Cerebral organoid and mouse models reveal a RAB39b-PI3K-mTOR pathway-dependent dysregulation of cortical development leading to macrocephaly/autism phenotypes.

Dysregulation of early neurodevelopment is implicated in macrocephaly/autism disorders. However, the mechanism underlying this dysregulation, particularly in human cells, remains poorly understood. Mutations in the small GTPase gene RAB39b are associated with X-linked macrocephaly, autism spectrum disorder (ASD), and intellectual disability. The in vivo roles of RAB39b in the brain remain unknown. We generated Rab39b knockout (KO) mice and found that they exhibited cortical neurogenesis impairment, macrocephaly, and hallmark ASD behaviors, which resembled patient phenotypes. We also produced mutant human cerebral organoids that were substantially enlarged due to the overproliferation and impaired differentiation of neural progenitor cells (NPCs), which resemble neurodevelopmental deficits in KO mice. Mechanistic studies reveal that RAB39b interacts with PI3K components and its deletion promotes PI3K-AKT-mTOR signaling in NPCs of mouse cortex and cerebral organoids. The mTOR activity is robustly enhanced in mutant outer radial glia cells (oRGs), a subtype of NPCs barely detectable in rodents but abundant in human brains. Inhibition of AKT signaling rescued enlarged organoid sizes and NPC overproliferation caused by RAB39b mutations. Therefore, RAB39b mutation promotes PI3K-AKT-mTOR activity and alters cortical neurogenesis, leading to macrocephaly and autistic-like behaviors. Our studies provide new insights into neurodevelopmental dysregulation and common pathways associated with ASD across species.

Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Clinical Significance of Serum CTRP3 Level in the Prediction of Cardiac and Intestinal Mucosal Barrier Dysfunction in Patients with Severe Acute Pancreatitis.

C1q/tumor necrosis factor-related protein 3 (CTRP3) has been demonstrated to play a protective role in mice with severe acute pancreatitis (SAP). However, its clinical significance in SAP remains unknown. This study was conducted to explore the clinical values of serum C1q/tumor necrosis factor-related protein 3 (CTRP3) level in the diagnosis of cardiac dysfunction (CD) and intestinal mucosal barrier dysfunction (IMBD) in SAP. Through RT-qPCR, we observed decreased CTRP3 level in the serum of SAP patients. Serum CTRP3 level was correlated with C-reactive protein, procalcitonin, creatine, modified computed tomography severity index score, and Acute Physiology and Chronic Health Evaluation II score. The receiver-operating characteristic curve revealed that CTRP3 serum level < 1.005 was conducive to SAP diagnosis with 72.55% sensitivity and 60.00% specificity, CTRP3 < 0.8400 was conducive to CD diagnosis with 80.49% sensitivity and specificity 65.57%, CTRP3 < 0.8900 was conducive to IMBD diagnosis with 94.87% sensitivity and 63.49% specificity, and CTRP3 < 0.6250 was conducive to the diagnosis of CD and IMBD co-existence with 65.22% sensitivity and 89.87% specificity. Generally, CTRP3 was downregulated in the serum of SAP patients and served as a candidate biomarker for the diagnosis of SAP and SAP-induced CD and IMBD.

Clinical Application of Tonsillectomy with Preservation of Capsule and Support Tissue.

Objective: The clinical effect of tonsillectomy with the preservation of tonsillar capsule and stent tissue and punctuated suture of tonsillar capsule and stent tissue was analyzed retrospectively. Methods: From January 2013 to January 2022, a total of 960 patients underwent tonsillectomy, consisting of 530 males and 430 females with ages ranging from 4 to 60 years (median age: 11 years). The capsule and scaffold tissues were preserved in all patients during the operation, and the surrounding mucosa, capsule, and scaffold tissues were sutured without tension. Indexes such as operation time, intraoperative blood loss, tonsillar white membrane, incidence of postoperative bleeding, postoperative pain score, and incidence of tonsillar remnant were recorded, and the school attendance of children (≤12 years old) was recorded. Results: The mucosal covering of tonsillar fossa healed well in all patients, and the sutures were completely removed at 4 weeks after reexamination. All patients were followed up for 1-8 years, and there was no residual hyperplasia or residual inflammation. Children under 12 years old could return to school 4 days after surgery without any postoperative complications. Conclusion: Tonsillectomy, preserving the tonsillar capsule and scaffold tissue followed by punctate suturing, offered several advantages: it resulted in less intraoperative blood loss and postoperative pain. Patients could resume a normal diet 6 hours after the surgery without an increased risk of complications. Moreover, it significantly reduced the risk of postoperative bleeding.

A novel fluffy PLGA/HA composite scaffold for bone defect repair.

Treatment of bone defects remains crucial challenge for successful bone healing, which arouses great interests in designing and fabricating ideal biomaterials. In this regard, the present study focuses on developing a novel fluffy scaffold of poly Lactide-co-glycolide (PLGA) composites with hydroxyapatite (HA) scaffold used in bone defect repair in rabbits. This fluffy PLGA/HA composite scaffold was fabricated by using multi-electro-spinning combined with biomineralization technology. In vitro analysis of human bone marrow mesenchymal stem cells (BMSCs) seeded onto fluffy PLGA/HA composite scaffold showed their ability to adhere, proliferate and cell viability. Transplant of fluffy PLGA/HA composite scaffold in a rabbit model showed a significant increase in mineralized tissue production compared to conventional and fluffy PLGA/HA composite scaffold. These findings are promising for fluffy PLGA/HA composite scaffolds used in bone defects.

A novel frameshift mutation of the endoglin(ENG) gene causes hereditary hemorrhagic telangiectasia in a Chinese family.

PURPOSE: Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited disorder that involves epistaxis, mucocutaneous telangiectases, and visceral arteriovenous malformations (AVMs). This study aims to investigate the genetic causes in a Chinese family with HHT. METHODS: HHT was confirmed according to Curaçao's diagnostic criteria. Three patients diagnosed with HHT and healthy members were recruited. Whole-exome sequencing (WES) and sanger sequencing were performed to define the patient's genetically pathogenic factor. RESULTS: The proband presented with recurrent epistaxis, hepatopulmonary arteriovenous malformation, and adenocarcinoma. A novel frameshift mutation (c.1376_1377delAC, p.H459Lfs*41) of the ENG gene was revealed in affected individuals by WES. There was no report of this variant and predicted to be highly damaging by causing truncation of the ENG protein. CONCLUSION: We report a novel variant in the ENG gene in Chinese that extends the mutational and phenotypic spectra of the ENG gene, and also demonstrates the feasibility of WES in the application of genetic diagnosis of HHT.

Ommaya Reservoir-Assisted Treatment for Giant Cystic Solid Craniopharyngioma in Children.

OBJECTIVE: In children with giant cystic solid craniopharyngioma (CP), the Ommaya reservoir was implanted in the CP cavity, and the cystic fluid was continuously drained for 5 days before the tumor resection. METHODS: An 11-year-old male patient was admitted to the hospital due to vision loss for 1 year, intermittent headache, vomiting for 6 months, and frequent urination for 2 months. Besides, magnetic resonance imaging of the head showed cystic solid lesions in the sellar region, suprasellar, and bilateral frontal lobes, with a size of 96.0×82.6×76.0 mm. Before the surgical resection, an Ommaya reservoir was implanted within the tumor cavity. The drainage was continued for 5 days and was 39 to 50 mL (43.80 ± 4.67 mL). Following the tumor shrank, a craniotomy was performed. RESULTS: Following surgical treatment, the CP was entirely removed. The child subsequently developed hypothyroidism and hypocortisolism, for which hormone replacement therapy was administered. No tumor recurrence was observed after 3 years of follow-up. CONCLUSION: The treatment of giant cystic solid CP in children is challenging. Preoperative implantation of the Ommaya reservoir, continuous drainage of cystic fluid, shrinkage of the tumor, and reduction of tumor tension are beneficial for tumor resection.

Diagnosis and Treatment of Sylvian Aqueduct Syndrome.

BACKGROUND: Sylvian aqueduct syndrome is a rare complication after ventriculoperitoneal (V-P) shunt surgery and is not easily diagnosed. METHODS: A 26-year-old male with obstructive hydrocephalus due to tectal glioma was treated with a V-P shunt surgery in another hospital. After the surgery, the patient developed an intractable disturbance of consciousness. When the V-P shunt pressure was raised or lowered, the patient's consciousness disorder still could not be improved. The patient was diagnosed with Sylvian aqueduct syndrome, a rare complication after V-P shunt operation. RESULTS: The paper clarifies the treatment experience with simultaneous endoscopic third ventriculostomy (ETV) and tectum gliomas biopsy, postoperative pathology suggestive of fibrillary astrocytoma; after surgery, the Sylvian aqueduct syndrome was cured and the patient recovered well. CONCLUSIONS: The preferred treatment for obstructive hydrocephalus caused by tumors in the Pineal region is the ETV operation. If an ETV operation and biopsy operation are performed simultaneously, more details need to be noted.

Bispectral Index Monitoring in the Nursing of Patients With Paroxysmal Sympathetic Hyperactivity.

AIM: To investigate the clinical nursing effect of bispectral index (BIS) monitoring for paroxysmal sympathetic hyperactivity (PSH) patients in the neurosurgical intensive care unit (NICU). METHODS: From January 2022 to June 2023, a total of 30 patients with PSH secondary to moderate to severe craniocerebral injury in the NICU were monitored for BIS. The patients' paroxysmal sympathetic hyperactivity-assessment measure (PSH-AM) scores were recorded. PSH patients generally appear in 3 states: calm state, seizure state, and postmedication state. Thirty PSH patients' BIS values were recorded during the calm period, during the seizure state, and postmedication state, and these 3 different stages' BIS values were divided into groups A, B, and C, using the Kruskal-Wallis H test to compare groups. RESULTS: The Kruskal-Wallis H test yielded a value of H=22.599, P <0.001. H0 was rejected against the test standard of α=0.05, and the BIS values of groups A, B, and C differed. The BIS values of group A and group B differed after a pairwise comparison, and the difference was statistically significant (adjusted P =0.001). Group B and group C had different BIS values, and the difference was statistically significant (adjusted P =0.001); group A and Group C had no difference in BIS values, and the difference was not statistically significant (adjusted P =1.00). CONCLUSIONS: Taking BIS value as the nursing observation index for PSH patients can make nursing work more objective, reasonable, and accurate, reduce the inducing factors of PSH attack, further reduce the attack of PSH, save nursing resources, and help guide the safety assessment of sedative use.

Report on Pseudoaneurysm Caused by Injury of Internal Carotid Artery During Endoscopic Pituitary Surgery and Rebleeding After Treatment With Willis Covered Stent.

OBJECTIVE: Report on a case of pseudoaneurysm which was caused by injury of the internal carotid artery (ICA) during endoscopic endonasal surgery (EES), which was followed by rebleeding after treatment with a Willis covered stent. METHODS: A woman, aged 68, underwent EES for the treatment of a pituitary adenoma. During the surgery, the right ICA was injured, and successfully hemostasis by packed with cottonoid and gelatin sponge. Besides, cerebral angiography was performed in the interventional operating room for the purpose of discovering the formation of a pseudoaneurysm in the cavernous sinus segment of ICA, which was treated with a covered stent. After successfully placing the covered stent, the patient was promptly transferred to the general operating room for the removal of the cottonoid and to address the bleeding once again. The authors employ crushed muscles and cottonoid to locally compress and stop bleeding. Owing to concerns about the risk of rebleeding in the patient, after stent implantation, the patient did not utilize antiplatelet drugs. After the surgery, the patient developed occlusion of the right ICA and massive cerebral infarction in the right hemisphere. Dehydration, anti-infection, rehabilitation, hyperbaric oxygen, as well as related treatments, were given. The cottonoid was removed in EES 2 months postsurgery, and no instances of bleeding were observed. Six months after surgery, the patient had clear consciousness and hemiplegia in the left limb, with a Glasgow Outcome Scale score of 4. RESULTS: The ICA was injured during EES, which resulted in the formation of a pseudoaneurysm, the Willis stent was adopted for treatment, and there was a risk of rebleeding after the nasal packing (cottonoid, crushed muscles) was removed immediately. CONCLUSIONS: The ICA was injured during EES after bleeding was controlled by packing with cottonoid, crushed muscles, etc, subsequently, the patient was given intravascular treatment, it is advised to make thorough preparations and, after a suitable period, remove nasal packing in the hybrid operating room to address unexpected situations and unforeseen circumstances.

Curettage combined with decompression for the treatment of ameloblastoma in children: report of two cases.

BACKGROUND: Ameloblastoma (AM) is the most common benign odontogenic tumor, which is more often detected in the mandible than maxilla, especially the mandibular body and mandibular angle. Pediatric AM is a rare disease, especially in patients aged 10 and younger. Compared with the mainstream osteotomy and reconstructive surgery for adult ameloblastoma, there is more room for discussion in the treatment of pediatric ameloblastoma. The postoperative functional and psychological influence can not be ignored. Especially for children in the period of growth and development, an osteotomy is often challenging to be accepted by their parents. We report two patients with ameloblastoma under 10 years old who are treated with curettage and fenestration, which is a beneficial method for children with ameloblastoma. CASE PRESENTATION: We present two cases of classic ameloblastoma in children. We describe in detail the patients' characteristics, treatment processes, and follow-up result. The bone formation and reconstruction in the lesion area after fenestration decompression and curettage are recorded at every clinic review. The surgical details and principles of curettage and decompression are also described and discussed. The two patients have good bone shape recovery and no recurrence. CONCLUSIONS: Children are in the growth and development period and possess an extremely strong ability of bone formation and reconstruction. Based on the principles of minimally invasive and functional preservation, we believe that curettage combined with decompression can be the first choice for treating AM in children, especially for mandibular lesions.

Exploring the EM-wave diffusion capabilities of axicon coding metasurfaces for stealth applications.

Coding metasurfaces for diffusion scattering of electromagnetic (EM) waves are important for stealth applications and have recently attracted researchers in physics and engineering communities. Typically, the available design approaches of coding metasurfaces lack a coding sequence design formula and sometimes cannot simultaneously ensure uniform diffusion and low reflected power intensity without extensive computational optimization. To the authors' best knowledge, the diffusion and radar-cross-section reduction (RCSR) of 2D axicon metasurfaces for cloaking and stealth applications have not been explored before. This article presents a single-layer coding metasurface design that exhibits an axicon phase mask on its aperture for efficient diffusion of EM-waves and RCSR of metallic objects. The proposed approach is robust and ensures greater than 10 dB of RCSR for normal incidence and a wide-range of off-normal incident angles. Theoretical calculations, numerical simulations, and experimental validations of the proposed axicon coding metasurface demonstrate that the 10 dB RCSR covers the frequency range of 15 to 35 GHz (fractional bandwidth is 80%) under normal incidence. Under off-normal incidence, the RCSR and the diffusive scattering behavior are preserved up to 60° regardless of the polarization of the far-field incident radar wave. Compared to other available approaches, the presented design approach is fast, robust, and can achieve more uniform diffusive scattering patterns with remarkable RCSR, which makes it very attractive for potential stealth applications.

Hybrid cubic-chessboard metasurfaces for wideband angle-independent diffusive scattering and enhanced stealth.

Because of the shortcomings associated with their scattering patterns, both the chessboard and cubic phased metasurfaces show non-perfect diffusion and hence sub-optimal radar cross section reduction (RCSR) properties. This paper presents a novel and powerful hybrid RCSR design approach for diffusive scattering by combining the unique attributes of cubic phase and chessboard phase profiles. The hybrid phase distribution is achieved by simultaneously imposing two distinct phase profiles (chessboard and cubic) on the hybrid metasurface area with the aid of geometric phase theory to further enhance the diffusive scattering and RCSR. It is shown in this paper that through the integration of cubic and chessboard phase profiles, a metasurface with the hybrid phase mask successfully overcomes all the above issues and shortcomings related to the RCSR of both chessboard and cubic metasurfaces. In addition, the proposed design leverages the unique scattering properties offered by these distinct phase profiles to achieve enhanced stealth capabilities over wide frequency ranges and for large incidence angles. Simulation and measurement results show that the designed hybrid metasurfaces using the proposed strategy achieved RCSR and low-level diffused scattering patterns from 12-28 GHz (80%) for normal incidence of a far-field CP radar plane wave. The hybrid metasurface shows a stable angular diffusion and RCSR performance when the azimuthal and elevation incidence angles are in the range of 0° → ± 75° which is wider than other designs in the literature. Therefore, this work can make objects significantly less detectable in complex radar environments when enhanced stealth is required.

Improvement of optical properties of InGaN-based red multiple quantum wells.

The realization of red-emitting InGaN quantum well (QW) is a hot issue in current nitride semiconductor research. It has been shown that using a low-Indium (In)-content pre-well layer is an effective method to improve the crystal quality of red QWs. On the other hand, keeping uniform composition distribution at higher In content in red QWs is an urgent problem to be solved. In this work, the optical properties of blue pre-QW and red QWs with different well width and growth conditions are investigated by photoluminescence (PL). The results prove that the higher-In-content blue pre-QW is beneficial to effectively relieve the residual stress. Meanwhile, higher growth temperature and growth rate can improve the uniformity of In content and the crystal quality of red QWs, enhancing the PL emission intensity. Possible physical process of stress evolution and the model of In fluctuation in the subsequent red QW are discussed. This study provides a useful reference for the development of InGaN-based red emission materials and devices.

Surgical Treatment of Craniofacial Fibrous Dysplasia With TP53 Gene Mutation.

BACKGROUND: To report the surgical treatment of craniofacial fibrous dysplasia (CFD) with TP53 gene mutation. METHODS: The patient was diagnosed with CFD by surgery at the age of 14 years. At the age of 35 years, the tumor recurred, and the patient took active treatment. The tumor was resected 4 times by neuroendoscopy due to recurrence in a short period. Meanwhile, genetic tests were performed on the patient. The patient's postoperative pathology indicated leiomyosarcoma and genetic testing indicated TP53 gene mutation. RESULTS: Despite the active surgical treatment, the patient finally died of a malignant tumor. The prognosis of patients with CFD malignancy accompanied by TP53 gene mutation is poor, and its treatment is difficult. CONCLUSIONS: The prognostic benefit of surgical treatment for patients with CFD malignancy is limited. It is hoped that more genetic mutations will be identified and reported in patients with CFD malignancy, and long-term follow-up is necessary for patients with current fibrous dysplasia or CFD.

Elective upper-neck versus whole-neck irradiation of the uninvolved neck in patients with nasopharyngeal carcinoma: an open-label, non-inferiority, multicentre, randomised phase 3 trial.

BACKGROUND: The aim of this trial was to address whether elective ipsilateral upper-neck irradiation (UNI) sparing the uninvolved lower neck provides similar regional relapse-free survival compared with standard whole-neck irradiation (WNI) in patients with nasopharyngeal carcinoma. METHODS: This open-label, non-inferiority, randomised, controlled, phase 3 trial was done at three Chinese medical centres. Patients aged 18-65 years with untreated, non-keratinising, non-distant metastatic (M0) nasopharyngeal carcinoma; with N0-N1 disease (according to International Union Against Cancer-American Joint Committee on Cancer TNM classification, seventh edition); and a Karnofsky performance status score of 70 or higher were randomly assigned (1:1) to receive elective UNI or WNI of the uninvolved neck. Total radiation doses of 70 Gy (for the primary tumour volume and the enlarged retropharyngeal nodes), 66-70 Gy (for the involved cervical lymph nodes), 60-62 Gy (for the high-risk target volume), and 54-56 Gy (for the low-risk target volume) were administered in 30-33 fractions, five fractions per week. Patients with stage II-IVA disease were recommended to receive combined intravenous cisplatin-based chemotherapy (either induction chemotherapy followed by concurrent chemoradiotherapy or concurrent chemoradiotherapy alone). Randomisation was done centrally by the Clinical Trials Centre of Sun Yat-sen University Cancer Centre by means of a computer-generated random number code with a block size of four. Patients were stratified according to treatment centre and nodal status. Investigators and patients were not masked to treatment allocation. The primary endpoint was regional relapse-free survival in the intention-to-treat population. Non-inferiority was indicated if the upper limit of the 95% CI of the difference in 3-year regional relapse-free survival between the UNI and WNI groups was within 8%. Adverse events were analysed in the safety population (defined as all patients who commenced the randomly assigned treatment). This study is registered with ClinicalTrials.gov, NCT02642107, and is closed. FINDINGS: Between Jan 22, 2016, and May 23, 2018, 446 patients from 469 screened were randomly assigned to receive UNI (n=224) or WNI (n=222). Median follow-up was 53 months (IQR 46-59). 3-year regional relapse-free survival was similar in the UNI and WNI groups (97·7% [95% CI 95·7-99·7] in the UNI group vs 96·3% [93·8-98·8] in the WNI group; difference -1·4% [95% CI -4·6 to 1·8]; pnon-inferiority<0·0001). Although acute radiation-related toxic effects were similar between the groups, the incidence of late toxicity was lower in the UNI group than in the WNI group, including any-grade hypothyroidism (66 [30%] of 222 patients vs 87 [39%] of 221), skin toxicity (32 [14%] vs 55 [25%]), dysphagia (38 [17%] vs 71 [32%]), and neck tissue damage (50 [23%] vs 88 [40%]). No patients died during treatment. After treatment, one patient in the WNI group died from a non-cancer-related cause (dermatomyositis). INTERPRETATION: Elective UNI of the uninvolved neck provides similar regional control and results in less radiation toxicity compared with standard WNI in patients with N0-N1 nasopharyngeal carcinoma. FUNDING: Sun Yat-sen University Clinical Research 5010 Program, the Natural Science Foundation of Guangdong Province, and the Overseas Expertise Introduction Project for Discipline Innovation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma.

BACKGROUND: Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials. METHODS: In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety. RESULTS: A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P = 0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group. CONCLUSIONS: Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.).

Lin28-mediated temporal promotion of protein synthesis is crucial for neural progenitor cell maintenance and brain development in mice.

Neural progenitor cells (NPCs) undergo rapid proliferation during neurulation. This rapid growth generates a high demand for mRNA translation in a timing-dependent manner, but its underlying mechanism remains poorly understood. Lin28 is an RNA-binding protein with two paralogs, Lin28a and Lin28b, in mammals. Mice with Lin28b deletion exhibit no developmental defects, whereas we have previously reported that Lin28a deletion leads to microcephaly. Here, we find that Lin28a/b double knockout (dKO) mice display neural tube defects (NTDs) coupled with reduced proliferation and precocious differentiation of NPCs. Using ribosomal protein 24 hypomorphic mice (Rpl24Bst/+ ) as a genetic tool to dampen global protein synthesis, we found that Lin28a-/-;Rpl24Bst/+ compound mutants exhibited NTDs resembling those seen in Lin28a/b dKO mice. Increased NPC numbers and brain sizes in Lin28a-overexpressing mice were rescued by Rpl24Bst/+ heterozygosity. Mechanistically, polysome profiling revealed reduced translation of genes involved in the regulation of cell cycle, ribosome biogenesis and translation in dKO mutants. Ribosome biogenesis was reduced in dKO and increased in Lin28a-overexpressing NPCs. Therefore, Lin28-mediated promotion of protein synthesis is essential for NPC maintenance and early brain development.

Novel recombinant human thyroid-stimulating hormone in aiding postoperative assessment of patients with differentiated thyroid cancer-phase I/II study.

PURPOSE: Thyroid hormone withdrawal (THW) inevitably induced hypothyroidism in patients with differentiated thyroid cancer (DTC), and we aimed to evaluate the safety and efficacy of a novel recombinant human thyroid-stimulating hormone (rhTSH, ZGrhTSH) as an alternative of THW in China. METHODS: Totally, 64 DTC patients were enrolled with 24 in the dose-escalation cohort equally grouped into 0.9 mg × 1 day, 0.9 mg × 2 day, 1.8 mg × 1 day, and 1.8 mg × 2 day dosage, and 40 further enrolled into 0.9 mg × 2 day dose-expansion cohort. All patients underwent both ZGrhTSH phase and levothyroxine (L-T4) withdrawal phase for self-comparison in terms of TSH levels, the radioactive iodine (RAI) uptake, stimulated thyroglobulin level, and the quality of life (QoL). RESULTS: In ZGrhTSH phase, no major serious adverse events were observed, and mild symptoms of headache were observed in 6.3%, lethargy in 4.7%, and asthenia in 3.1% of the patients, and mostly resolved spontaneously within 2 days. Concordant RAI uptake was noticed in 89.1% (57/64) of the patients between ZGrhTSH and L-T4 withdrawal phases. The concordant thyroglobulin level with a cut-off of 1 µg/L was noticed in 84.7% (50/59) of the patients without the interference of anti-thyroglobulin antibody. The QoL was far better during ZGrhTSH phase than L-T4 withdrawal phase, with lower Billewicz (- 51.30 ± 4.70 vs. - 39.10 ± 16.61, P < 0.001) and POMS (91.70 ± 16.70 vs. 100.40 ± 22.11, P = 0.011) scores which indicate the lower the better. Serum TSH level rose from basal 0.11 ± 0.12 mU/L to a peak of 122.11 ± 42.44 mU/L 24 h after the last dose of ZGrhTSH. In L-T4 withdrawal phase, a median of 23 days after L-T4 withdrawal was needed, with the mean TSH level of 82.20 ± 31.37 mU/L. The half-life for ZGrhTSH clearance was about 20 h. CONCLUSION: The ZGrhTSH held the promise to be a safe and effective modality in facilitating RAI uptake and serum thyroglobulin stimulation, with better QoL of patients with DTC compared with L-T4 withdrawal.

GRP78 facilitates M2 macrophage polarization and tumour progression.

This study investigated the regulation of GRP78 in tumour-associated macrophage polarization in lung cancer. First, our results showed that GRP78 was upregulated in macrophages during M2 polarization and in a conditioned medium derived from lung cancer cells. Next, we found that knocking down GRP78 in macrophages promoted M1 differentiation and suppressed M2 polarization via the Janus kinase/signal transducer and activator of transcription signalling. Moreover, conditioned medium from GRP78- or insulin-like growth factor 1-knockdown macrophages attenuated the survival, proliferation, and migration of lung cancer cells, while conditioned medium from GRP78-overexpressing macrophages had the opposite effects. Additionally, GRP78 knockdown reduced both the secretion of insulin-like growth factor 1 and the phosphorylation of the insulin-like growth factor 1 receptor. Interestingly, insulin-like growth factor 1 neutralization downregulated GRP78 and suppressed GRP78 overexpression-induced M2 polarization. Mechanistically, insulin-like growth factor 1 treatment induced the translocation of GRP78 to the plasma membrane and promoted its association with the insulin-like growth factor 1 receptor. Finally, IGF-1 blockade and knockdown as well as GRP78 knockdown in macrophages inhibited M2 macrophage-induced survival, proliferation, and migration of lung cancer cells both in vitro and in vivo.