Continuous motion of particles attached to cavitation bubbles.

Microbubble-mediated therapeutic gene or drug delivery is a promising strategy for various cardiovascular diseases (CVDs), but the efficiency and precision need to be improved. Here, we propose a cavitation bubble-driven drug delivery strategy that can be applied to CVDs. A bubble-pulse-driving theory was proposed, and the formula of time-averaged thrust driven by bubble pulses was derived. The continuous motion of particles propelled by cavitation bubbles in the ultrasonic field is investigated experimentally by high-speed photography. The cavitation bubbles grow and collapse continuously, and generate periodic pulse thrust to drive the particles to move in the liquid. Particles attached to bubbles will move in various ways, such as ejection, collision, translation, rotation, attitude variation, and circular motion. The cavity attached to the particle is a relatively large cavitation bubble, which does not collapse to the particle surface, but to the axis of the bubble perpendicular to the particle surface. The cavitation bubble expands spherically and collapses asymmetrically, which makes the push on the particle generated by the bubble expansion greater than the pull on the particle generated by the bubble collapse. The time-averaged force of the cavitation bubble during its growth and collapse is the cavitation-bubble-driven force that propels the particle. Both the cavitation-bubble-driven force and the primary Bjerknes force act in the same position on the particle surface, but in different directions. In addition to the above two forces, particles are also affected by the mass force acting on the center of mass and the motion resistance acting on the surface, so the complex motion of particles can be explained.

The crucial role of age and site in incidence and prognosis of female neuroendocrine neoplasms in the United States: a population-based study from 2000 to 2018.

BACKGROUND: As the incidence continues to rise, global concern about neuroendocrine neoplasms (NENs) is mounting. However, little is known about how NENs affect women patients. METHODS: The annual percentage change (APC) was calculated to describe the incidence. Cox proportional hazards multivariable regression was used to identify risk factors. The nomograms were employed to estimate prognosis. RESULTS: A total of 39,237 female NENs (fNENs) cases were identified. The incidence of fNENs increased annually (APC = 4.5, 95% CI 4.1-4.8, P < 0.05), and the incidence pattern and survival outcomes showed age and site-specificity. Appendiceal, rectal, and pulmonary fNENs were major contributors to the incidence of patients younger than 40, between 40-59, and over 60 years old, respectively. The Cox proportional hazards regression model revealed that age, tumor size, grade, stage, and primary sites were closely related to survival. The worst survival outcomes appeared in breast, reproductive system, and liver fNENs for patients under 40, between 40-49, and over 50 years old, respectively. A nomogram based on these developed with higher predictive accuracy of prognosis, with a C index of 0.906 in the training cohort and 0.901 in the validation cohort. CONCLUSIONS: Our findings revealed distinct site-specific tendencies in the incidence and survival patterns among fNEN patients across various age groups. Thus, reasonable patient screening and stratification strategies should be implemented, especially for young patients.

Design, Synthesis, and Mode of Action of Thioacetamide Derivatives as the Algicide Candidate Based on Active Substructure Splicing Strategy.

Lakes and reservoirs worldwide are experiencing a growing problem with harmful cyanobacterial blooms (HCBs), which have significant implications for ecosystem health and water quality. Algaecide is an effective way to control HCBs effectively. In this study, we applied an active substructure splicing strategy for rapid discovery of algicides. Through this strategy, we first optimized the structure of the lead compound S5, designed and synthesized three series of thioacetamide derivatives (series A, B, C), and then evaluated their algicidal activities. Finally, compound A3 with excellent performance was found, which accelerated the process of discovering and developing new algicides. The biological activity assay data showed that A3 had a significant inhibitory effect on M. aeruginosa. FACHB905 (EC50 = 0.46 µM) and Synechocystis sp. PCC6803 (EC50 = 0.95 µM), which was better than the commercial algicide prometryn (M. aeruginosa. FACHB905, EC50 = 6.52 µM; Synechocystis sp. PCC6803, EC50 = 4.64 µM) as well as better than lead compound S5 (M. aeruginosa. FACHB905, EC50 = 8.80 µM; Synechocystis sp. PCC6803, EC50 = 7.70 µM). The relationship between the surface electrostatic potential, chemical reactivity, and global electrophilicity of the compounds and their activities was discussed by density functional theory (DFT). Physiological and biochemical studies have shown that A3 might affect the photosynthesis pathway and antioxidant system in cyanobacteria, resulting in the morphological changes of cyanobacterial cells. Our work demonstrated that A3 might be a promising candidate for the development of novel algicides and provided a new active skeleton for the development of subsequent chemical algicides.

Evolving landscape of treatments targeting the microenvironment of liver metastases in non-small cell lung cancer.

ABSTRACT: Liver metastases (LMs) are common in lung cancer. Despite substantial advances in diagnosis and treatment, the survival rate of patients with LM remains low as the immune-suppressive microenvironment of the liver allows tumor cells to evade the immune system. The impact of LMs on the outcomes of immune checkpoint inhibitors in patients with solid tumors has been the main focus of recent translational and clinical research. Growing evidence indicates that the hepatic microenvironment delivers paracrine and autocrine signals from non-parenchymal and parenchymal cells. Overall, these microenvironments create pre- and post-metastatic conditions for the progression of LMs. Herein, we reviewed the epidemiology, physiology, pathology and immunology, of LMs associated with non-small cell lung cancer and the role and potential targets of the liver microenvironment in LM in each phase of metastasis. Additionally, we reviewed the current treatment strategies and challenges that should be overcome in preclinical and clinical investigations. These approaches target liver elements as the basis for future clinical trials, including combinatorial interventions reported to resolve hepatic immune suppression, such as immunotherapy plus chemotherapy, immunotherapy plus radiotherapy, immunotherapy plus anti-angiogenesis therapy, and surgical resection.

Radioiodine-refractory differentiated thyroid cancer: Molecular mechanisms and therapeutic strategies for radioiodine resistance.

Radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) is difficult to treat with radioactive iodine because of the absence of the sodium iodide transporter in the basement membrane of thyroid follicular cells for iodine uptake. This is usually due to the mutation or rearrangement of genes and the aberrant activation of signal pathways, which result in abnormal expression of thyroid-specific genes, leading to resistance of differentiated thyroid cancer cells to radioiodine therapy. Therefore, inhibiting the proliferation and growth of RAIR-DTC with multikinase inhibitors and other drugs or restoring its differentiation and then carrying out radioiodine therapy have become the first-line treatment strategies and main research directions. The drugs that regulate these kinases or signaling pathways have been studied in clinical and preclinical settings. In this review, we summarized the major gene mutations, gene rearrangements and abnormal activation of signaling pathways that led to radioiodine resistance of RAIR-DTC, as well as the medicine that have been tested in clinical and preclinical trials.

Repression of LSD1 potentiates homologous recombination-proficient ovarian cancer to PARP inhibitors through down-regulation of BRCA1/2 and RAD51.

Poly (ADP-ribose) polymerase inhibitors (PARPi) are selectively active in ovarian cancer (OC) with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1/2 and other DNA repair pathway members. We sought molecular targeted therapy that induce HRD in HR-proficient cells to induce synthetic lethality with PARPi and extend the utility of PARPi. Here, we demonstrate that lysine-specific demethylase 1 (LSD1) is an important regulator for OC. Importantly, genetic depletion or pharmacological inhibition of LSD1 induces HRD and sensitizes HR-proficient OC cells to PARPi in vitro and in multiple in vivo models. Mechanistically, LSD1 inhibition directly impairs transcription of BRCA1/2 and RAD51, three genes essential for HR, dependently of its canonical demethylase function. Collectively, our work indicates combination with LSD1 inhibitor could greatly expand the utility of PARPi to patients with HR-proficient tumor, warranting assessment in human clinical trials.

QTL analysis of traits related to seed size and shape in sesame (Sesamum indicum L.).

Seed size and shape are important traits that determine seed yield in sesame. Understanding the genetic basis of seed size and shape is essential for improving the yield of sesame. In this study, F2 and BC1 populations were developed by crossing the Yuzhi 4 and Bengal small-seed (BS) lines for detecting the quantitative trait loci (QTLs) of traits related to seed size and shape. A total of 52 QTLs, including 13 in F2 and 39 in BC1 populations, for seed length (SL), seed width (SW), and length to width ratio (L/W) were identified, explaining phenotypic variations from 3.68 to 21.64%. Of these QTLs, nine stable major QTLs were identified in the two populations. Notably, three major QTLs qSL-LG3-2, qSW-LG3-2, and qSW-LG3-F2 that accounted for 4.94-16.34% of the phenotypic variations were co-localized in a 2.08 Mb interval on chromosome 1 (chr1) with 279 candidate genes. Three stable major QTLs qSL-LG6-2, qLW-LG6, and qLW-LG6-F2 that explained 8.14-33.74% of the phenotypic variations were co-localized in a 3.27 Mb region on chr9 with 398 candidate genes. In addition, the stable major QTL qSL-LG5 was co-localized with minor QTLs qLW-LG5-3 and qSW-LG5 to a 1.82 Mb region on chr3 with 195 candidate genes. Gene annotation, orthologous gene analysis, and sequence analysis indicated that three genes are likely involved in sesame seed development. These results obtained herein provide valuable in-formation for functional gene cloning and improving the seed yield of sesame.

Efficacy and safety of reduced-dose chemotherapy plus immunotherapy in patients with lung squamous cell carcinoma: A real-world observational study.

BACKGROUND: Recently, chemotherapy plus immunotherapy has achieved remarkable efficacy in lung squamous cell carcinoma (LUSC). However, some patients, especially frail people, cannot tolerate full-dose chemotherapy in the real world. To reduce toxicity, appropriate dose reduction in chemotherapy is necessary. Therefore, this study aimed to demonstrate the efficacy and safety of reduced-dose chemotherapy plus immunotherapy in LUSC patients in the real world. METHODS: A real-world observational study was conducted concerning patients who received chemotherapy plus immunotherapy in our situation. The primary endpoints were objective response rate (ORR) and disease control rate (DCR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: Between December 2018 and January 2022, 110 patients were enrolled, of whom 54 patients were chemotherapy reduced-dose group and 56 patients were chemotherapy standard-dose group. The ORR in the reduced-dose group is similar to standard-dose group (85.19% vs. 71.43%, p = 0.082). Similar DCR were observed (100% vs. 94.64%, p = 0.086). Median PFS was 12 months in the reduced-dose group and standard-dose group, respectively. Median OS was 15 months and 16 months in the reduced-dose group and standard-dose group, respectively. We reported a lower incidence of grade 3-4 toxicity in the reduced-dose group compared with standard-dose group (27.78% vs. 42.86%, p = 0.100). The major toxic reactions were better alleviated in the reduced-dose group than in the standard-dose group, especially in the thrombocytopenia (p = 0.044), peripheral nerve damage (p = 0.001), gastrointestinal reactions (p < 0.0001), and fatigue (p = 0.001). CONCLUSIONS: The modified regimen with attenuated doses of chemotherapy in combination with immunotherapy was effective and well tolerated in patients with LUSC. The efficacy of this modified regimen is similar to that of the full-dose regimen.

Experimental study on damage mechanism of blood vessel by cavitation bubbles.

Ultrasound-induced cavitation in blood vessels is a common scenario in medical procedures. This paper focuses on understanding the mechanism of microscopic damage to vessel walls caused by the evolution of cavitation bubbles within the vessels. In this study, cavitation bubbles were generated using the low-voltage discharge method in 0.9% sodium chloride saline, and vessel models with wall thicknesses ranging from 0.7 mm to 2 mm were made using a 3D laminating process. The interaction between cavitation bubbles and vessel models with different wall thicknesses was observed using a combination of high-speed photography. Results show that cavitation bubble morphology and collapse time increased and then stabilized as the vessel wall thickness increased. When the cavitation bubble was located in vessel axial line, pair of opposing micro-jets were formed along the axis of the vessel, and the peak of micro-jet velocity decreased with increasing wall thickness. However, when the cavitation bubble deviated from the vessel model center, no micro-jet towards the vessel model wall was observed. Further analysis of the vessel wall deformation under varying distances from the cavitation bubble to the vessel wall revealed that the magnitude of vessel wall stretch due to the cavitation bubble expansion was greater than that of the contraction. A comparative analysis of the interaction of between the cavitation bubble and different forms of elastic membranes showed that the oscillation period of the cavitation bubble under the influence of elastic vessel model was lower than the elastic membrane. Furthermore, the degree of deformation of elastic vessel models under the expansion of the cavitation bubble was smaller than that of elastic membranes, whereas the degree of deformation of elastic vessel models in the contraction phase of the cavitation bubble was larger than that of elastic membranes. These new findings provide important theoretical insights into the microscopic mechanisms of blood vessel potential damage caused by ultrasound-induced cavitation bubble, as well as cavitation in pipelines in hydrodynamic systems.

(+)-/(-)-Rutabenzofuran A and (+)-/(-)- Rutabenzofuran B: Two unprecedented pairs of Z/E isomeric benzofuran enantiomers from the aerial part of Ruta graveolens L.

Two pairs of Z/E isomeric benzofuran enantiomers possessing unprecedented carbon skeletons featuring ring cleavage and addition reactions in the α-pyrone ring of furocoumarin, named rutabenzofuran A [(+)-1 and (-)-1], and rutabenzofuran B [(+)-2 and (-)-2], respectively, were isolated as minor compounds from the water extract of the aerial part of Ruta graveolens L. Their structures were determined by extensive spectroscopic data analysis. The absolute configurations were assigned by comparing the optical rotation with previous research and the experimental circular dichroism (CD) spectra with the calculated electronic CD (ECD) spectra. (-)-1, (+)-2, and (-)-2 were evaluated for antibacterial, anticoagulant, anticancer, and acetylcholinesterase (AChE) inhibitory activities. No anticancer or anticoagulant activities were observed, yet (-)-2 exhibited weak antibacterial activity against Salmonella enterica subsp. Enterica. At the same time, (-)-1, (+)-2, and (-)-2 displayed weak inhibitory activity on AChE.

Sleeve gastrectomy improved microvascular phenotypes from obesity cohort, detected with optical coherence tomography angiography.

AIMS: To examine how metabolic status is associated with microvascular phenotype and to identify variables associated with vascular remodeling after bariatric surgery, using noninvasive optical coherence tomography angiography (OCTA). METHODS: The study included 136 obese subjects scheduled for bariatric surgery and 52 normal-weight controls. Patients with obesity were divided into metabolically healthy obesity (MHO) and metabolic syndrome (MetS) groups according to the diagnosis criteria of the Chinese Diabetes Society. Retinal microvascular parameters were measured by OCTA, including superficial capillary plexus (SCP) and deep capillary plexus (DCP) vessel densities. Follow-ups were performed at the baseline and 6 months after bariatric surgery. RESULTS: Fovea SCP, average DCP, fovea DCP, parafovea DCP, and perifovea DCP vessel densities were significantly lower in the MetS group, compared to controls (19.91% vs. 22.49%, 51.60% vs. 54.20%, 36.64% vs. 39.14%, 56.24% vs. 57.65% and 52.59% vs. 55.58%, respectively, all p < .05). Parafovea SCP, average DCP, parafovea DCP, and perifovea DCP vessel densities significantly improved in patients with obesity 6 months after surgery, compared to baseline (54.21% vs. 52.97%, 54.43% vs. 50.95%, 58.29% vs. 55.54% and 55.76% vs. 51.82%, respectively, all p < .05). Multivariable analyses showed that baseline blood pressure and insulin were independent predictors of vessel density changes 6 months after surgery. CONCLUSIONS: Retinal microvascular impairment occurred mainly in MetS rather than MHO patients. Retinal microvascular phenotype improved 6 months after bariatric surgery and baseline blood pressure and insulin status may be key determinants. OCTA may be a reliable method to evaluate the microvascular complications associated with obesity.

Genetic mapping of QTLs controlling brown seed coat traits by genome resequencing in sesame (Sesamum indicum L.).

Introduction: Sesame seeds have become an irreplaceable source of edible oils and food products with rich nutrients and a unique flavor, and their metabolite contents and physiological functions vary widely across different seed coat colors. Although the quantitative trait loci (QTLs) for genetic variation in seed coat color have been extensively investigated, the identification of unique genetic loci for intermediate colors such as brown has not been reported due to their complexity. Methods: Here, we crossed the white sesame 'Yuzhi No. 8' (YZ8) and the brown sesame 'Yanzhou Erhongpi' (YZEHP) to construct a recombinant inbred line (RIL) population with consecutive self-fertilization for ten generations. Results: The selfed F1 seeds were brown which was controlled by a dominant gene. Based on the genotyping by whole-genome resequencing of the RILs, a major-effect QTL for brown coat color was identified through both bulk segregant analysis (BSA) and genetic linkage mapping in sesame, which was located within a 1.19 Mb interval on chromosome 6 (qBSCchr6). Moreover, we found that the YZEHP seed coat initially became pigmented at 20 days post-anthesis (DPA) and was substantially colored at 30 DPA. We screened 13 possible candidate genes based on the effects of genetic variants on protein coding and predicted gene functions. Furthermore, qRT‒PCR was used to verify the expression patterns of these genes in different post-anthesis developmental periods. We noted that in comparison to YZ8 seeds, YZEHP seeds had expression of SIN_1023239 that was significantly up-regulated 2.5-, 9.41-, 6.0-, and 5.9-fold at 15, 20, 25, and 30 DPA, respectively, which was consistent with the pattern of brown seed coat pigment accumulation. Discussion: This study identified the first major-effect QTL for the control of the brown seed coat trait in sesame. This finding lays the foundation for further fine mapping and cloning as well as investigating the regulatory mechanism of seed coat color in sesame.

Surgical strategies for recurrent parastomal hernia after a primary repair with a Dynamesh® IPST mesh.

PURPOSE: To introduce our surgical strategies for recurrent parastomal hernia after a primary repair with a Dynamesh® IPST mesh. METHODS: Ten patients who underwent recurrent parastomal hernia repair with previous Dynamesh® IPST mesh use were analyzed retrospectively. Distinct surgery strategies were applied. Accordingly, we investigated the recurrence rate and postoperative complications in these patients, who were followed for an average of 35.9 months after surgery. RESULTS: There was no recorded death and no readmission during the 30-day postoperative period. And the lap-re-do Sugarbaker group had no recurrence, whereas the open suture group had one recurrence (16.7%). One patient in the Sugarbaker group developed ileus and recovered conservatively during the follow-up period. There were no other complications, including seroma, mesh infection and bulging, or prolonged postoperative pain. CONCLUSIONS: We offer two predominant surgery strategies for recurrent parastomal hernia with a previous Dynamesh® IPST mesh usage, the open suture repair, and the Lap-re-do Sugarbaker repair. Even though the results of the Lap-re-do Sugarbaker repair are satisfactory, we recommend the open suture technique as it is safer in a setting of dense adhesions in recurrent parastomal hernias.

Au nanoparticles-anchored defective metal-organic frameworks for photocatalytic transformation of amines to imines under visible light.

Designing efficient metal organic frameworks (MOF)-based photocatalysts has recently attracted wide attention. In this work, Au nanoparticles(NPs)-decorated defective DUT-67(Zr) (Au@DUT-67(Zr)) with enlarged channels was successfully fabricated and achieved 7.5 times higher conversion than Au NPs-decorated UiO-66(Zr) (Au@UiO-66(Zr)) for photocatalytic selective oxidation of amines to imines driven by visible light. Au NPs are more effectively fixed on DUT-67(Zr) due to its partially hollow structure. Au@DUT-67(Zr) possesses more active sites including unsaturated Zr atoms and oxygen vacancies (VO) than Au@UiO-66(Zr). In situ Fourier transform infrared (FTIR) spectrum reveals that benzylamine is activated on unsaturated Zr sites via HN…Zr species, facilitating deprotonation of -CH2 in benzylamine. VO can not only adsorb and activate oxygen (O2) but also capture plasmonic hot electrons, enhancing the forming of superoxide radical (O2-). Plasmonic hot holes assisted with O2- effectively achieve the selective oxidation of benzylamine. Finally, a possible synergetic mechanism combining the plasmon with the molecular activation is presented to illustrate the photocatalytic pathway at the molecular level.

[Effect of electroacupuncture regulating NLRP3/Caspase-1 pathway on pyroptosis of dopaminergic neurons in rats with Parkinson's disease].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on the pyrolysis of dopaminergic neurons in rats with Parkinson's disease (PD), so as to explore its underlying molecular mechanism. METHODS: Male SD rats were randomly divided into the sham operation, model, EA, MCC950 and EA+MCC950 groups, with 12 rats in each group. The PD rat model was established by two-point injection of 6-OHDA. Rats in the MCC950 group were injected with MCC950 at the dose of 10 mg/kg, once a day; for rats of EA group, EA was applied to "Taichong" (LR3) and "Fengfu"(GV16) for 30 min, once a day; rats in the EA+ MCC950 group were given MCC950 injection and EA once a day. All above interventions were performed for 2 weeks. After the intervention, the behavioral changes of rats were observed using rotating induction experiment, rotating rod experiment and open field experiment; the positive expressions of dopaminergic neuronal markers tyrosine hydroxylase (TH) and α-Synuclein (α-Syn) in substantia nigra striatum were detected by immunohistochemistry; the damage of dopaminergic neurons in substantia nigra striatum was observed after HE staining; immunopositive coexpression of brain nucleotide-binding oligomerization domain like receptor protein 3 (NLRP3), Caspase-1 and ionized calcium binding adapter1 (Iba-1) were detected by immunofluorescence double staining; the levels of interleukin (IL)-1ß and IL-18 in brain tissues were detected by ELISA; the protein expression levels of NLRP3, Cleaved Caspase-1 and apoptosis-associated speck-like protein containing a CARD (ASC) in the substantia nigra striatum were detected by Western blot. RESULTS: Compared with the sham operation group, the number of rotations of rotating induction experiment, the residence time in the central area of open field experiment, the positive expression of α-Syn, the positive co-expressions of NLRP3/Iba-1 and Caspase-1/Iba-1, the contents of IL-1ß and IL-18 in brain tissues, and the protein expression levels of NLRP3, ASC and Cleaved Caspase-1 in substantia nigra striatum were significantly increased (P<0.05), while the drop latency of rotating rod experiment, the rearing times and the total distance of open field experiment, and the positive expression of TH in substantia nigra striatum were significantly decreased (P<0.05) in the model group. Compared with the model group, the above mentioned markers were reversed in EA, MCC950 and EA+MCC950 groups (P<0.05), and the improvement of the EA+MCC950 group was more obvious than those of the MCC950 and EA groups. In the model group, the neurons were disorderly arranged, the number of neurons was reduced, the cytoplasm was swollen, and some of them were vacuolar degeneration; while the degree of neuronal arrangement disorder, cytoplasmic swelling and the vacuolar degeneration were reduced in varying degrees in the MCC950, EA and EA+MCC950 groups. CONCLUSION: The ameliorative effect of EA on dopaminergic neuron damage in PD rats may be related to its effects in inhibiting NLRP3/Caspase-1 mediated neuronal pyrosis.

Classical ALK G1202R resistance mutation was identified in a lung adenocarcinoma patient with rare LOC388942-ALK fusion after sequential treatment with ALK-TKIs and anlotinib: a case report.

Background: Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) is a heterogeneous disease. To date, more than ninety ALK fusions in lung cancer have been found. Here, we report for the first time a rare LOC388942-ALK fusion in NSCLC was sensitive to crizotinib but resistant to the sequential ceritinib and alectinib and acquired classical ALK G1202R resistance mutation after long-term treatment with anlotinib. This case highlights dynamic monitoring of gene alteration using next-generation sequencing (NGS) is necessary during the anti-tumor process. Case Description: A 55-year-old male, with no history of smoking history and no family history of cancer, was found malignant pleural effusion and multiple metastasis nodules in the left lung. He was histopathologically diagnosed with ALK-positive cT4N0M1a adenocarcinoma in June 2016. NGS of the tumor identified a rare LOC388942-ALK fusion (L intergenic: A 20, 1.41%). Then, the patient was treated with chemotherapy, crizotinib, ceritinib, alectinib, and anlotinib sequentially. The patient achieved partial response (PR) to chemotherapy and crizotinib. No evidence of a secondary resistant molecular event was found after resistance to crizotinib, ceritinib, or Alectinib. After 8 months of alectinib treatment, the tumor gradually enlarged again. Anlotinib was followed for 13 months. Thirteen months later, new lesions in the lower lobe of the right lung appeared and increased gradually, indicating definite progression of the tumor. Classical ALK G1202R resistance mutations was detected using cfDNA NGS. The patient refused to receive lorlatinib targeting G1202R resistance mutations and continued with anlotinib. He dead in August 2022, achieving 5-year overall survival (OS). Conclusions: Distinct ALK fusions in NSCLC have different cancer biology, leading to different response to ALK tyrosine kinase inhibitors (ALK-TKIs), even developed different resistance mechanism. Reporting the clinical details of rare ALK fusions in NSCLC is necessary to guide the treatment for clinicians and researchers.

Locally advanced undifferentiated small round cell sarcoma of the lung with novel SDCCAG8-AKT3 fusion and type II tumor immunity in the microenvironment: a rare case report.

Background: Despite significant recent advances in characterizing the molecular pathogenesis of undifferentiated small round cell sarcoma (USRCS), rare cases without reported gene alterations remain unclassified. To date, the efficacy and prognostic biomarker of immunotherapy in the treatment of unresectable USRCS has not been demonstrated, especially when these cases occurring in uncommon thoracic visceral organs with a novel gene fusion. Case Description: We report a case of locally advanced and unresectable USRCS of the lung (cT4N1M0) with SDCCAG8-AKT3 fusion identified by RNA-based next-generation sequencing (NGS). He initially admitted to our hospital chiefly complained of cough and dyspnea without any intervention. Imaging examinations, positron emission tomography/computed tomography (PET/CT), tumor biopsy, and a series of molecular tests based on tumor specimens were conducted for diagnosis. The molecular tests supplied more information delineating the case's molecular characteristics including PMS2 mutation, CD274 amplification, high tumor mutational burden (TMB-H), and high microsatellite instability (MSI-H). Multiple immunofluorescence (mIF) staining further revealed a specific immune-microenvironment phenotype with a 100% programmed death ligand 1 (PD-L1) expression and type II tumor immunity in the microenvironment (type II TIME) of this case. This 31-year-old non-smoking male received vincristine sulfate, dactinomycin, and cyclophosphamide (VAC) regimen chemotherapy combined with pembrolizumab and sequential radiotherapy. He had maintained a partial response (PR) according to response evaluation criteria in solid tumors (RECIST) 1.1 and a good quality of life for almost 14 months except for mild loss of appetite and hair loss after chemotherapy to the latest follow-up date. Conclusions: Our study showed a rare case of lung USRCS harboring a novel SDCCAG8-AKT3 fusion. And we indicated that a comprehensive treatment including the combination of systemic VAC chemotherapy and anti-programmed cell death protein 1 (PD-1) immunotherapy, and sequential radiotherapy could be considered for similar cases, prophylactic managements of chemotherapy-related myelosuppression and urotoxicity should be administrated along with chemotherapy as well. Tumor immune microenvironment analysis and gene sequencing are recommended to obtain more prognostic biomarkers in addition to routine pathologic examinations in diagnosis and treatment of USRCS.