Functional genomics analysis reveals the evolutionary adaptation and demographic history of pygmy lorises.

Lorises are a group of globally threatened strepsirrhine primates that exhibit many unusual physiological and behavioral features, including a low metabolic rate, slow movement, and hibernation. Here, we assembled a chromosome-level genome sequence of the pygmy loris (Xanthonycticebus pygmaeus) and resequenced whole genomes from 50 pygmy lorises and 6 Bengal slow lorises (Nycticebus bengalensis). We found that many gene families involved in detoxification have been specifically expanded in the pygmy loris, including the GSTA gene family, with many newly derived copies functioning specifically in the liver. We detected many genes displaying evolutionary convergence between pygmy loris and koala, including PITRM1. Significant decreases in PITRM1 enzymatic activity in these two species may have contributed to their characteristic low rate of metabolism. We also detected many evolutionarily convergent genes and positively selected genes in the pygmy loris that are involved in muscle development. Functional assays demonstrated the decreased ability of one positively selected gene, MYOF, to up-regulate the fast-type muscle fiber, consistent with the lower proportion of fast-twitch muscle fibers in the pygmy loris. The protein product of another positively selected gene in the pygmy loris, PER2, exhibited weaker binding to the key circadian core protein CRY, a finding that may be related to this species' unusual circadian rhythm. Finally, population genomics analysis revealed that these two extant loris species, which coexist in the same habitat, have exhibited an inverse relationship in terms of their demography over the past 1 million years, implying strong interspecies competition after speciation.

Integrative Omics Reveals Rapidly Evolving Regulatory Sequences Driving Primate Brain Evolution.

Although the continual expansion of the brain during primate evolution accounts for our enhanced cognitive capabilities, the drivers of brain evolution have scarcely been explored in these ancestral nodes. Here, we performed large-scale comparative genomic, transcriptomic, and epigenomic analyses to investigate the evolutionary alterations acquired by brain genes and provide comprehensive listings of innovatory genetic elements along the evolutionary path from ancestral primates to human. The regulatory sequences associated with brain-expressed genes experienced rapid change, particularly in the ancestor of the Simiiformes. Extensive comparisons of single-cell and bulk transcriptomic data between primate and nonprimate brains revealed that these regulatory sequences may drive the high expression of certain genes in primate brains. Employing in utero electroporation into mouse embryonic cortex, we show that the primate-specific brain-biased gene BMP7 was recruited, probably in the ancestor of the Simiiformes, to regulate neuronal proliferation in the primate ventricular zone. Our study provides a comprehensive listing of genes and regulatory changes along the brain evolution lineage of ancestral primates leading to human. These data should be invaluable for future functional studies that will deepen our understanding not only of the genetic basis of human brain evolution but also of inherited disease.

Long-term efficacy and safety of microwave ablation for hepatocellular carcinoma adjacent to the gallbladder with a diameter ≤ 5 cm: a multicenter, propensity score matching study.

OBJECTIVE: To compare the long-term efficacy and safety of microwave ablation (MWA) as first-line therapy for hepatocellular carcinoma (HCC) adjacent versus nonadjacent to the gallbladder. MATERIALS AND METHODS: From 2006 to 2018, 657 patients with ≤5 cm HCC who underwent percutaneous ultrasound-guided MWA as first-line therapy from 5 hospitals were enrolled in this retrospective study. Patients were grouped into the adjacent group (n = 49) and the nonadjacent group (n = 608) according to whether the tumor was adjacent to the gallbladder. Propensity score matching (PSM) was used to balance baseline variables between the two groups. RESULTS: Forty-eight patient pairs were matched after PSM. For the PSM cohort, during a median follow-up time of 60 months, there were no differences in PFS (hazard ratio [HR], 1.011; 95% confidence interval [CI], 0.647-1.578; p = 0.963) or OS (HR 0.925; 95% CI 0.522-1.639; p = 0.789) between the adjacent and nonadjacent groups. Univariate and multivariate analyses revealed that the tumor adjacent to the gallbladder was not an independent risk factor for PFS or OS (all p > 0.05). Subgroup analysis showed comparable PFS and OS between the two groups in the <3 cm subgroup and the 3-5 cm subgroups (all p > 0.05). In addition to more use of assistive technology (p < 0.05), the adjacent group shared comparable local tumor progression, complications, technical success rate, and hospital stay (all p > 0.05) to the nonadjacent group. CONCLUSION: There were comparable long-term efficacy and complications between patients with HCC adjacent and nonadjacent to the gallbladder treated with MWA.

The application of MWA to HCC adjacent and nonadjacent to the gallbladder resulted in comparable PFS and OS and complications.For both cohorts, MWA shared comparable complications (immediate and delayed), LTP, hospitalization, and operative time.MWA might be a first-line alternative for ≤5 cm HCC adjacent to the gallbladder with the use of assistive technologies and advances in technology.

Early intervention with supplemental parenteral nutrition reduces the incidence of granulocytopenia-related infections in patients with lung cancer: a retrospective cohort study.

BACKGROUND AND OBJECTIVES: The optimal timing for initiating supplemental parenteral nutrition in chemotherapy- induced severe granulocytopenia in patients with lung cancer remains uncertain. METHODS AND STUDY DESIGN: A retrospective study was conducted among patients with lung cancer from February 2016 to June 2018. In total, 182 eligible patients were included and divided into 2 groups according to the time of supplemental parenteral nutrition intervention: early initiation (within 72 hours of development of granulocytopenia) and late initiation (over 72 hours). The primary outcomes of the study were bacterial infection and fungal infection, and the secondary outcomes were duration of absolute neutrophil count less than 1.0×109 cells/L, length of hospital stay, mortality rate, and rate of chemotherapy (4 cycles) completion. RESULTS: The incidence rates of bacterial infection and fungal infection were significantly lower among patients who received supplemental parenteral nutrition early than among patients who received it late. No significant difference in mortality was observed between the groups. In addition, compared with late supplemental parenteral nutrition, early supplemental parenteral nutrition was associated with a higher rate of completion of 4 chemotherapy cycles and shorter hospital stays and leukocyte recovery periods in our cohort. Univariate and multivariate logistic regression analyses revealed that the subgroup of patients with an NRS-2002 score of 2 benefited from early supplemental parenteral nutrition. CONCLUSIONS: Early supplemental parenteral nutrition after chemotherapy-induced severe granulocytopenia could reduce the risk of infection, improve the likelihood of chemotherapy completion, and shorten hospital stays and leukocyte recovery times.

High polymorphism in MHC-DRB genes in golden snub-nosed monkeys reveals balancing selection in small, isolated populations.

BACKGROUND: Maintaining variation in immune genes, such as those of the major histocompatibility complex (MHC), is important for individuals in small, isolated populations to resist pathogens and parasites. The golden snub-nosed monkey (Rhinopithecus roxellana), an endangered primate endemic to China, has experienced a rapid reduction in numbers and severe population fragmentation over recent years. For this study, we measured the DRB diversity among 122 monkeys from three populations in the Qinling Mountains, and estimated the relative importance of different agents of selection in maintaining variation of DRB genes. RESULTS: We identified a total of 19 DRB sequences, in which five alleles were novel. We found high DRB variation in R. roxellana and three branches of evidence suggesting that balancing selection has contributed to maintaining MHC polymorphism over the long term in this species: i) different patterns of both genetic diversity and population differentiation were detected at MHC and neutral markers; ii) an excess of non-synonymous substitutions compared to synonymous substitutions at antigen binding sites, and maximum-likelihood-based random-site models, showed significant positive selection; and iii) phylogenetic analyses revealed a pattern of trans-species evolution for DRB genes. CONCLUSIONS: High levels of DRB diversity in these R. roxellana populations may reflect strong selection pressure in this species. Patterns of genetic diversity and population differentiation, positive selection, as well as trans-species evolution, suggest that pathogen-mediated balancing selection has contributed to maintaining MHC polymorphism in R. roxellana over the long term. This study furthers our understanding of the role pathogen-mediated balancing selection has in maintaining variation in MHC genes in small and fragmented populations of free-ranging vertebrates.

Male-Male Mounting Behaviour in Free-Ranging Golden Snub-Nosed Monkeys (Rhinopithecus roxellana).

An all-male band of golden snub-nosed monkeys (Rhinopithecus roxellana) was observed for 3 months in the Qinling Mountains of China, in order to collect data on the frequencies and contextual significance of male-male mounting behaviour. Mounts occurred in a variety of affiliative, dominance-related and sexual contexts, which differed depending upon the ages of the males involved. Mounting behaviour in this group was mainly initiated by adults. Juveniles mounted each other in affiliative contexts (during play and prior to grooming). Adult males mounted subadult and juvenile partners in a greater variety of sociosexual contexts (dominance/rank-related interactions; reconciliation following agonistic encounters, and sometimes as a prelude to receiving grooming). However, subadults and juveniles were never observed to mount adults. In one dyad, involving an adult male and a subadult partner, mounting was more frequent and prolonged, and included bouts of deep pelvic thrusting. Two mounts resulted in anal intromissions and, in 1 case, the subadult partner exhibited seminal emission. Given that the study took place during the annual mating peak period of R. roxellana, it is possible that this unusual male-male sexual activity was related to the absence of mating opportunities for those adults that were excluded from 1-male units.

Male cooperation for breeding opportunities contributes to the evolution of multilevel societies.

A small number of primate species including snub-nosed monkeys (colobines), geladas (papionins) and humans live in multilevel societies (MLSs), in which multiple one-male polygamous units (OMUs) coexist to form a band, and non-breeding males associate in bachelor groups. Phylogenetic reconstructions indicate that the papionin MLS appears to have evolved through internal fissioning of large mixed-sex groups, whereas the colobine MLS evolved through the aggregation of small, isolated OMUs. However, how agonistic males maintain tolerance under intensive competition over limited breeding opportunities remains unclear. Using a combination of behavioural analysis, satellite telemetry and genetic data, we quantified the social network of males in a bachelor group of golden snub-nosed monkeys. The results show a strong effect of kinship on social bonds among bachelors. Their interactions ranged from cooperation to agonism, and were regulated by access to mating partners. We suggest that an 'arms race' between breeding males' collective defence against usurpation attempts by bachelor males and bachelor males' aggregative offence to obtain reproductive opportunities has selected for larger group size on both sides. The results provide insight into the role that kin selection plays in shaping inter-male cohesion which facilities the evolution of multilevel societies. These findings have implications for understanding human social evolution, as male-male bonds are a hallmark of small- and large-scale human societies.

A new conservation strategy for China-A model starting with primates.

Although the evolutionary history of primates in China dates to the Eocene, and includes major radiations of lorisids, hominoids, cercopithecines, and colobines during the Miocene, Pliocene, and Pleistocene, extensive human-induced habitat change and deforestation over the past few centuries has resulted in 22 of 25 extant species listed as threatened or endangered, and two species of gibbons extirpated in the last few years. This commentary briefly reviews factors that have contributed to the decline of primates in China over the past 400 years, and in particular how major social events and economic development in modern China have resulted in unsustainable environmental change. In response, we describe our efforts to develop a strategic scientific, educational and conservation partnership in China, focusing on primates, in which GIS technology will be used to integrate geographical profiles, climatic information, and changes in land use patterns and human and nonhuman primate distributions to highlight issues of immediate concern and to develop priority-based conservation solutions. Our goal is to evaluate how human-induced environmental change has impacted primates over time and to predict the likelihood of primate population extinctions in the near future. This model represents an early warning system that will be widely available to the Chinese government, public, educational institutions, researchers, and NGOs through social media and educational videos in order to arouse public awareness and promote wildlife conservation. We encourage colleagues across a broad range of academic disciplines, political ideologies, and the public to help move this strategy into reality, the sooner the better. Am. J. Primatol. 78:1137-1148, 2016. © 2016 Wiley Periodicals, Inc.

Age- and sex-based patterns of positional behavior and substrate utilization in the golden snub-nosed monkey (Rhinopithecus roxellana).

Body mass plays an important role in primate positional behavior and in sexually dimorphic arboreal primate species may influence how immature and adult individuals travel through the forest canopy and access food resources. In this study, we examined age- and sex-based patterns of positional behavior and substrate utilization in wild golden snub-nosed monkeys (Rhinopithecus roxellana), an endangered species of Asian colobine. Our results indicated that among all age and sex classes, sitting was the most common feeding and resting posture and during travel, quadrupedal walking was the dominant locomotor behavior. Despite the fact that adult male R. roxellana are reported to exhibit a body mass nearly two times that of adult females, we found no significant sex differences in the positional repertoire during feeding and traveling. In addition, we found that while infants and juveniles used similar postural and locomotor behaviors as their adult counterparts, younger golden snub-nosed monkeys more frequently engaged in risky or escape-oriented behaviors such as climbing, running, leaping, and forelimb suspension. With increasing age, the use of quadrupedal walking and dropping (downward in-air displacement of body mass that does not require hindlimb propulsion) increased and the use of leaping, suspensory postures, and bridging decreased. Finally, given differences in the positional repertoire of adult and immature golden snub-nosed monkeys, we argue that studies of ontogenetic patterns of positional behavior should emphasize what it takes to survive at each life stage rather than what it takes to match an adult repertoire.

Postconflict Conciliation within One-Male Breeding Units in Sichuan Snub-Nosed Monkeys in the Qinling Mountains, China.

This study analyzed conflict and postconflict (PC) conciliation between males and females within one-male breeding units in Sichuan snub-nosed monkeys (Rhinopithecus roxellana) in the Qinling Mountains, China. The PC matched-control and time rule methods were used to collect and analyze data recorded from September 2013 to June 2014. The conciliatory tendency among individuals following conflict was 82.07%, and affiliation occurred within a few minutes after the conflict, which was not significantly different between mating and nonmating seasons. The PC conciliation scenarios were different from those reported from captivity. Lumbar hold and grooming were the most common expressions in reconciliation. In addition, bystander affiliation was uniquely found, which may be associated with the more terrestrial locomotion of R. roxellana, compared with other colobines.

Combinatorial efficiency evaluation: the knapsack problem in data envelopment analysis.

The traditional data envelopment analysis (DEA) literatures generally concentrated on the efficiency evaluation of single decision making unit (DMU). However, in many practical problems, the decision makers are required to choose a number of DMUs instead of a single one from the DMUs set. Therefore, it is necessary to study the combinatorial efficiency evaluation problem which can be illustrated as a knapsack problem naturally. It is indicated that the basic model proposed by Cook and Green may have some drawbacks and a modified model, which is combined with the super efficiency model, is proposed in this paper. What is more, our proposed model is more persuasive to the decision makers because it is able to provide a unique best combination of DMUs. An adapted local search algorithm is developed as a solver of this problem. Finally, numerical examples are provided to examine the validity of our proposed model and the adapted local search algorithm.

Influence of human activities on the historical and current distribution of Sichuan snub-nosed monkeys in the Qinling Mountains, China.

Due to their rich animal diversity and the presence of rare and endemic species, the Qinling Mountains are listed as a significant global biodiversity area. The Sichuan snub-nosed monkey (Rhinopithecus roxellana) has been distributed in this area since the Middle Pleistocene. Due to the gradual encroachment of humans into their habitat, both the distribution range and population sizes of R. roxellana have significantly decreased. Based on literature research as well as field and questionnaires, we investigated the influence of human activities on R. roxellana distribution in the Qinling Mountains. Human activity within the habitat of R. roxellana began in the Stone and Bronze Ages, though initially it had no significant influence on its populations. When China entered the Iron Age, however, different historical and social periods had a considerable impact on R. roxellana distribution. Although national and provincial level governments introduced strict protection policies with the establishment of the People's Republic of China in 1949, human activities continued to influence R. roxellana distribution. Since the launch of the Natural Forest Protection Project across the Qinling Mountains in 1999, the quality of R. roxellana habitat has shown marked improvement. This research will help promote the survival and conservation of the Sichuan snub-nosed monkey in the Qinling Mountains.

Dynamic foraging strategy adaptation to heterogeneous environments contributes to social aggregation in snub-nosed monkeys.

The dynamics of animal social structures are heavily influenced by environmental patterns of competition and cooperation. In folivorous colobine primates, prevailing theories suggest that larger group sizes should be favored in rainforests with a year-round abundance of food, thereby reducing feeding competition. Yet, paradoxically, larger groups are frequently found in high-altitude or high-latitude montane ecosystems characterized by a seasonal scarcity of leaves. This contradiction is posited to arise from cooperative benefits in heterogeneous environments. To investigate this hypothesis, we carried out a six-year field study on two neighboring groups of golden snub-nosed monkey ( Rhinopithecus roxellana), a species representing the northernmost distribution of colobine primates. Results showed that the groups adjusted their movement and habitat selection in response to fluctuating climates and spatiotemporal variability of resources, indicative of a dynamic foraging strategy. Notably, during the cold, resource-scarce conditions in winter, the large group occupied food-rich habitats but did not exhibit significantly longer daily travel distances than the smaller neighboring group. Subsequently, we compiled an eco-behavioral dataset of 52 colobine species to explore their evolutionary trajectories. Analysis of this dataset suggested that the increase in group size may have evolved via home range expansion in response to the cold and heterogeneous climates found at higher altitudes or latitudes. Hence, we developed a multi-benefits framework to interpret the formation of larger groups by integrating environmental heterogeneity. In cold and diverse environments, even smaller groups require larger home ranges to meet their dynamic survival needs. The spatiotemporal distribution of high-quality resources within these expanded home ranges facilitates more frequent interactions between groups, thereby encouraging social aggregation into larger groups. This process enhances the benefits of collaborative actions and reproductive opportunities, while simultaneously optimizing travel costs through a dynamic foraging strategy.

Eighty million years of rapid evolution of the primate Y chromosome.

The Y chromosome usually plays a critical role in determining male sex and comprises sequence classes that have experienced unique evolutionary trajectories. Here we generated 19 new primate sex chromosome assemblies, analysed them with 10 existing assemblies and report rapid evolution of the Y chromosome across primates. The pseudoautosomal boundary has shifted at least six times during primate evolution, leading to the formation of a Simiiformes-specific evolutionary stratum and to the independent start of young strata in Catarrhini and Platyrrhini. Different primate lineages experienced different rates of gene loss and structural and chromatin change on their Y chromosomes. Selection on several Y-linked genes has contributed to the evolution of male developmental traits across the primates. Additionally, lineage-specific expansions of ampliconic regions have further increased the diversification of the structure and gene composition of the Y chromosome. Overall, our comprehensive analysis has broadened our knowledge of the evolution of the primate Y chromosome.

Adaptations to a cold climate promoted social evolution in Asian colobine primates.

The biological mechanisms that underpin primate social evolution remain poorly understood. Asian colobines display a range of social organizations, which makes them good models for investigating social evolution. By integrating ecological, geological, fossil, behavioral, and genomic analyses, we found that colobine primates that inhabit colder environments tend to live in larger, more complex groups. Specifically, glacial periods during the past 6 million years promoted the selection of genes involved in cold-related energy metabolism and neurohormonal regulation. More-efficient dopamine and oxytocin pathways developed in odd-nosed monkeys, which may have favored the prolongation of maternal care and lactation, increasing infant survival in cold environments. These adaptive changes appear to have strengthened interindividual affiliation, increased male-male tolerance, and facilitated the stepwise aggregation from independent one-male groups to large multilevel societies.

Comparative genomics reveals the hybrid origin of a macaque group.

Although species can arise through hybridization, compelling evidence for hybrid speciation has been reported only rarely in animals. Here, we present phylogenomic analyses on genomes from 12 macaque species and show that the fascicularis group originated from an ancient hybridization between the sinica and silenus groups ~3.45 to 3.56 million years ago. The X chromosomes and low-recombination regions exhibited equal contributions from each parental lineage, suggesting that they were less affected by subsequent backcrossing and hence could have played an important role in maintaining hybrid integrity. We identified many reproduction-associated genes that could have contributed to the development of the mixed sexual phenotypes characteristic of the fascicularis group. The phylogeny within the silenus group was also resolved, and functional experimentation confirmed that all extant Western silenus species are susceptible to HIV-1 infection. Our study provides novel insights into macaque evolution and reveals a hybrid speciation event that has occurred only very rarely in primates.

Phylogenomic analyses provide insights into primate evolution.

Comparative analysis of primate genomes within a phylogenetic context is essential for understanding the evolution of human genetic architecture and primate diversity. We present such a study of 50 primate species spanning 38 genera and 14 families, including 27 genomes first reported here, with many from previously less well represented groups, the New World monkeys and the Strepsirrhini. Our analyses reveal heterogeneous rates of genomic rearrangement and gene evolution across primate lineages. Thousands of genes under positive selection in different lineages play roles in the nervous, skeletal, and digestive systems and may have contributed to primate innovations and adaptations. Our study reveals that many key genomic innovations occurred in the Simiiformes ancestral node and may have had an impact on the adaptive radiation of the Simiiformes and human evolution.

Serum interleukin-33 levels in patients with gastric cancer.

BACKGROUND: Interleukin-33 (IL-33) is a novel member of the IL-1 family of cytokines, and it is closely related to IL-18, one of the best characterized members of the IL-1 family. It's been demonstrated that elevated levels of IL-18 are involved in a wide variety of tumors, especially in gastric cancer. AIMS: The purpose of this study was to determine the correlations between serum IL-33 levels and the clinicopathologic features in gastric cancer patients. METHODS: Serum samples were collected from 68 patients with gastric cancer and 57 controls. Serum IL-33 levels were measured by ELISA. Classical tumor markers of CEA and CA19-9 levels were routinely detected by chemiluminescence immunoassay. Western blot analysis was used to detect IL-33 expression in gastric cancer tissue samples and cell lines. The relationship between serum levels of IL-33 and clinical characteristics in patients was analyzed. RESULTS: IL-33 levels in the serum of gastric cancer patients were significantly elevated in comparison with that of healthy volunteers. Furthermore, higher serum levels of IL-33 in gastric cancer patients were found to correlate with several poor prognostic factors like depth of invasion, distant metastasis and advanced stage (stage III/IV). On the other hand, serum IL-33 levels did not correlate with CEA and CA19-9. The expression of IL-33 protein was upregulated in carcinoma tissues in comparison with matched normal tissues, and no statistically significant difference was found between the four gastric cancer cell lines and human gastric epithelial cell line GES-1. CONCLUSIONS: Serum IL-33 may be a useful biomarker for predicting the prognosis of gastric cancer.

Sexual interference in the Golden snub-nosed monkey (Rhinopithecus roxellana): a test of the sexual competition hypothesis in a polygynous species.

Sexual interference (SI), which is defined as any disturbance directed to a mating pair by other individuals, has been reported in several primate species. It is widely suggested that successful harassers experience improved mating success by increasing their access to reproductive partners as well as by reducing the mating success of rivals. Although theories of primate sexual conflict highlight male intra-sexual mating competition, females also are reported to actively disrupt copulations between mating partners. In this study, we investigated SI in a multilevel troop of Golden snub-nosed monkeys (Rhinopithecus roxellana) inhabiting the Qinling Mountains, China. Behavioral observations of 11 one-male units (OMU) that comprised the multilevel troop were conducted from September 2007 to May 2008. During this period 17.1% of 652 documented intra-OMU sexual encounters were characterized either by mild or aggressive forms of harassment. Sexual harassment was typically performed by a single individual (91.9%), and in 75.7% of cases the harasser was an adult or sub-adult female. The frequency of female harassment was positively correlated with the number of adult and sub-adult females residing in an OMU, and resulted in a significant decrease in matings ending in ejaculation. We found that the amount of SI a female received was not a significant predictor of her reproductive success. However, females who conceived during the mating season directed higher levels of harassment at other females than females who did not conceive. We evaluate the strength of the sexual competition hypothesis and the hormonally modulated aggression hypothesis in explaining patterns of SI in female Golden snub-nosed monkeys.

Response to first-line treatment predicts progression-free survival benefit of small-cell lung cancer patients treated with anlotinib.

BACKGROUND: Anlotinib significantly extended progression-free survival (PFS) and overall survival (OS) in small-cell lung cancer (SCLC) as third or later line treatment. METHODS: In this study, we retrospectively analyzed the efficacy and safety of anlotinib in the clinical practice and aimed to identify risk factors for predicting the clinical benefit of anlotinib in SCLC patients. 29 SCLC patients treated with anlotinib monotherapy or combination therapy as second or later line treatment were included. PFS, OS, objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were analyzed. RESULTS: In whole patients, the median PFS was 2.1 months (95% confidence interval (CI): 1.1-3.2 months); The ORR and DCR were 10.3% and 48.3%, respectively; The median OS was 7.2 months (95%CI: 3.2-11.2 months). Cox regression analysis demonstrated that response to first-line treatment was the independent risk factor for PFS. The ORR (20.0% vs. 0%) and DCR (53.3% vs. 42.9%) were promoted in patients treated with anlotinib combination therapy comparing to anlotinib monotherapy. The most common AEs were hoarseness, fatigue, decreased appetite, oral mucositis, and anemia. No treatment-related AEs graded 3 or more. CONCLUSION: Anlotinib is an effective option for SCLC patients with tolerable toxicity as second or later line treatment. Patients sensitive to first-line treatment had longer PFS when treated with anlotinib. Anloitnib combined with other therapy increased the efficacy without adding toxicity.