BioInstruct: instruction tuning of large language models for biomedical natural language processing.

OBJECTIVES: To enhance the performance of large language models (LLMs) in biomedical natural language processing (BioNLP) by introducing a domain-specific instruction dataset and examining its impact when combined with multi-task learning principles. MATERIALS AND METHODS: We created the BioInstruct, comprising 25 005 instructions to instruction-tune LLMs (LLaMA 1 and 2, 7B and 13B version). The instructions were created by prompting the GPT-4 language model with 3-seed samples randomly drawn from an 80 human curated instructions. We employed Low-Rank Adaptation (LoRA) for parameter-efficient fine-tuning. We then evaluated these instruction-tuned LLMs on several BioNLP tasks, which can be grouped into 3 major categories: question answering (QA), information extraction (IE), and text generation (GEN). We also examined whether categories (eg, QA, IE, and generation) of instructions impact model performance. RESULTS AND DISCUSSION: Comparing with LLMs without instruction-tuned, our instruction-tuned LLMs demonstrated marked performance gains: 17.3% in QA on average accuracy metric, 5.7% in IE on average F1 metric, and 96% in Generation tasks on average GPT-4 score metric. Our 7B-parameter instruction-tuned LLaMA 1 model was competitive or even surpassed other LLMs in the biomedical domain that were also fine-tuned from LLaMA 1 with vast domain-specific data or a variety of tasks. Our results also show that the performance gain is significantly higher when instruction fine-tuning is conducted with closely related tasks. Our findings align with the observations of multi-task learning, suggesting the synergies between 2 tasks. CONCLUSION: The BioInstruct dataset serves as a valuable resource and instruction tuned LLMs lead to the best performing BioNLP applications.

Encapsulation of W/O/W Acerola Emulsion by Spray Drying: Optimization, Release Kinetics, and Storage Stability.

Acerola (Malpighia emarginata DC.) is a sub-tropical and tropical fruit renowned for its high levels of vitamin C and phenolic compounds, which offer health benefits. This study aimed to optimize the spray drying process by determining the inlet and outlet temperatures using response surface methodology (RSM) with the central composite design. Additionally, it aimed to evaluate the release kinetics in the hydrophilic food simulation environment and the stability of the resulting powder under various storage temperatures. The RSM method determined the optimal inlet and outlet temperatures as 157 °C and 91 °C, respectively. High-accuracy prediction equations (R2 ≥ 0.88) were developed for moisture content (3.02%), process yield (91.15%), and the encapsulation yield of total polyphenol content (61.44%), total flavonoid content (37.42%), and vitamin C (27.19%), with a predicted monolayer moisture content below 4.01%, according to the BET equation. The powder exhibited good dissolution characteristics in the acidic hydrophilic food simulation environment and showed greater stability when stored at 10 °C for 30 days, compared to storage at 35 °C and 45 °C.

Determination of intracellular tenofovir-diphosphate and emtricitabine-triphosphate concentrations in dried blood spots for pre-exposure prophylaxis adherence.

OBJECTIVES: We measured the intracellular concentrations of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in dried blood spots (DBS) for pre-exposure prophylaxis (PrEP) adherence using sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS). METHODS: A total of 191 DBS were obtained from 85 participants who were receiving tenofovir disoproxil fumarate (TDF; 300 mg) and emtricitabine (FTC; 200 mg) as PrEP at the Sexual Health Clinic, National Center for Global Health and Medicine, Tokyo, Japan. DBS punch (3 mm) added to 25 µL of 50% methanol and 400 µL of internal standard solution was used for solid phase extraction. Chromatographic separation was achieved on an Atlantis Premier BEH C18 AX Column (50 mm × 2.1 mm i.d.; particle size 1.7 µm) using gradient elution (flow rate: 0.6 mL/min); injection volume: 7 µL and run time: 5.5 min. Calibration curves for the two drugs were linear in the range 0.05-12.5 ng/punch. RESULTS: We determined the intracellular TFV-DP and FTC-TP concentrations in 191 DBS obtained from 85 patients administered with TDF and FTC as PrEP. The analytical performance data (calibration curve and QC samples) for all the analytical runs met the acceptance criteria. Intracellular concentrations of TFV-DP and FTC-TP in the DBS remained stable for at least 24 h after oral administration. CONCLUSIONS: A multiplex LC-MS/MS method was successfully developed for DBS, which can be useful for monitoring the levels of TFV-DP and FTC-TP in individuals receiving PrEP.

Healthcare Challenges in the Management of Primary Aldosteronism in Southeast Asia.

OBJECTIVE: While guidelines have been formulated for the management of primary aldosteronism (PA), following these recommendations may be challenging in developing countries with limited healthcare access. Hence, we aimed to assess the availability and affordability of healthcare resources for managing PA in the Association of Southeast Asian Nations (ASEAN) region, which includes low-middle-income countries. DESIGN: We instituted a questionnaire-based survey to specialists managing PA, assessing the availability and affordability of investigations and treatment. Population and income status data were taken from the national census and registries. RESULTS: Nine ASEAN country members (48 respondents) participated. While screening with aldosterone-renin-ratio is performed in all countries, confirmatory testing is routinely performed in only six countries due to lack of facilities and local assays, and cost constraint. Assays are only locally available in four countries, and some centers have a test turnaround time exceeding three weeks. In seven countries (combined population of 442 million), adrenal vein sampling (AVS) is not routinely performed due to insufficient radiological facilities or trained personnel, and cost constraint. Most patients have access to adrenalectomy and medications. In six countries, the cost of AVS and adrenalectomy combined is >30% of its annual gross domestic product per capita. While most patients had access to spironolactone, it was not universally affordable. CONCLUSION: Large populations currently do not have access to the healthcare resources required for the optimal management of PA. Greater efforts are required to improve healthcare access and affordability. Future guideline revisions for PA may need to consider these limitations.

An Undetected Pheochromocytoma Leading to Fulminant Adrenergic Myocarditis Complicated by Cardiogenic Shock.

Pheochromocytomas are rare catecholamine-secreting neuroendocrine tumors. Their episodic nature is correlated with abrupt catecholamine release and clinical manifestations that mimic other vascular conditions, leading to delayed diagnosis and potentially life-threatening complications, such as acute myocarditis and pheochromocytoma crises. In this report, we described the case of fulminant adrenergic myocarditis-induced cardiogenic shock requiring extracorporeal membrane oxygenation support in a Vietnamese middle-aged man with a 5-year history of Brugada syndrome, hypertension, and previously undiagnosed pheochromocytoma. After stabilization, the patient was medically treated with a combination of α- and ß-blockers before undergoing laparoscopic right adrenalectomy.

Relationship between BMI and prognosis of chronic heart failure outpatients in Vietnam: a single-center study.

Background: Insufficient data exists regarding the relationship between body mass index (BMI) and the prognosis of chronic heart failure (CHF) specifically within low- and middle-income Asian countries. The objective of this study was to evaluate the impact of BMI on adverse outcomes of ambulatory patients with CHF in Vietnam. Methods: Between 2018 and 2020, we prospectively enrolled consecutive outpatients with clinically stable CHF in an observational cohort, single-center study. The participants were stratified according to Asian-specific BMI thresholds. The relationships between BMI and adverse outcomes (all-cause death and all-cause hospitalization) were analyzed by Kaplan-Meier survival curves and Cox proportional-hazards model. Results: Among 320 participants (age 63.5 ± 13.3 years, 57.9% male), the median BMI was 21.4 kg/m2 (IQR 19.5-23.6), and 10.9% were underweight (BMI <18.50 kg/m2). Over a median follow-up time of 32 months, the cumulative incidence of all-cause mortality and hospitalization were 5.6% and 19.1%, respectively. After multivariable adjustment, underweight patients had a significantly higher risk of all-cause mortality than patients with normal BMI (adjusted hazard ratios = 3.03 [95% CI: 1.07-8.55]). Lower BMI remained significantly associated with a worse prognosis when analyzed as a continuous variable (adjusted hazard ratios = 1.27 [95% CI: 1.03-1.55] per 1 kg/m2 decrease for all-cause mortality). However, BMI was not found to be significantly associated with the risk of all-cause hospitalization (p > 0.05). Conclusion: In ambulatory patients with CHF in Vietnam, lower BMI, especially underweight status (BMI < 18.5 kg/m2), was associated with a higher risk of all-cause mortality. These findings suggest that BMI should be considered for use in risk classification, and underweight patients should be managed by a team consisting of cardiologists, nutritionists, and geriatricians.

Steady-state pharmacokinetics of plasma tenofovir alafenamide (TAF), tenofovir (TFV) and emtricitabine (FTC), and intracellular TFV-diphosphate and FTC-triphosphate in HIV-1 infected old Japanese patients treated with bictegravir/FTC/TAF.

Emtricitabine (FTC) plus tenofovir alafenamide (TAF) has demonstrated efficacy and safety for pre-exposure prophylaxis (PrEP) to prevent HIV-1 infection. We measured the plasma PK of FTC, tenofovir (TFV), and TAF in a steady-state pharmacokinetic (PK) study of bictegravir/FTC/TAF in HIV-1-infected patients. Furthermore, validated liquid chromatography-tandem mass spectrometry was used to measure intracellular TFV-diphosphate (DP) and FTC-triphosphate (TP), the active metabolites of TFV and FTC, respectively. Plasma and dried blood spot samples were collected from 10 male patients aged ≥ 50 years at various time intervals: 0 (trough), 1, 2, 3, 4, 6, 8, 12, and 24 h after drug administration. The mean ± standard deviation of plasma PK parameters were as follows: The maximum concentrations of TAF, TFV, and FTC were 104.0 ± 72.5, 27.9 ± 5.2, and 3,976.0 ± 683.6 ng/mL, respectively. Additionally, their terminal elimination half-lives were 0.6 ± 0.5, 31.6 ± 10.4, and 6.9 ± 1.4 h, respectively. These results were consistent with previously reported data. The intracellular levels of TFV-DP and FTC-TP varied widely among individuals; however, they remained stable over 24 h in each individual at approximately 1,000-1,500 and 2,000-3,000 fmol/punch, respectively, indicating that plasma concentrations did not affect the intracellular concentrations of their active metabolites. These results demonstrated that measuring intracellular TFV-DP and FTC-TP could be useful for monitoring adherence to PrEP in clients on this regimen.

Prevalence and risk factors of prehypertension/hypertension among freshman students from the Vietnam National University: a cross-sectional study.

BACKGROUND: Prehypertension (PHT) and hypertension (HTN) in young adults are essential risk factors for other cardiovascular diseases (CVD) in later years of life. However, there is a lack of knowledge about the burden and risk factors of PHT/HTN for Vietnamese youth. The aim of this study was to investigate the prevalence of PHT/HTN and risk factors among university students in Hanoi, Vietnam. METHODS: This study was designed as a cross-sectional investigation with 840 students (394 males and 446 females) randomly sampled from freshmen of Vietnam National University, Hanoi (VNU). Socio-demographic, anthropometric, and lifestyle data were collected using questionnaire forms and physical measurements. HTN was defined as blood pressure (BP) ≥ 140/90 mmHg and/or current treatment with antihypertensive medications. PHT was defined as a systolic BP from 120 to 139 mmHg and/or a diastolic BP from 80 to 89 mmHg. Body mass index (BMI) was classified according to the WHO diagnostic criteria for Asian adults: normal weight (BMI 18.5-22.9 kg/m2), underweight (BMI < 18.5 kg/m2), overweight (BMI 23-24.9 kg/m2), and obese (BMI ≥ 25 kg/m2). Bivariable and multivariable log-binomial regression analyses were conducted to explore the association of PHT/HTN with different risk factors. RESULTS: The overall prevalence of prehypertension and hypertension was 33.5% [95% CI: 30.3-36.8%] (54.1% in men and 15.3% in women) and 1.4% [95% CI: 0.7-2.5%] (2.5% in men and 0.5% in women), respectively. Regarding CVD major risk factors, 119 (14.2%) were identified as overweight/obese, 461 (54.9%) were physical inactivity, 29.4% of men and 8.1% of women reported consuming alcohol. The multivariable analysis indicated the male sex (adjusted prevalence ratio [aPR] = 3.07; 95% CI: 2.32-4.06), alcohol consumption (aPR = 1.28; 95% CI: 1.03-1.59) and obesity (aPR = 1.35; 95% CI: 1.08-1.68) as the independent risk factors for PHT/HTN. CONCLUSIONS: The results revealed the high burden of prehypertension and hypertension among university freshmen in VNU. Male sex, alcohol consumption, and obesity were identified as important risk factors for PHT/HTN. Our study suggests an early screening program for PHT/HTN and campaigns to promote a healthy lifestyle for young adults in Vietnam.

Synthesis of solar-driven Cu-doped graphitic carbon nitride photocatalyst for enhanced removal of caffeine in wastewater.

Caffeine (CaF), a widely consumed compound, has been associated with various harmful effects on human health, including metabolic, cardiovascular disease, and reproductive disorders. Moreover, it poses a signifincant threat to organisms and aquatic ecosystems, leading to water pollution concerns. Therefore, the removal of CaF from wastewater is crucial for mitigating water pollution and minimizing its detrimental impacts on both humans and the environment. In this study, a solar-driven Cu-doped graphitic carbon nitride (Cu/CN) photocatalyst was synthesized and evaluated for its effectiveness in oxidizing CaF in wastewater. The Cu/CN photocatalyst, with a low band gap energy of 2.58eV, exhibited superior performance in degrading CaF compared to pure graphitic carbon nitride (CN). Under solar light irradiation, CuCN achieved a remarkable CaF degradation efficiency of 98.7% CaF, surpassing CN's efficiency of 74.5% by 24.2%. The synthesized Cu/CN photocatalyst demonstrated excellent removal capability, achieving a removal rate of over 88% for CaF in wastewater. Moreover, the reusability test showed that Cu/CN could be successfully reused up to five cycles maintaining a high removal efficiency of 74% for CaF in the fifth cycle. Additionally, the study elucidated the oxidation mechanism of CaF using solar-driven Cu/CN photocatalyst and highlighted the environmental implications of the process.

Organo-photocatalytic C-H bond oxidation: an operationally simple and scalable method to prepare ketones with ambient air.

Oxidative C-H functionalization with O2 is a sustainable strategy to convert feedstock-like chemicals into valuable products. Nevertheless, eco-friendly O2-utilizing chemical processes, which are scalable yet operationally simple, are challenging to develop. Here, we report our efforts, via organo-photocatalysis, in devising such protocols for catalytic C-H bond oxidation of alcohols and alkylbenzenes to ketones using ambient air as the oxidant. The protocols employed tetrabutylammonium anthraquinone-2-sulfonate as the organic photocatalyst which is readily available from a scalable ion exchange of inexpensive salts and is easy to separate from neutral organic products. Cobalt(ii) acetylacetonate was found to be greatly instrumental to oxidation of alcohols and therefore was included as an additive in evaluating the alcohol scope. The protocols employed a nontoxic solvent, could accommodate a variety of functional groups, and were readily scaled to 500 mmol scale in a simple batch setting using round-bottom flasks and ambient air. A preliminary mechanistic study of C-H bond oxidation of alcohols supported the validity of one possible mechanistic pathway, nested in a more complex network of potential pathways, in which the anthraquinone form - the oxidized form - of the photocatalyst activates alcohols and the anthrahydroquinone form - the relevant reduced form of the photocatalyst - activates O2. A detailed mechanism, which reflected such a pathway and was consistent with previously accepted mechanisms, was proposed to account for formation of ketones from aerobic C-H bond oxidation of both alcohols and alkylbenzenes.

Modified hepaticocholecystoenterostomy technique for certain hepatobiliary and pancreatic diseases: Case series report by a single surgeon.

Prior to this research, very few reports of hepaticocholecystoenterostomy (HCE) and its modification have been published. Two anastomoses were used to establish a biliary bypass using the gallbladder as a conduit by a senior hepato-biliary surgeon. Between 2013 and 2019, 11 patients (five men and six women) with a mean age of 61.7±15.7 (range, 31-85) years were seen. Disease indications included periampullary malignant tumours of Vater (7 cases), chronic pancreatitis (1 patient), cystic pancreatic head tumours (2 patients), and choledochal cysts (1 patient). Pancreaticoduodenectomy, bypass, cholangiocarcinoma, and choledochal cystectomy were performed on 4, 4, 2, and 1 patients, respectively. Follow-up showed no jaundice at all with no recurrent biliary obstruction. HCE is both safe and effective in a subgroup of patients. This is a treatment of choice in some instances, such as a small common bile duct, a limited surgical field in the hilar area, or a difficult hepaticojejunostomy.

A review on the status and modeling of suitable habitats of the southern white-cheeked gibbon.

The southern white-cheeked gibbon Nomascus siki is endemic to Indochina and is classified as critically endangered on the International Union for Conservation of Nature (IUCN) Red List. The most updated information on the status of this species dates back to a decade ago. As hunting has tremendous impacts on wildlife in Southeast Asia, the population of N. siki might have changed a lot in the last decade. Updated information on the status and potential distribution of this species is critically important for conservation and prioritization, especially for N. siki because of its undefined distribution range. The goal of this study was to review the population status of N. siki in Vietnam and Lao People's Democratic Republic (PDR) and to model its potential distribution. In Vietnam, this species has been intensively surveyed in all major areas of occurrence from 2016 to 2021. The total number of N. siki groups recorded and estimated in Vietnam were 324 and 483, respectively. In Lao PDR, the occurrence of N. siki has been confirmed in Nam Kading, Nakai Nam Theun, Hin Nam No, and Phou Hinpoun national protected areas. However, population estimates are generally lacking. The suitable habitat of N. siki was predicted from about 105.00° to 106.80° E longitude and from about 16.60° to 17.90° N latitude located in Quang Binh and Quang Tri provinces (Vietnam), and Khammounan and Savannakhet provinces (Lao PDR). The area of the potential distribution range is about 9894.15 km2, both in Vietnam and Lao PDR. Particularly, the high, medium, and low suitable habitats were estimated at around 1229.58 km2, 3019.68 km2, and 5644.89 km2, respectively. The area of suitable habitat of N. siki in Vietnam was predicted to be 4151.25 km2, of which only 1257.93 km2 (30.30%) is in the protected area network. Dong Chau-Khe Nuoc Trong and Bac Huong Hoa Nature Reserves, and Phong Nha-Ke Bang National Park should receive priority for conservation of N. siki in Vietnam. Improving conservation beyond the protected areas' boundaries or transforming the forest enterprises and watershed protection forests into protected areas should also be considered as an alternative for the conservation of N. siki. In Lao PDR, surveys of the species in its entire distribution range should be the first priority.

Epileptic seizure clustering and accumulation at transition from activity to rest in GAERS rats.

Knowing when seizures occur may help patients and can also provide insight into epileptogenesis mechanisms. We recorded seizures over periods of several days in the Genetic Absence Epileptic Rat from Strasbourg (GAERS) model of absence epilepsy, while we monitored behavioral activity with a combined head accelerometer (ACCEL), neck electromyogram (EMG), and electrooculogram (EOG). The three markers consistently discriminated between states of behavioral activity and rest. Both GAERS and control Wistar rats spent more time in rest (55-66%) than in activity (34-45%), yet GAERS showed prolonged continuous episodes of activity (23 vs. 18 min) and rest (34 vs. 30 min). On average, seizures lasted 13 s and were separated by 3.2 min. Isolated seizures were associated with a decrease in the power of the activity markers from steep for ACCEL to moderate for EMG and weak for EOG, with ACCEL and EMG power changes starting before seizure onset. Seizures tended to occur in bursts, with the probability of seizing significantly increasing around a seizure in a window of ±4 min. Furthermore, the seizure rate was strongly increased for several minutes when transitioning from activity to rest. These results point to mechanisms that control behavioral states as determining factors of seizure occurrence.

Application of Machine Learning in Epileptic Seizure Detection.

Epileptic seizure is a neurological condition caused by short and unexpectedly occurring electrical disruptions in the brain. It is estimated that roughly 60 million individuals worldwide have had an epileptic seizure. Experiencing an epileptic seizure can have serious consequences for the patient. Automatic seizure detection on electroencephalogram (EEG) recordings is essential due to the irregular and unpredictable nature of seizures. By thoroughly analyzing EEG records, neurophysiologists can discover important information and patterns, and proper and timely treatments can be provided for the patients. This research presents a novel machine learning-based approach for detecting epileptic seizures in EEG signals. A public EEG dataset from the University of Bonn was used to validate the approach. Meaningful statistical features were extracted from the original data using discrete wavelet transform analysis, then the relevant features were selected using feature selection based on the binary particle swarm optimizer. This facilitated the reduction of 75% data dimensionality and 47% computational time, which eventually sped up the classification process. After having been selected, relevant features were used to train different machine learning models, then hyperparameter optimization was utilized to further enhance the models' performance. The results achieved up to 98.4% accuracy and showed that the proposed method was very effective and practical in detecting seizure presence in EEG signals. In clinical applications, this method could help relieve the suffering of epilepsy patients and alleviate the workload of neurologists.

Laparoscopic Surgery for Intestinal Obstruction Caused by an Internal Paracecal Hernia.

Paracecal hernia is rarely associated with ischemia and has seldom been reported in the few published studies in the review literature. We present a case of incarcerated paracecal hernia with intestinal obstruction that was effectively treated with laparoscopic intervention. A 64-year-old woman who had not previously undergone any intestinal surgery arrived complaining of abdominal pain and vomiting at our hospital. Abdominal computed tomography suggested intestinal obstruction. A laparoscopic emergency procedure demonstrated an incarcerated small bowel loop in the paracecal region. The confined small bowel was removed from the paracecal area. On the fourth postoperative day, the patient was discharged. This case is unusual because the patient presented with small bowel strangulation, leading to intestinal obstruction. Laparoscopic surgery is beneficial for diagnosing internal hernias and curing small-bowel obstructions caused by paracecal hernias.

Got milk? Maternal immune activation during the mid-lactational period affects nutritional milk quality and adolescent offspring sensory processing in male and female rats.

Previous studies have underscored the importance of breastfeeding and parental care on offspring development and behavior. However, their contribution as dynamic variables in animal models of early life stress are often overlooked. In the present study, we investigated how lipopolysaccharide (LPS)-induced maternal immune activation (MIA) on postnatal day (P)10 affects maternal care, milk, and offspring development. MIA was associated with elevated milk corticosterone concentrations on P10, which recovered by P11. In contrast, both milk triglyceride and percent creamatocrit values demonstrated a prolonged decrease following inflammatory challenge. Adolescent MIA offspring were heavier, which is often suggestive of poor early life nutrition. While MIA did not decrease maternal care quality, there was a significant compensatory increase in maternal licking and grooming the day following inflammatory challenge. However, this did not protect against disrupted neonatal huddling or later-life alterations in sensorimotor gating, conditioned fear, mechanical allodynia, or reductions in hippocampal parvalbumin expression in MIA offspring. MIA-associated changes in brain and behavior were likely driven by differences in milk nutritional values and not by direct exposure to LPS or inflammatory molecules as neither LPS binding protein nor interleukin-6 milk levels differed between groups. These findings reflected comparable microbiome and transcriptomic patterns at the genome-wide level. Animal models of early life stress can impact both parents and their offspring. One mechanism that can mediate the effects of such stressors is changes to maternal lactation quality which our data show can confer multifaceted and compounding effects on offspring physiology and behavior.

Milking It for All It's Worth: The Effects of Environmental Enrichment on Maternal Nurturance, Lactation Quality, and Offspring Social Behavior.

Breastfeeding confers robust benefits to offspring development in terms of growth, immunity, and neurophysiology. Similarly, improving environmental complexity, i.e., environmental enrichment (EE), contributes developmental advantages to both humans and laboratory animal models. However, the impact of environmental context on maternal care and milk quality has not been thoroughly evaluated, nor are the biological underpinnings of EE on offspring development understood. Here, Sprague Dawley rats were housed and bred in either EE or standard-housed (SD) conditions. EE dams gave birth to a larger number of pups, and litters were standardized and cross-fostered across groups on postnatal day (P)1. Maternal milk samples were then collected on P1 (transitional milk phase) and P10 (mature milk phase) for analysis. While EE dams spent less time nursing, postnatal enrichment exposure was associated with heavier offspring bodyweights. Milk from EE mothers had increased triglyceride levels, a greater microbiome diversity, and a significantly higher abundance of bacterial families related to bodyweight and energy metabolism. These differences reflected comparable transcriptomic changes at the genome-wide level. In addition to changes in lactational quality, we observed elevated levels of cannabinoid receptor 1 in the hypothalamus of EE dams, and sex-dependent and time-dependent effects of EE on offspring social behavior. Together, these results underscore the multidimensional impact of the combined neonatal and maternal environments on offspring development and maternal health. Moreover, they highlight potential deficiencies in the use of "gold standard" laboratory housing in the attempt to design translationally relevant animal models in biomedical research.

A ruptured pancreatic pseudocyst causes acute peritonitis with clinical characteristics of a gastrointestinal tract perforation.

Intraperitoneal air in pancreatic pseudocysts is a rare complication that can jeopardize hemodynamic stability and requires emergency surgery. A 61-year-old man was admitted to our hospital after abdominal pain, vomiting and diarrhea. Computed tomography showed a hollow visceral perforation with intraperitoneal air and two pseudocysts close to the pancreas. The patient was transferred to the emergency operating room with symptoms of septic shock. We histopathologically diagnosed a ruptured pancreatic pseudocyst combined with an intracystic haemorrhage. We resected a portion of the pseudocyst wall using surface electrocautery inside the lumen, cholecystectomy and peritoneal toilet and maintained adequate external drainage. The patient was discharged on postoperative Day 12. The patient achieved relapse-free survival for 12 months postoperatively. Ruptured pancreatic pseudocysts with extraluminal gas are dangerous if effective medical interventions are not performed. Emergency surgery should be completed as soon as possible to drain the pancreatic cyst and cleanse the abdomen.

IL6 and CCL18 Mediate Cross-talk between VHL-Deficient Kidney Cells and Macrophages during Development of Renal Cell Carcinoma.

Loss of the von Hippel-Lindau (VHL) tumor suppressor gene function accounts for 70% to 80% of all clear-cell renal cell carcinoma (ccRCC) cases, the most prevalent form of RCC. Accumulating evidence has indicated that ccRCC arises from sites of chronic inflammation, yet how ccRCC tumor cells interact with immune components of the microenvironment has not been fully elucidated. In this study, we used unbiased proteomic and genomic analyses on components of the tumor microenvironment under different conditions, identifying the molecular and cellular mechanisms that underlie the cross-talk between VHL-deficient kidney tubule cells and macrophages. In vitro and in a Vhlh conditional knockout mouse model, VHL-deficient noncancerous kidney epithelial cells, representing the early stage of ccRCC initiation, secreted IL6 that induced macrophage infiltration and polarization toward the protumorigenic M2 phenotype. Activated human macrophages secreted CCL18 and TGFß1 to stimulate epithelial-to-mesenchymal transition (EMT) of the kidney tubule cells. Treatment with IL6-neutralizing antibody rescued inflammatory, proliferative, and EMT phenotypes of kidney epithelial cells in Vhlh conditional knockout mice. Furthermore, in a human ccRCC xenograft model, exogenous human primary or cultured macrophages significantly promoted primary tumor growth and metastasis in a CCL18-dependent manner. These findings identify specific factors involved in reciprocal cross-talk between tumor cells and immune components in the microenvironment, thus providing an avenue for early intervention in ccRCC. SIGNIFICANCE: The identification of VHL-deficient kidney tubule cell cross-talk with macrophages regulated by IL6 and CCL18 reveals potential targets for the prevention and treatment of ccRCC.

A streamlined platform for analyzing tera-scale DDA and DIA mass spectrometry data enables highly sensitive immunopeptidomics.

Integrating data-dependent acquisition (DDA) and data-independent acquisition (DIA) approaches can enable highly sensitive mass spectrometry, especially for imunnopeptidomics applications. Here we report a streamlined platform for both DDA and DIA data analysis. The platform integrates deep learning-based solutions of spectral library search, database search, and de novo sequencing under a unified framework, which not only boosts the sensitivity but also accurately controls the specificity of peptide identification. Our platform identifies 5-30% more peptide precursors than other state-of-the-art systems on multiple benchmark datasets. When evaluated on immunopeptidomics datasets, we identify 1.7-4.1 and 1.4-2.2 times more peptides from DDA and DIA data, respectively, than previously reported results. We also discover six T-cell epitopes from SARS-CoV-2 immunopeptidome that might represent potential targets for COVID-19 vaccine development. The platform supports data formats from all major instruments and is implemented with the distributed high-performance computing technology, allowing analysis of tera-scale datasets of thousands of samples for clinical applications.