(21/59)), the ratio of history of carbapenems exposure (42.6%(20/47) vs 64.4%(38/59)), the ratio of complicated with lower respiratory tract infection (44.7%(21/47) vs 78.0%(46/59)), the ratio of admission to intensive care unit (34.0%(16/47) vs 81.4%(48/59)), the ratio of septic shock (19.1%(9/47) vs 69.5%(41/59)), the ratio of complicated with multiple organ dysfunction syndrome (MODS) (10.6%(5/47) vs 74.6%(44/59)), the ratio of solid organ transplantation status (40.4%(19/47) vs 18.6%(11/59)), the ratio of surgery (51.1%(24/47) vs 32.2%(19/59)), the ratio of mechanical ventilation (23.4%(11/47) vs 74.6%(44/59)), the Pitt bacteremia scores ≥4 points (21.3%(10/47) vs 69.5%(41/59)), the quick sequential organ failure assessment (qSOFA) scores ≥2 points (14.9%(7/47) vs 81.4%(48/59)), the ratio of platelets counts<100×10 9/L (31.9%(15/47) vs 62.7%(37/59)) had statistical differences between the poor prognosis group and the good prognosis group ( Z=-3.72, χ2=4.54, 5.04, 12.46, 24.48, 26.61, 43.02, 6.12, 3.86, 27.44, 24.36, 46.29 and 9.93, respectively; all P<0.050). Multivariate analysis showed that BSI complicated with lower respiratory tract infection (odds ratio ( OR)=3.293, 95% confidence interval ( CI) 1.138 to 9.528, P=0.028) and MODS ( OR=21.750, 95% CI 7.079 to 66.829, P<0.001) were independent risk factors for poor prognosis of CRKP BSI. Conclusions:Patients with CRKP BSI complicated with lower respiratory tract infection are more likely to have a poor prognosis. Timely maintenance of organ function may improve the prognosis of CRKP BSI.

Objective:To update the disease burden of colorectal cancer (CRC) in Chinese population by integrating the latest multi-source evidences.Methods:Groups of data from GLOBOCAN, series of Chinese Cancer Registry Annual Report (annual report), Cancer Incidence in Five Continents (CI5), Global Burden of Disease Project 2017 (GBD), China Death Cause Surveillance Datasets and China Health Statistical Yearbooks (yearbook) were used to extract the information. Data on incidence, mortality, disability-adjusted life year (DALY) and percentage distribution of sub-location of CRC were used to analyze the latest disease burden in China, and age-standardized rates by world standard population were mainly used. Joinpoint Trend Analysis Software 4.7.0.0 was applied for time trend analysis. Data related to the economic burden of CRC in China were gathered by literature review.Results:(1) Current status: according to the latest annual report, the incidence and mortality rates of CRC were 17.1 per 100 000 and 7.9 per 100 000, respectively among the covered registration sites in 2015. The incidence ratios of male to female and that of urban to rural were 1.5 and 1.4, with the mortality ratios were 1.6 and 1.4, respectively. Similar to data from the annual report, the mortality rate was reported as 6.9 per 100 000 in 2017 by the surveillance data sets. Data from the GBD project showed that, the DALYs caused by CRC in China in 2017 was 4.254 million person years (doubled compared with that of 1990), accounting for 22.4 % of the global burden of CRC. (2) Time trends: according to the annual reports, from 2009 to 2015, the incidence rate and mortality rate of CRC in China decreased by 10.2 % and 9.5 %, respectively. The same trend was also observed in urban sites, but was opposite in rural areas (increased 20.0 % in incidence and 15.2 % in mortality). Results from the Joinpoint analysis showed that the averaged annual percentage change (AAPC) was estimated as -1.6 % ( P<0.05) in the national mortality rate. Similarly, in the incidence and mortality rates of urban sites appeared as AAPC=-1.5 % and -1.4 % (all P<0.05), but inversely in the incidence rate from the rural sites as AAPC=3.3 % ( P<0.05). The yearbook data showed a 9.8 % increase in urban and 20.6 % increase in rural on the mortality in 2017 when compared with 2004, but the Joinpoint analysis showed no statistical significance ( P<0.05). (3) Distribution of sub-location of CRC: the annual report showed that among all the new CRC cases in China in 2015, colon, rectal and anal cancer accounted for 49.6 %, 49.2 % and 1.2 %, respectively, while the proportions were 51.3 %, 47.6 % and 1.1 %, respectively in 2009. The proportion of colon cancer was continuously higher in the urban (>52 %) than that in the rural areas (<44 %). The CI5 Ⅺ data showed that ascending and sigmoid colons were more commonly seen among all the colon cancers. (4) Economic burden: the average annual growth rate of the medical expenditure per CRC patient in China ranged from 6.9 % to 9.2 %, and the 1-year out-of-pocket expenditure of a newly diagnosed patient accounted for about 60 % of their previous-year household income. Conclusions:In China, the overall disease burden of CRC might have been decreased slightly but generally remained stable in the last several years, however, the rising burden appeared in the rural areas should not be ignored. In consistent with findings from a previous review, men and people from the urban areas are considered the target populations for CRC. The finding of higher proportion of colon cancer in urban areas suggests the impact of development of socioeconomic and medical technologies on CRC development and detection. The economic burden of CRC continued to grow.

Objective:To analyze the difference of immune damage between patients with severe fever with thrombocytopenia syndrome (SFTS) and patients with tsutsugamushi disease.Methods:A prospective case-control study was conducted. Thirty-one patients with SFTS and 16 patients with tsutsugamushi disease admitted to the First Affiliated Hospital of Anhui Medical University from October 2014 to June 2017 were enrolled, and another 10 healthy people were enrolled as control. The counts of CD4 + and CD8 + T lymphocytes, and the proportion of CD3 + T lymphocytes, natural kill cells (NK cells), B lymphocytes and plasma cells were detected by flow cytometry. Thirty-four inflammatory mediators were determined by a multiplex Luminex? system synchronously. The differences of lymphocytes and cytokines between the two groups were compared. Results:The proportion of CD3 + T lymphocytes, the counts of CD4 + and CD8 + T lymphocytes in SFTS patients were significantly lower than those in patients with tsutsugamushi disease ( t values were 4.860, 9.411 and 5.030, respectively, all P < 0.01), and the proportion of NK cells and B lymphocytes were significantly higher than those in patients with tsutsugamushi disease ( t values were 2.344 and 5.896, respectively, both P < 0.05). The proportion of plasma cells in peripheral blood of SFTS patients was (7.7±1.2)%, the highest proportion of plasma cells in severe SFTS patients was up to 30%, and all patients showed λ monoclonal cell group in plasma cells. No plasma cells were detected in tsutsugamushi disease patients. The abnormal expressions of interleukin-1 receptor antibody (IL-1RA), interleukin (IL-6, IL-15, IL-10, IL-8), tumor necrosis factor-α (TNF-α), γ-interferon (IFN-γ), granulocyte colony-stimulating factor (G-CSF), eosinophil chemotactic factor (Eotaxin), IFN-γ-inducible protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP-1α, MIP-1β), platelet-derived growth factor (PDGF-AA, PDGF-AB/BB), activated regulatory normal T cells and secretion factors (RANTES) were found in patients with SFTS and tsutsugamushi disease. The levels of IL-1RA, IL-6, IL-15, IL-10, TNF-α, IFN-γ, G-CSF, Eotaxin, IL-8, IP-10, MCP-1 and MIP-1α in SFTS patients were significantly higher than those in patients with tsutsugamushi disease ( Z values were 2.312, 2.447, 3.660, 5.444, 1.965, 2.402, 2.402, 2.997, 3.525, 2.481, 3.817, and 2.211, respectively, all P < 0.05), while PDGF-AA, PDGF-AB/BB and RANTES were significantly lower than those in patients with tsutsugamushi disease ( Z values were 3.728, 2.514, 2.649, respectively, all P < 0.05). Correlation analysis showed that RANTES, PDGF-AA and PDGF-AB/BB levels were significantly positively correlated with the level of platelet in patients with SFTS and tsutsugamushi disease (SFTS: r values were 0.223, 0.365, 0.330; tsutsugamushi disease: r values were 0.263, 0.632, 0.407, respectively, all P < 0.05). In SFTS patients, compared with the survival group ( n = 21), the CD3 + and CD4 + T lymphocytes in the death group ( n = 10) significantly decreased, while the plasma cells significantly increased ( t values were 3.980, 3.314 and 26.692, respectively, all P < 0.01); IL-1RA, IL-6, IL-15, IL-10, TNF-α, IFN-γ, G-CSF, Eotaxin, IL-8, IP-10, MCP-1, MIP-1α and MIP-1β significantly increased, while PDGF-AA, PDGF-AB/BB and RANTES significantly decreased ( Z values were 3.930, 4.014, 2.832, 3.592, 2.958, 3.508, 2.578, 3.254, 4.270, 3.465, 2.663, 3.085, 3.107, 3.639, 3.043 and 3.825, respectively, all P < 0.05). Conclusions:The immune function was impaired more seriously in SFTS patients than that in tsutsugamushi disease patients. Excessive humoral immunity and apoptosis of T lymphocytes are closely related to the death in SFTS patients. The detection of CD4 cells, plasma cells and proinflammatory and anti-inflammatory cytokines (e.g. IL-6, IL-10) had great clinical significance for the differentiation and illness evaluation in disease with SFTS or tsutsugamushi disease.