68Ga-FAPI-04 positron emission tomography/CT and laparoscopy for the diagnosis of occult peritoneal metastasis in newly diagnosed locally advanced gastric cancer: study protocol of a single-centre prospective cohort study.

INTRODUCTION: Accurate baseline clinical staging is critical to inform treatment decision-making for patients with gastric cancers. Peritoneal metastasis (PM) is the most common form of metastasis in gastric cancer and mainly diagnosed by diagnostic laparoscopy and peritoneal lavage evaluation. However, diagnostic laparoscopy is invasive and less cost-effective. It is urgent to develop a safe, fast and non-invasive functional imaging method to verify the peritoneal metastasis of gastric cancer. The aim of our study was to evaluate the proportion of patients in whom 68Ga-FAPI-04 positron emission tomography/CT (PET/CT) led to a change in treatment strategy and to assess the diagnostic accuracy of 68Ga-FAPI-04 PET/CT for the detection of occult peritoneal metastasis compared with laparoscopic exploration. METHODS AND ANALYSIS: In this single-centre, prospective diagnostic test accuracy study, a total of 48 patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma (cT4a-b, N0-3, M0, based on CT images) who are considering radical tumour surgery will be recruited. All participants will undergo 68Ga-FAPI-04 PET/CT before the initiation of laparoscopic exploration. The primary outcome is the proportion of patients with occult peritoneal metastatic lesions detected by 68Ga-FAPI-04 PET/CT, leading to a change in therapy strategy. The secondary outcomes include the diagnostic performance of 68Ga-FAPI-04 PET/CT for occult peritoneal metastasis, including sensitivity, specificity, accuracy, positive predictive value and negative predictive value. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of West China Hospital, Sichuan University (2022-1484). Study results will be presented at public and scientific conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR2300067591.

Efficacy and safety of fruquintinib dose-escalation strategy for elderly patients with refractory metastatic colorectal cancer: A single-arm, multicenter, phase II study.

BACKGROUND: Fruquintinib has demonstrated significant improvement in overall survival (OS) among previously treated metastatic colorectal cancer (mCRC) patients. However, the utilization of fruquintinib has been constrained by various toxicities, such as hand-foot skin reaction (HFSR) and hypertension, particularly in elderly patients with reduced tolerance to the standard dosage. This study aims to investigate the efficacy and safety of fruquintinib dose-escalation strategy for elderly refractory mCRC patients. PATIENTS AND METHODS: This open-label, single-arm, phase II trial included patients aged 65 years or over with mCRC who had progressed after two or more lines of chemotherapy. Fruquintinib was administered for 21 consecutive days of a 28-day treatment cycle. The starting dose of fruquintinib was 3 mg/day and escalated to 4 mg/day in Week 2 and 5 mg/day in Week 3 if no significant drug-related toxicity was observed. The highest tolerated dose from Cycle 1 would be administered in Cycle 2 and all subsequent cycles. Before commencing treatment, all enrolled patients underwent a G8 questionnaire and comprehensive geriatric assessments. The primary endpoint of the study was progression-free survival (PFS). RESULTS: A total of 29 patients were enrolled and all started fruquintinib at 3 mg/day. Fifteen patients (51.7%) were subsequently escalated to 4 mg/day and 4 (13.8%) to 5 mg/day. Only four (13.8%) patients discontinued treatment due to adverse events (AEs). The median PFS was 3.8 months (95% CI, 2.7-4.9), and the median OS was 7.6 months (95% CI, 6.5-8.7). Treatment-related adverse events (TRAEs) were observed in all 29 patients (100%). The most frequently occurring (>10%) TRAEs greater than Grade 3 were HFSR (20.7%), hypertension (20.7%), and diarrhea (10.3%). CONCLUSION: Our study indicated that a dose of 4 mg/day was well tolerated by most elderly patients, suggesting that fruquintinib dose-escalation strategy during the first cycle could serve as a viable alternative to the standard 5 mg/day dosing.

Case report: Remarkable response to sintilimab, lenvatinib, and nab-paclitaxel in postoperative metastatic chemotherapy-resistant combined hepatocellular-cholangiocarcinoma.

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a highly aggressive malignancy with a poor prognosis. However, there are no consensus treatment guidelines, and decisions are usually extrapolated from intrahepatic cholangiocarcinoma (ICC) or hepatocellular carcinoma (HCC). Given that cHCC-CCA owns the unequivocal presence of both hepatocytic and cholangiocytic differentiation, a combination regimen of anti-PD1 antibody, multikinase inhibitor, and chemotherapy targeting against both components might be an optimal choice. Case presentation: We present the case of a patient with postoperative metastatic chemotherapy-resistant cHCC-CCA who exhibited a durable response and reasonable tolerability to a combination therapy consisting of the anti-PD1 antibody sintilimab, multikinase inhibitor lenvatinib, and nab-paclitaxel, despite having a low tumor mutational burden (TMB-L), microsatellite stability (MSS), and negative programmed cell death 1 ligand 1 (PD-L1). Conclusion: The combination regimen of immune checkpoint inhibitor sintilimab, multikinase inhibitor lenvatinib, and chemotherapy with nab-paclitaxel, which targets both the HCC and ICC components, may represent a promising treatment option for patients with cHCC-CCA. Further research is warranted to validate these findings in larger patient cohorts.

Sintilimab plus nab-paclitaxel as second-line treatment for advanced biliary tract cancer: study protocol for an investigator-initiated phase 2 trial (NapaSinti trial).

BACKGROUND: Biliary tract cancer (BTC) is a relatively rare but highly aggressive malignancy. However, there is currently no satisfactory second-line regimen for patients without specific genetic mutations. Nanoparticle albumin-bound paclitaxel, also known as nab-paclitaxel (Abraxane, Bristol Myers Squibb), has shown activity in patients with BTC. Studies investigating the immunogenic features of BTC suggested that checkpoint inhibition may lead to antitumor immune responses. In recent years, improved survival has been observed in patients treated with chemotherapy combined with immunotherapy across multiple cancer types, including BTC. This clinical trial aims to evaluate the efficacy and safety of second-line sintilimab in combination with nab-paclitaxel in advanced BTC patients. METHODS: The NapaSinti trial is a prospective, nonrandomized, open-label, phase 2 study conducted at a tertiary hospital in Chengdu, China. Eligible patients are those with histologically or cytologically confirmed locally advanced non-resectable or metastatic adenocarcinoma in the biliary tract (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer), aged between 18 and 75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, who have experienced disease progression after prior gemcitabine- or fluorouracil-based chemotherapy and have not received taxane or immune checkpoint inhibitor treatment. Enrolled patients will receive intravenous administration of sintilimab 200 mg on day 1 and nab-paclitaxel 125 mg/m2 on days 1 and 8, every three weeks. The primary endpoint is the objective response rate (ORR), while the secondary endpoints include overall survival (OS), progression-free survival (PFS), and safety. Exploratory objectives aim to identify biomarkers and molecular signatures for predicting response or prognosis. Using Simon's two-stage design, a total of 63 participants will be enrolled in the study. This trial was initiated in March 2022 in China. DISCUSSION: The NapaSinti trial evaluates the efficacy and safety of second-line sintilimab plus nab-paclitaxel for advanced biliary tract cancer. Additionally, the trial provides an opportunity for translational research. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100052118. Registered October 19, 2021.

Zeolitic Imidazolate Framework-8 (ZIF-8) as a Drug Delivery Vehicle for the Transport and Release of Telomerase Inhibitor BIBR 1532.

Telomerase is constitutively overexpressed in the majority of human cancers and telomerase inhibition provides a promising broad-spectrum anticancer therapeutic strategy. BIBR 1532 is a well-known synthetic telomerase inhibitor that blocks the enzymatic activity of hTERT, the catalytic subunit of telomerase. However, water insolubility of BIBR 1532 leads to low cellular uptake and inadequate delivery and thus, limits its anti-tumor effects. Zeolitic imidazolate framework-8 (ZIF-8) is considered as an attractive drug delivery vehicle for improved transport, release and anti-tumor effects of BIBR 1532. Herein, ZIF-8 and BIBR 1532@ZIF-8 were synthesized, respectively, and the physicochemical characterizations confirmed the successful encapsulation of BIBR 1532 in ZIF-8 coupled with an improved stability of BIBR 1532. ZIF-8 could alter the permeability of lysosomal membrane probably by the imidazole ring-dependent protonation. Moreover, ZIF-8 encapsulation facilitated the cellular uptake and release of BIBR 1532 with more accumulation in the nucleus. BIBR 1532 encapsulation with ZIF-8 triggered a more obvious growth inhibition of cancer cells as compared with free BIBR 1532. A more potent inhibition on hTERT mRNA expression, aggravated G0/G1 arrest accompanied with an increased cellular senescence were detected in BIBR 1532@ZIF-8-treated cancer cells. Our work has provided preliminary information on improving the transport, release and efficacy of water-insoluble small molecule drugs by using ZIF-8 as a delivery vehicle.

Possible rodent equivalent of the posterior cingulate cortex (area 23) interconnects with multimodal cortical and subcortical regions.

Posterior cingulate cortex (area 23, A23) in human and monkeys is a critical component of the default mode network and is involved in many diseases such as Alzheimer's disease, autism, depression, attention deficit hyperactivity disorder and schizophrenia. However, A23 has not yet identified in rodents, and this makes modeling related circuits and diseases in rodents very difficult. Using a comparative approach, molecular markers and unique connectional patterns this study has uncovered the location and extent of possible rodent equivalent (A23~) of the primate A23. A23 ~ but not adjoining areas in the rodents displays strong reciprocal connections with anteromedial thalamic nucleus. Rodent A23 ~ reciprocally connects with the medial pulvinar and claustrum as well as with anterior cingulate, granular retrosplenial, medial orbitofrontal, postrhinal, and visual and auditory association cortices. Rodent A23 ~ projects to dorsal striatum, ventral lateral geniculate nucleus, zona incerta, pretectal nucleus, superior colliculus, periaqueductal gray, and brainstem. All these findings support the versatility of A23 in the integration and modulation of multimodal sensory information underlying spatial processing, episodic memory, self-reflection, attention, value assessment and many adaptive behaviors. Additionally, this study also suggests that the rodents could be used to model monkey and human A23 in future structural, functional, pathological, and neuromodulation studies.

The effects of bilateral prostriata lesions on spatial learning and memory in the rat.

Area prostriata is the primary limbic structure for rapid response to the visual stimuli in the far peripheral visual field. Recent studies have revealed that the prostriata receives inputs not only from the visual and auditory cortices but also from many structures critical for spatial processing and navigation. To gain insight into the functions of the prostriata in spatial learning and memory the present study examines the effects of bilateral lesions of the prostriata on motor ability, exploratory interest and spatial learning and memory using the open field, elevated plus-maze and Morris water maze tests. Our results show that the spatial learning and memory abilities of the rats with bilateral prostriata lesions are significantly reduced compared to the control and sham groups. In addition, the lesion rats are found to be less interested in space exploration and more anxious while the exercise capacity of the rats is not affected based on the first two behavioral tests. These findings suggest that the prostriata plays important roles in spatial learning and memory and may be involved in anxiety as well.

Effects of Titanium Dioxide Nanoparticles on Cell Growth and Migration of A549 Cells under Simulated Microgravity.

With the increasing application of nanomaterials in aerospace technology, the long-term space exposure to nanomaterials especially in the space full of radiation coupled with microgravity condition has aroused great health concerns of the astronauts. However, few studies have been conducted to assess these effects, which are crucial for seeking the possible intervention strategy. Herein, using a random positioning machine (RPM) to simulate microgravity, we investigated the behaviors of cells under simulated microgravity and also evaluated the possible toxicity of titanium dioxide nanoparticles (TiO2 NPs), a multifunctional nanomaterial with potential application in aerospace. Pulmonary epithelial cells A549 were exposed to normal gravity (1 g) and simulated gravity (~10-3 g), respectively. The results showed that simulated microgravity had no significant effect on the viability of A549 cells as compared with normal gravity within 48 h. The effects of TiO2 NPs exposure on cell viability and apoptosis were marginal with only a slightly decrease in cell viability and a subtle increase in apoptosis rate observed at a high concentration of TiO2 NPs (100 µg/mL). However, it was observed that the exposure to simulated microgravity could obviously reduce A549 cell migration compared with normal gravity. The disruption of F-actin network and the deactivation of FAK (Tyr397) might be responsible for the impaired mobility of simulated microgravity-exposed A549 cells. TiO2 NPs exposure inhibited cell migration under two different gravity conditions, but to different degrees, with a milder inhibition under simulated microgravity. Meanwhile, it was found that A549 cells internalized more TiO2 NPs under normal gravity than simulated microgravity, which may account for the lower cytotoxicity and the lighter inhibition of cell migration induced by the same exposure concentration of TiO2 NPs under simulated microgravity at least partially. Our study has provided some tentative information on the effects of TiO2 NPs exposure on cell behaviors under simulated microgravity.

Global epidemiology of leprosy from 2010 to 2020: A systematic review and meta-analysis of the proportion of sex, type, grade 2 deformity and age.

The objectives of this study were to explore global epidemiological characteristics of leprosy, and to provide reference for the construction of prevention strategies for leprosy. Computer retrieval of the study on the epidemiology of leprosy from 2010 to 2020 in Web of Science, PubMed, and SCOPUS databases were summarized. The included studies were assessed for the quality of the AHRQ; the proportions of the study indices were meta-analyzed with Stata 16.0. A random effects model was adopted to merge categories, including sex, type, grade 2 deformity (G2D) and age group for meta-analysis. The subgroup analysis used region as a stratification factor to analyze whether there were differences in the indicators. The meta-analysis included 30 studies totaling 11,353 cases. The global pooled proportion of male to female subjects with leprosy was 63% (95% CI 59%, 66%) to 37% (95% CI 34%, 41%), respectively. The pooled multibacillary proportion and paucibacillary proportion were 69% (95% CI 62%, 76%) and 31% (95% CI 24%, 38%), respectively. The pooled grade 2 deformity (G2D) proportion was 22% (95% CI 15%, 30%). Among age groups, the pooled children proportion was 11% (95% CI 8%, 13%), and the pooled adult proportion was 89% (95% CI 87%, 92%). The subgroup analysis indicated that epidemiological indicators varied from country to country. This study suggested that disparities existed between sex, type, grade 2 deformity (G2D) and age group characteristics of leprosy from country to country.

Chemoarchitecture of area prostriata in adult and developing mice: Comparison with presubiculum and parasubiculum.

Retrosplenial area 29e, which was a cortical region described mostly in earlier rodent literature, is often included in the dorsal presubiculum (PrSd) or postsubiculum (PoS) in modern literature and commonly used brain atlases. Recent anatomical and molecular studies have revealed that retrosplenial area 29e belongs to the superficial layers of area prostriata, which in primates is found to be important in fast analysis of quickly moving objects in far peripheral visual field. As in primates, the prostriata in rodents adjoins area 29 (granular retrosplenial area), area 30 (agranular retrosplenial area), medial visual cortex, PrSd/PoS, parasubiculum (PaS), and postrhinal cortex (PoR). The present study aims to reveal the chemoarchitecture of the prostriata versus PrSd/PoS or PaS by means of a systematic survey of gene expression patterns in adult and developing mouse brains. First, we find many genes that display differential expression across the prostriata, PrSd/PoS, and PaS and that show obvious laminar expression patterns. Second, we reveal subsets of genes that selectively express in the dorsal or ventral parts of the prostriata, suggesting the existence of at least two subdivisions. Third, we detect some genes that shows differential expression in the prostriata of postnatal mouse brains from adjoining regions, thus enabling identification of the developing area prostriata. Fourth, gene expression difference of the prostriata from the medial primary visual cortex and PoR is also observed. Finally, molecular and connectional features of the prostriata in rodents and nonhuman primates are discussed and compared.

Rodent Area Prostriata Converges Multimodal Hierarchical Inputs and Projects to the Structures Important for Visuomotor Behaviors.

Area prostriata is a limbic structure critical to fast processing of moving stimuli in far peripheral visual field. Neural substrates underlying this function remain to be discovered. Using both retrograde and anterograde tracing methods, the present study reveals that the prostriata in rat and mouse receives inputs from multimodal hierarchical cortical areas such as primary, secondary, and association visual and auditory cortices and subcortical regions such as the anterior and midline thalamic nuclei and claustrum. Surprisingly, the prostriata also receives strong afferents directly from the rostral part of the dorsal lateral geniculate nucleus. This shortcut pathway probably serves as one of the shortest circuits for fast processing of the peripheral vision and unconscious blindsight since it bypasses the primary visual cortex. The outputs of the prostriata mainly target the presubiculum (including postsubiculum), pulvinar, ventral lateral geniculate nucleus, lateral dorsal thalamic nucleus, and zona incerta as well as the pontine and pretectal nuclei, most of which are heavily involved in subcortical visuomotor functions. Taken together, these results suggest that the prostriata is poised to quickly receive and analyze peripheral visual and other related information and timely initiates and modulates adaptive visuomotor behaviors, particularly in response to unexpected quickly looming threats.

Identifying clinical risk factors correlate with suicide attempts in patients with first episode major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is the most common mental disorder associated with suicide attempts. When a patient first visits the clinic, clinicians are often expected to make concrete diagnose about acute suicidal risk. However, the timeliness of suicide attempts correlates with patients with MDD has not been tested. METHODS: We divided 1718 first-episode and untreated MDD outpatients into those who did not have suicide attempts (non-attempts), recent suicide attempters (≤14 days before assessment) and long - dated suicide attempters (> 30 days before assessment). Positive Symptom Scale of Positive and Negative Syndrome Scale (PANSS), the 17-item Hamilton Depression Scale, 14 - item Hamilton Anxiety Scale, and clinical global impression of severity scale (CGI-S) was assessed. Body mass index, some glycolipid metabolism and thyroid hormone parameters were measured. A gradient-boosted decision trees statistical model was used to generate equally weighted classification for distinguishing recent and long - dated suicide attempters from non-attempts. RESULTS: The classifier identified higher excitement, hostility, anxiety, depression symptoms and higher free thyroxine (FT4) as risk factors for recent suicide attempters with an estimated accuracy of 87% (sensitivity, 59.1%; specificity, 61.2 %). For long - dated suicide attempters' risk factors, single status, higher anxiety and hostility symptoms, higher LDLC and lower BMI, the estimated accuracy was 88% (sensitivity, 52.8%; specificity, 49.6%). CONCLUSIONS: Risk factors for suicide attempt among patients with MDD can be identified by integrating demographic, clinical, and biological variables as early as possible during the first time see a doctor.