Background/Aims: Liver transplantation (LT) following total hepatectomy is a life-saving treatment for hepatocellular carcinoma (HCC). The HCC recurrence after LT hinders the effectiveness of the procedure. The objective of this study is to develop a pre-operative risk stratification model based on a liquid biopsy. Methods: We conducted a comprehensive multi-omics study of 260 HCC patients from three centers, including clinical data, low-coverage whole-genome sequencing of cell-free DNA (cfDNA) from plasma, as well as whole-exome, single-nucleus RNA, and spatial transcriptomics from matched tumor and non-tumor tissues. Results: We identified cfDNA-derived copy number alteration (CNA) signatures associated with post-transplant recurrence. By integrating cfDNA-derived CNA profiles with single-cell transcriptomic data, we traced recurrence-associated cfDNA to a distinct subpopulation of malignant cells within the primary tumor. These cells were embedded in a pro-metastatic microenvironment of specialized endothelial subtypes and cancer-associated fibroblasts. Notably, most recurrence-associated lesions were detectable in cfDNA prior to liver transplantation (LT). Building on these insights, we developed the ZJU Criteria based on CNA fragments and tumor markers, a pre-LT risk prediction tool that integrates conventional clinical factors with cfDNA-derived CNA signatures, and validated it using internal and independent external cohorts. Conclusion Our findings suggest that post-transplant recurrence commonly originates from advanced subclones that emerge late during tumor evolution. The ZJU Criteria provides an accurate, non-invasive strategy that significantly improves pre-LT risk stratification and clinical decision-making for patients with HCC.

This paper has summarized current studies on retinitis pigmentosa （RP） from two perspectives， which were disease mechanism insights from western medicine， and etiology， pathogenesis and therapeutic principles in traditional Chinese medicine （TCM）. From the perspective of western medicine， the understanding of RP has evolved from an early single-factor explanation focusing on pathogenic gene mutations to a more comprehensive， multifactorial model involving genetic abnormalities， photoreceptor cell degeneration， retinal pigment epithelium dysfunction， oxidative stress， inflammatory responses， microenvironmental imbalance， and vascular insufficiency. In TCM， RP is considered to be a disorder manifested in the eyes but rooted in dysfunction of the zang-fu （脏腑） organs. Its pathogenesis is primarily associated with congenital insufficiency， liver-kidney depletion， impaired spleen function of transportation and transformation， and stasis obstructing the meridians. The core pathological mechanism can be summarized as "deficiency complicated by stasis"， emphasizing holistic imbalance， dynamic disease progression， and syndrome differentiation and treatment. The differences and complementarities between the two medical systems in understanding disease progression are further discussed. RP is proposed to be more appropriately regarded as a complex disease characterized by long-term progression， stage-dependent evolution， and persistent decompensation. Western medicine contributes to elucidating the molecular mechanisms underlying RP and provides the foundation for targeted therapeutic interventions， whereas TCM offers a holistic perspective for understanding disease evolution through the assessment of overall functional status， disease-stage stratification， and long-term syndrome-based regulation.

This paper has summarized current studies on retinitis pigmentosa （RP） from two perspectives， which were disease mechanism insights from western medicine， and etiology， pathogenesis and therapeutic principles in traditional Chinese medicine （TCM）. From the perspective of western medicine， the understanding of RP has evolved from an early single-factor explanation focusing on pathogenic gene mutations to a more comprehensive， multifactorial model involving genetic abnormalities， photoreceptor cell degeneration， retinal pigment epithelium dysfunction， oxidative stress， inflammatory responses， microenvironmental imbalance， and vascular insufficiency. In TCM， RP is considered to be a disorder manifested in the eyes but rooted in dysfunction of the zang-fu （脏腑） organs. Its pathogenesis is primarily associated with congenital insufficiency， liver-kidney depletion， impaired spleen function of transportation and transformation， and stasis obstructing the meridians. The core pathological mechanism can be summarized as "deficiency complicated by stasis"， emphasizing holistic imbalance， dynamic disease progression， and syndrome differentiation and treatment. The differences and complementarities between the two medical systems in understanding disease progression are further discussed. RP is proposed to be more appropriately regarded as a complex disease characterized by long-term progression， stage-dependent evolution， and persistent decompensation. Western medicine contributes to elucidating the molecular mechanisms underlying RP and provides the foundation for targeted therapeutic interventions， whereas TCM offers a holistic perspective for understanding disease evolution through the assessment of overall functional status， disease-stage stratification， and long-term syndrome-based regulation.

ObjectiveTo elucidate the epidemiological characteristics, evolution of the pathogen spectrum, and spatial distribution patterns of other infectious diarrheal diseases (excluding cholera, typhoid fever, paratyphoid fever, and bacillary dysentery) in Yangpu District of Shanghai from 2005 to 2024, thereby providing a scientific basis for the formulation of targeted prevention and control strategies. MethodsInformation on other infectious diarrhea cases with a current address in Yangpu District of Shanghai, and onset dates from January 1, 2005 to December 31, 2024, was extracted from the Chinese Center for Disease Control and Prevention Information System. Data on cases, including gender, age, occupation, and pathogen testing results, were collected. Descriptive epidemiological methods were employed to analyze the temporal, spatial, and demographic distribution of reported incidence rates and the epidemiological characteristics of pathogens for other infectious diarrheal diseases in Yangpu District from 2005 to 2024. Spatial autocorrelation analyses of reported incidence rates for viral and bacterial diarrhea were conducted using Moran’s Index (Moran’s I）. Local spatial autocorrelation analyses were performed using local indicators of spatial association (LISA), with a first-order Queen contiguity spatial weight matrix, and significance was tested via 999 random permutations. Time-series and radar chart analyses were used to examine the temporal patterns of other infectious diarrhea cases caused by major pathogens. ResultsFrom 2005 to 2024, a total of 5 211 cases of other infectious diarrhea were reported in Yangpu District. The cases were predominantly males (2 714 cases, accounting for 52.08%) and children under 5 years of age (1 639 cases, accounting for 31.45%). The primary occupational groups were scattered children (1 433 cases, accounting for 27.50%) and retired personnel (1 403 cases, accounting for 26.92%). The annual average reported incidence rate was 20.36/100 000, showing an overall fluctuating trend with peaks around 2009 and 2024. Peak incidence occurred in summer and autumn (July‒September), with the highest reported incidence rate observed in summer (June‒August) (7.31/100 000). Children under 5 years of age (116.00/100 000) and adults aged 60 and older (21.39/100 000) were the top two age groups in terms of reported incidence. Global spatial autocorrelation analyses showed that the reported incidence rates of viral diarrhea across the sub-districts in Yangpu District in 2020 exhibited a significant positive spatial correlation (Moran’s I =0.30, P=0.016). The spatial autocorrelation of reported incidence rates of viral diarrhea in each sub-district for the periods 2008‒2019 and 2021‒2024 was not statistically significant (all P>0.05). Local spatial autocorrelation analyses of viral diarrhea incidence in 2020 revealed that Xinjiangwancheng Sub-district exhibited a low‑low clustering trend (local Moran’s I =0.49, P=0.018), while Dinghai Road Sub-district exhibited a high‑high clustering trend (local Moran’s I =1.33, P=0.024). The global spatial autocorrelation of reported incidence rates of bacterial diarrhea across the sub-districts of Yangpu District from 2005 to 2024 was not statistically significant (all P>0.05). Among the 5 211 cases, 4 049 had definitive pathogen test results. Bacterial diarrhea accounted for a relatively high proportion (55.52%, 2 248/4 049). The pathogens with the highest proportions were rotavirus (32.33%, 1 309/4 049), Vibrio spp. (31.69%, 1 283/4 049), Salmonella spp. (19.63%, 795/4 049), and norovirus (9.16%, 371/4 049). The radar chart showed that diarrhea cases caused by norovirus had no obvious seasonality, rotavirus cases were mainly concentrated in winter, and cases caused by Salmonella spp. and Vibrio spp. were mainly concentrated in summer and autumn. Among cases under 20 years of age, rotavirus accounted for a relatively high proportion, especially in children under 5 years of age. Among cases aged 20 years and older, Vibrio spp. and Salmonella spp. accounted for relatively high proportions. ConclusionFrom 2005 to 2024, other infectious diarrhea in Yangpu District of Shanghai was most prevalent in summer and autumn. Children under 5 years of age and adults aged 60 years and older were high-risk groups. In 2020, Dinghai Road Sub-district was a high-risk area for viral diarrhea. Rotavirus, Vibrio spp., Salmonella spp., and norovirus were the dominant pathogens. Prevention and control efforts for other infectious diarrhea should be strengthened among key populations (e.g., children under 5 years of age and adults aged 60 years and older) and in high-risk areas such as Dinghai Road Sub-district. During summer and autumn, priority should be given to the prevention and control of bacterial diarrhea caused by Salmonella spp. and Vibrio spp., especially among individuals aged 20 years and older (particularly those aged 60 and above). During winter, priority should be given to the prevention and control of diarrhea caused by rotavirus infection among individuals under 20 years of age, particularly children under 5 years of age.

Objective The aim of the study is to analyze the incidence patterns and epidemiological characteristics of parasitic and vector-borne diseases in the Minhang and Jinshan districts of Shanghai, and provide evidence-based information for optimizing prevention and control measures. Methods We collected information from epidemic reports and epidemiological investigation forms for cases of parasitic and vector-borne diseases from 2005 to 2024 in Shanghai's Minhang and Jinshan districts. Descriptive epidemiological method were adopted to conduct a comparative analysis of incidence trends, epidemic characteristics, and infection sources. Results A total of 229 cases in 7 categories were reported between 2005 and 2024, with an average annual incidence rate of 0.36/100 000. The average annual incidence rate in Minhang District was significantly higher than that in Jinshan District. The most prevalent diseases were malaria and dengue fever, followed by Japanese encephalitis. Monthly case reports were available, predominantly from June to October, with a peak in July-August. A statistically significant difference was observed between the two districts in case distribution during June-October (P＜0.001), whereas no significant difference was found for July-August (P=0.331). The majority of cases were young men (111/229,48.47%), aged 20-39 years. Migrant workers/farmers constituted the largest occupational group (55/229, 24.02%). Registered residents of other provinces and cities (147/229,64.19%), and the main source of infection was overseas importation (112/229,48.91%). There were no statistically significant differences in gender and household-registration composition between the two districts (P＞0.05). Significant differences existed in age, occupation, and source of infection (P＜0.05). The imported diseases were malaria and dengue fever, with Africa and Southeast Asia being the primary source locations. Malaria was the predominant disease imported from other provinces and cities, with cases having been imported from abroad since 2012. Local infections were mainly Japanese encephalitis, followed by malaria (with the last local case reported in 2010). Cases between 2005 and 2009 were predominantly imported from other provinces and cities. The proportion of cases imported from abroad increased sharply after 2010, particularly in Minhang District. Local infections sometimes arise in Jinshan District, with Japanese encephalitis serving as the primary type. Conclusions Incidence rates of parasitic and vector-borne diseases in Minhang and Jinshan districts have generally remained low. To further reduce this disease burden, it will be necessary to strengthen joint measures for prevention and control, eliminate the environmental risk factors of vector organisms, enhance monitoring and precise control of the environment and inbound personnel to prevent the occurrence and transmission of parasitic and vector-borne diseases.

ObjectiveTranscranial magneto-acoustic stimulation (TMAS) is an emerging non-invasive neuromodulation technique that may provide a novel non-pharmacological intervention strategy for Parkinson's disease (PD). PD is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), leading to motor impairments such as bradykinesia, tremor, and rigidity. Increasing evidence indicates that mitochondrial dysfunction and impaired mitochondrial quality control are central mechanisms underlying dopaminergic neuronal loss. In particular, abnormalities in mitophagy and mitochondrial fission-fusion balance contribute substantially to oxidative stress, energy metabolic failure, and neuronal injury. At present, most clinical treatments for PD mainly alleviate symptoms but do not effectively halt disease progression. Therefore, exploring new interventions targeting the core pathological mechanisms is of considerable significance. This study aims to investigate whether TMAS can improve neural damage and motor dysfunction in PD mice by regulating mitophagy and the fission/fusion dynamic balance, thereby providing theoretical and experimental support for its application in PD treatment. MethodsMale C57BL/6 mice were used in this study. A PD model was established by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 7 consecutive days. After model induction, mice in the intervention group received TMAS once daily for 14 consecutive days, whereas the corresponding control group received sham stimulation. The stimulation target was positioned over the primary motor cortex (M1). Motor performance was evaluated using the pole test and the open-field test. To verify the activation effect of TMAS on the target cortical region, c-Fos immunohistochemistry was performed in the M1. To assess nigral dopaminergic neuronal injury, tyrosine hydroxylase (TH) immunohistochemistry was used to quantify TH-positive neurons in the SNc. Mitochondrial function was evaluated by measuring reactive oxygen species (ROS) levels and adenosine triphosphate (ATP) content in the SNc. Western blot was further performed to determine the expression of mitophagy-related proteins, including PINK1, Parkin, LC3-II, and p62, as well as mitochondrial dynamics-related proteins, including Drp1 and Opa1. ResultsTMAS significantly increased the number of c-Fos-positive cells in M1 (P<0.000 1), indicating effective activation of neurons in the targeted cortical region. Compared with the control group, MPTP-treated mice exhibited marked motor dysfunction, including a significant reduction in total distance traveled in the open-field test (P<0.000 1) and mean speed (P=0.000 1), as well as significant prolongation of turn time and total climbing time in the pole test (P<0.000 1). These behavioral impairments were accompanied by a substantial loss of TH-positive dopaminergic neurons in the SNc, whereas TMAS significantly increased TH-positive neuron survival (P<0.000 1). In parallel, MPTP induced a pronounced increase in ROS levels and a significant reduction in ATP content, indicating severe mitochondrial dysfunction and energy metabolism impairment (P<0.01). TMAS treatment significantly improved motor performance, as reflected by the reversal of MPTP-induced impairment in the open-field and pole tests, and significantly reduced ROS accumulation (P<0.01) while restoring ATP production (P<0.001). At the molecular level, MPTP markedly downregulated PINK1 and Parkin, decreased p62 expression, increased LC3-II accumulation, elevated Drp1 expression, and reduced Opa1 expression, whereas TMAS significantly reversed these abnormalities, suggesting restoration of mitophagy-related mitochondrial quality control and re-establishment of mitochondrial fission-fusion balance. Collectively, these findings indicate that TMAS ameliorates MPTP-induced neurotoxicity and restores mitochondrial homeostasis and energy metabolism. ConclusionTMAS effectively attenuates neural damage and improves motor dysfunction in MPTP-induced PD mice. Its neuroprotective effects are closely associated with multidimensional regulation of the mitochondrial quality control system, including restoration of PINK1/Parkin-mediated mitophagy and rebalancing of Drp1/Opa1-related mitochondrial dynamics. Rather than acting only as a symptomatic neuromodulatory intervention, TMAS may influence a key pathological axis of PD by improving mitochondrial homeostasis in SNc and protecting nigral dopaminergic neurons. These findings provide experimental evidence supporting TMAS as a promising non-invasive physical intervention for PD.

ObjectiveTranscranial magneto-acoustic stimulation (TMAS) is an emerging non-invasive neuromodulation technique that may provide a novel non-pharmacological intervention strategy for Parkinson's disease (PD). PD is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), leading to motor impairments such as bradykinesia, tremor, and rigidity. Increasing evidence indicates that mitochondrial dysfunction and impaired mitochondrial quality control are central mechanisms underlying dopaminergic neuronal loss. In particular, abnormalities in mitophagy and mitochondrial fission-fusion balance contribute substantially to oxidative stress, energy metabolic failure, and neuronal injury. At present, most clinical treatments for PD mainly alleviate symptoms but do not effectively halt disease progression. Therefore, exploring new interventions targeting the core pathological mechanisms is of considerable significance. This study aims to investigate whether TMAS can improve neural damage and motor dysfunction in PD mice by regulating mitophagy and the fission/fusion dynamic balance, thereby providing theoretical and experimental support for its application in PD treatment. MethodsMale C57BL/6 mice were used in this study. A PD model was established by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 7 consecutive days. After model induction, mice in the intervention group received TMAS once daily for 14 consecutive days, whereas the corresponding control group received sham stimulation. The stimulation target was positioned over the primary motor cortex (M1). Motor performance was evaluated using the pole test and the open-field test. To verify the activation effect of TMAS on the target cortical region, c-Fos immunohistochemistry was performed in the M1. To assess nigral dopaminergic neuronal injury, tyrosine hydroxylase (TH) immunohistochemistry was used to quantify TH-positive neurons in the SNc. Mitochondrial function was evaluated by measuring reactive oxygen species (ROS) levels and adenosine triphosphate (ATP) content in the SNc. Western blot was further performed to determine the expression of mitophagy-related proteins, including PINK1, Parkin, LC3-II, and p62, as well as mitochondrial dynamics-related proteins, including Drp1 and Opa1. ResultsTMAS significantly increased the number of c-Fos-positive cells in M1 (P<0.000 1), indicating effective activation of neurons in the targeted cortical region. Compared with the control group, MPTP-treated mice exhibited marked motor dysfunction, including a significant reduction in total distance traveled in the open-field test (P<0.000 1) and mean speed (P=0.000 1), as well as significant prolongation of turn time and total climbing time in the pole test (P<0.000 1). These behavioral impairments were accompanied by a substantial loss of TH-positive dopaminergic neurons in the SNc, whereas TMAS significantly increased TH-positive neuron survival (P<0.000 1). In parallel, MPTP induced a pronounced increase in ROS levels and a significant reduction in ATP content, indicating severe mitochondrial dysfunction and energy metabolism impairment (P<0.01). TMAS treatment significantly improved motor performance, as reflected by the reversal of MPTP-induced impairment in the open-field and pole tests, and significantly reduced ROS accumulation (P<0.01) while restoring ATP production (P<0.001). At the molecular level, MPTP markedly downregulated PINK1 and Parkin, decreased p62 expression, increased LC3-II accumulation, elevated Drp1 expression, and reduced Opa1 expression, whereas TMAS significantly reversed these abnormalities, suggesting restoration of mitophagy-related mitochondrial quality control and re-establishment of mitochondrial fission-fusion balance. Collectively, these findings indicate that TMAS ameliorates MPTP-induced neurotoxicity and restores mitochondrial homeostasis and energy metabolism. ConclusionTMAS effectively attenuates neural damage and improves motor dysfunction in MPTP-induced PD mice. Its neuroprotective effects are closely associated with multidimensional regulation of the mitochondrial quality control system, including restoration of PINK1/Parkin-mediated mitophagy and rebalancing of Drp1/Opa1-related mitochondrial dynamics. Rather than acting only as a symptomatic neuromodulatory intervention, TMAS may influence a key pathological axis of PD by improving mitochondrial homeostasis in SNc and protecting nigral dopaminergic neurons. These findings provide experimental evidence supporting TMAS as a promising non-invasive physical intervention for PD.

ObjectiveTo explore the effects of angle and original moisture content on the moisture distribution， migration and contents of effective components in the drying process of sliced Salviae Miltiorrhizae Radix et Rhizoma（SMRR）. MethodsSet the slicing angles of SMRR at 30°， 45°， and 90°. Cut the fresh samples， 1/3 dehydrated samples， and 2/3 dehydrated samples， dry them in an oven at 40 ℃ and take samples at the set time points. Low-field nuclear magnetic resonance（LF-NMR） and magnetic resonance imaging（MRI） were used to analyze the changes in transverse relaxation time（T₂） of SMRR samples in 9 treatment groups at specific times， as well as the distribution and migration of water in the samples. The contents of tanshinone Ⅱ_A， tanshinone Ⅰ， cryptotanshinone， and salvianolic acid B in samples from 9 different treatment groups were determined by high performance liquid chromatography（HPLC）， and the best processing technology of SMRR was screened by combining with One-way ANOVA， Duncan multiple comparison and principal component analysis（PCA）. ResultsThe moisture content of dry basis of SMRR in each treatment group decreased with the extension of drying time. The drying rate of fresh cut group decreased slowly at first， while the drying rate of water loss group showed a trend of increasing at first and then decreasing. The internal water of SMRR could be divided into three states， including bound water， non flowing water and free water. During the drying process， the water migration law showed that the free water of fresh cut group disappeared after drying for 12 h， the content of bound water gradually decreased， and the overall fluidity deteriorated. In the water loss group， part of the free water was transformed into more cohesive and non flowing water after drying for 3 h， and the three kinds of water basically disappeared after drying for 12 h. The MRI results showed that the entire dehydration process slowly moved from the outer side to the center， and the internal water eventually dissipated. In terms of the contents of active ingredients， the order of the effect of slicing angle on the total content of active ingredients in SMRR was 30°>45°>90°. The content of tanshinones was ranked as 1/3 dehydrated group>2/3 dehydrated group>fresh cut group， and the content of salvianolic acid B was ranked as 1/3 dehydrated group>fresh cut group>2/3 dehydrated group. Combined with the results of PCA and comprehensive scoring results， the overall level of effective component content in SMRR was the highest when cut at 30° after 1/3 of water loss. ConclusionAfter comprehensive evaluation， SMRR can be sliced at 30° after 1/3 of water loss. It is not only easy to cut， but also the surface and cross-sectional colors remain basically unchanged after drying， which is similar to the color under traditional processing， and the effective ingredients are preserved the highest. This study can provide a basis for the optimization of processing technology of SMRR.

Objective:To investigate the complications, along with their diagnosis and management, that follow local excision for rectal cancer after neoadjuvant therapy.Methods:The clinical data of 53 patients with rectal cancer who underwent local resection after neoadjuvant treatment in Peking Union Medical College Hospital from January, 2010 to December, 2024 were retrospectively collected for this descriptive case series study. Indications for local resection were: (1) age ≥ 18 years; (2) American Society of Anesthesiologists (ASA) classification I-III; (3) pathologically confirmed rectal adenocarcinoma; (4) distance from the lower edge of the tumor to the anal edge of less than 8 cm; and (5) use of preoperative neoadjuvant therapy. Contraindications of local resection were: (1) multiple primary colorectal cancer and (2) intestinal obstruction, intestinal perforation, or and gastrointestinal bleeding that required emergency surgery. There were 36 males and 17 females, and the median age was 62 (26-85) years. After neoadjuvant therapy, the median distance from the tumor to the anal margin was 4.5 (range, 2.2-6.9) cm. The main outcome measures included: surgical details, pathological findings, postoperative complications, anorectal function, and oncological outcomes (recurrence and survival).Results:Surgical methods included transanal endoscopic microsurgery (TEM) in 47 cases, transanal minimally invasive surgery (TAMIS) in 3 cases, and traditional transanal local resection in 3 cases. Of the 53 patients, 29 (54.7%) had pathological complete response (pCR), namely pT0 stage; 8 cases were pT1, 15 cases were pT2, and 1 case was pT3. Twenty-four cases (45.3%) had 33 complications. Clavien-Dindo grade I-II accounted for 97.0% (32/33), including 14 cases (26.4%) of wound dehiscence. Low anterior resection syndrome (LARS) occurred in 7 cases (13.2%), including 5 minor cases and 2 major cases. Postoperative fever occurred in 7 cases (13.2%); urinary retention occurred in 3 cases (5.7%); and diarrhea occurred in 1 case (1.9%). Clavien Dindo grade III was observed in only 3.0% (1/33) of patients, which was a rectovaginal fistula. Among the 14 patients with wound dehiscence, 7 cases only suffered anal pain and were cured after symptomatic analgesic treatment. Five cases suffered anal pain with hematochezia but improved after treatment with essential diet, hemostasis, intravenous antibiotics, pain relief, and sitz bath. Two cases of secondary perianal infection were treated with intravenous antibiotics, local drainage, parenteral nutrition support, and symptomatic treatment, and the wounds healed within 2 months. One patient with rectovaginal fistula underwent transverse colostomy. After six months, the fistula healed and stoma reversal was performed. Seven patients with LARS received anal lifting exercise and defecation reflex training, and anal function recovered to the preoperative level after 1 year. Other complications improved after symptomatic treatment, pain relief, or catheter replacement. The median follow-up time was 60 months. Local recurrence occurred in 4 patients (7.5%) and distant metastasis occurred in 12 patients (22.6%). Seven patients (13.2%) died. The 5-year disease-free survival rate was 75.5%, and the 5-year overall survival rate was 86.8%.Conclusions:Local excision for rectal cancer following neoadjuvant therapy has a high incidence of complications, mainly wound-related, due to the decline of rectal wound healing ability after radiotherapy. However, most of the complications were relieved after symptomatic treatment, and the risk was controllable.

Dry eye disease (DED) is a prevalent and intractable ocular disease induced by a variety of causes. Elevated sphingomyelin (SM) levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients, particularly in the meibomian glands. Sphingomyelin synthase 2 (SMS2), one of the proteins involved in SM synthesis, would light a novel way of developing a DED therapy strategy. Herein, we report the design and optimization of a series of novel thiophene carboxamide derivatives to afford 14l with an improved highly potent inhibitory activity on SM synthesis (IC_{50, SMS2} = 28 nmol/L). Moreover, 14l exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells (HCEC) under TNF-α-hyperosmotic stress conditions in vitro, with an acceptable ocular specific distribution (corneas and meibomian glands) and pharmacokinetics (PK) profiles (t _{1/2, cornea} = 1.11 h; t _{1/2, meibomian glands} = 4.32 h) in rats. Furthermore, 14l alleviated the dry eye symptoms including corneal fluorescein staining scores and tear secretion in a dose-dependent manner in mice. Mechanically, 14l reduced the mRNA expression of Tnf-α, Il-1β and Mmp-9 in corneas, as well as the proportion of very long chain SM in meibomian glands. Our findings provide a new strategy for DED therapy based on selective SMS2 inhibitors.