Discovery and SAR of JTE-151: A Novel RORγ Inhibitor for Clinical Development.

A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future development. As was expected from the general homology of nuclear receptor ligands, insufficient selectivity as well as poor physicochemical properties were identified as potential risks for a RORγ program. Based on such considerations, we conducted a SAR investigation by prioritizing drug-like properties to mitigate such potential drawbacks. After an intensive SAR exploration with strong emphasis on "drug-likeness" indices, an orally available RORγ inhibitor, JTE-151, was finally generated and was advanced to a human clinical trial. The compound was confirmed to possess highly selective profiles along with good metabolic stability, and most beneficially, no serious adverse events (SAE) and good PK profiles were observed in the human clinical trial.

Therapeutic Effect of Colony Stimulating Factor 1 Receptor Kinase Inhibitor, JTE-952, on Methotrexate-Refractory Pathology in a Rat Model of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and the destruction of bone and cartilage in affected joints. One of the unmet medical needs in the treatment of RA is to effectively prevent the structural destruction of joints, especially bone, which progresses because of resistance to conventional drugs that mainly have anti-inflammatory effects, and directly leads to a decline in the QOL of patients. We previously developed a novel and orally available type II kinase inhibitor of colony-stimulating factor-1 receptor (CSF1R), JTE-952. CSF1R is specifically expressed by monocytic-lineage cells, including bone-resorbing osteoclasts, and is important for promoting the differentiation and proliferation of osteoclasts. In the present study, we investigated the therapeutic effect of JTE-952 on methotrexate (MTX)-refractory joint destruction in a clinically established adjuvant-induced arthritis rat model. JTE-952 did not suppress paw swelling under inflammatory conditions, but it inhibited the destruction of joint structural components including bone and cartilage in the inflamed joints. In addition, decreased range of joint motion and mechanical hyperalgesia after disease onset were suppressed by JTE-952. These results suggest that JTE-952 is expected to prevent the progression of the structural destruction of joints and its associated effects on joint motion and pain by inhibiting CSF1/CSF1R signaling in RA pathology, which is resistant to conventional disease-modifying anti-rheumatic drugs such as MTX.

A desmoid tumor with fluorodeoxyglucose accumulation arising from the anastomotic site of postoperative gastric cancer: a case report.

BACKGROUND: Desmoid tumors are extremely rare borderline benign and malignant tumors that do not exhibit accumulation on fluorodeoxyglucose positron emission tomography-computed tomography. In the present study, we report a rare case of a desmoid tumor with fluorodeoxyglucose accumulation at the anastomotic postoperative gastric cancer site. CASE PRESENTATION: A 68-year-old Japanese man underwent robot-assisted laparoscopic distal gastrectomy for early-stage gastric cancer in 2019. The pathological diagnosis was stage IA cancer, and no adjuvant chemotherapy was administered. Two years after surgery, a soft mass appeared on the greater curvature side of the anastomosis on computed tomography. Fluorodeoxyglucose positron emission tomography-computed tomography revealed fluorodeoxyglucose accumulation, which suggested a malignancy; therefore, surgery was performed for diagnostic treatment. The histopathological findings led to the diagnosis of a desmoid tumor. The patient has not experienced recurrence to date. CONCLUSIONS: In the present study, we encountered a desmoid tumor arising from the anastomotic site of a postoperative gastric cancer. This case is rare as fluorodeoxyglucose positron emission tomography-computed tomography showed fluorodeoxyglucose accumulation in the desmoid tumor, and a preoperative diagnosis could not be reached. We hope that further studies will improve the accuracy of preoperative diagnosis.

Risk factors associated with hospitalization in patients with asymptomatic or mild COVID-19 in public accommodation facilities in Tokyo.

INTRODUCTION: In Japan, patients with coronavirus disease 2019 (COVID-19) who do not require medical intervention are provided care in recovery accommodation facilities (RAFs). However, some patients may require hospitalization if their symptoms become more severe during their stay. We conducted an observational study using epidemiological data of patients with COVID-19 admitted to RAFs in Tokyo. METHODS: This was an observational cohort study using data from COVID-19 patients admitted to one of the RAFs in Tokyo from December 2020 to November 2021. Admissions to the facilities were limited to patients with asymptomatic or mild COVID-19 with no underlying disease or at least stable underlying disease at the time of admission. Patients were hospitalized when they required oxygen administration or when they had, or persistent fever, or severe respiratory symptoms. We evaluated the association between hospitalization and the risk factors for hospitalization using a Cox regression model. RESULTS: The number of patients with COVID-19 admitted to the RAF was 6176. The number of hospitalized patients was 393 (6.4%), and the median length of stay was 5.50 days (IQR: 4.50, 6.50). In the Cox regression analysis, the hazard ratio increased with age and was significantly higher among patients aged >60 years (HR = 10.23, 95% CI: 6.72-15.57) than those in other age groups. This trend is similar to that observed in the sensitivity analysis. CONCLUSION: Patients with diabetes, the elderly, obesity, and medications for gout and psychiatric diseases may be at a high risk of hospitalization. In particular, an age over 60 years was strongly associated with hospitalization.

Money flow network among firms' accounts in a regional bank of Japan.

In this study, we investigate the flow of money among bank accounts possessed by firms in a region by employing an exhaustive list of all the bank transfers in a regional bank in Japan, to clarify how the network of money flow is related to the economic activities of the firms. The network statistics and structures are examined and shown to be similar to those of a nationwide production network. Specifically, the bowtie analysis indicates what we refer to as a "walnut" structure with core and upstream/downstream components. To quantify the location of an individual account in the network, we used the Hodge decomposition method and found that the Hodge potential of the account has a significant correlation to its position in the bowtie structure as well as to its net flow of incoming and outgoing money and links, namely the net demand/supply of individual accounts. In addition, we used non-negative matrix factorization to identify important factors underlying the entire flow of money; it can be interpreted that these factors are associated with regional economic activities. One factor has a feature whereby the remittance source is localized to the largest city in the region, while the destination is scattered. The other factors correspond to the economic activities specific to different local places. This study serves as a basis for further investigation on the relationship between money flow and economic activities of firms.

Preoperative Magnetic Resonance Cholangiopancreatography for Detecting Difficult Laparoscopic Cholecystectomy in Acute Cholecystitis.

Previous studies have shown that signal intensity variations in the gallbladder wall on magnetic resonance imaging (MRI) are associated with necrosis and fibrosis in the gallbladder of acute cholecystitis (AC). However, the association between MRI findings and operative outcomes remains unclear. We retrospectively identified 321 patients who underwent preoperative magnetic resonance cholangiopancreatography (MRCP) and early laparoscopic cholecystectomy (LC) for AC. Based on the gallbladder wall signal intensity on MRI, these patients were divided into high signal intensity (HSI), intermediate signal intensity (ISI), and low signal intensity (LSI) groups. Comparisons of bailout procedure rates (open conversion and laparoscopic subtotal cholecystectomy) and operating times were performed. The recorded bailout procedure rates were 6.8% (7/103 cases), 26.7% (31/116 cases), and 40.2% (41/102 cases), and the median operating times were 95, 110, and 138 minutes in the HSI, ISI, and LSI groups, respectively (both p < 0.001). During the multivariate analysis, the LSI of the gallbladder wall was an independent predictor of both the bailout procedure (odds ratio [OR] 5.30; 95% CI 2.11-13.30; p < 0.001) and prolonged surgery (≥144 min) (OR 6.10, 95% CI 2.74-13.60, p < 0.001). Preoperative MRCP/MRI assessment could be a novel method for predicting surgical difficulty during LC for AC.

JTE-952 Suppresses Bone Destruction in Collagen-Induced Arthritis in Mice by Inhibiting Colony Stimulating Factor 1 Receptor.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and structural destruction of the joints. Bone damage occurs in an early stage after onset and osteoclast activation plays a substantial role in its progression. Colony stimulating factor 1 receptor (CSF1R) is a receptor protein tyrosine kinase specifically expressed in monocytic-lineage cells such as macrophages and osteoclasts. Here, we investigated the effect of JTE-952, a novel CSF1R tyrosine kinase inhibitor, on osteoclast formation in vitro and on bone destruction in a mouse model of collagen-induced arthritis. JTE-952 completely inhibited osteoclast differentiation from human monocytes, with an IC50 of 2.8 nmol/L, and reduced osteoclast formation from the synovial cells of RA patients. Detectable levels of colony stimulating factor 1 (CSF1), a ligand of CSF1R, were observed in the synovial tissues of the arthritis model, similar to those observed in the pathology of human RA. JTE-952 significantly suppressed increases in the bone destruction score, the number of tartrate-resistant-acid-phosphatase-positive cells, and the severity of arthritis in the model mice. We also examined the efficacy of JTE-952 combined with methotrexate. This combination therapy more effectively reduced the severity of bone destruction and arthritis than monotherapy with either agent alone. In summary, JTE-952 potently inhibited human osteoclast formation in vitro and suppressed bone destruction in an experimental arthritis model, especially when combined with methotrexate. These results indicate that JTE-952 should strongly inhibit bone destruction and joint inflammation in RA patients and effectively prevent the progression of the structural destruction of joints.

Estimation of the percentages of undiagnosed patients of the novel coronavirus (SARS-CoV-2) infection in Hokkaido, Japan by using birth-death process with recursive full tracing.

Estimating the percentages of undiagnosed and asymptomatic patients is essential for controlling the outbreak of SARS-CoV-2, and for assessing any strategy for controlling the disease. In this paper, we propose a novel analysis based on the birth-death process with recursive full tracing. We estimated the numbers of undiagnosed symptomatic patients and the lower bound of the number of total infected individuals per diagnosed patient before and after the declaration of the state of emergency in Hokkaido, Japan. The median of the estimated number of undiagnosed symptomatic patients per diagnosed patient decreased from 1.7 to 0.77 after the declaration, and the median of the estimated lower bound of the number of total infected individuals per diagnosed patient decreased from 4.2 to 2.4. We will discuss the limitations and possible expansions of the model.

Simulation-based assessment of model selection criteria during the application of benchmark dose method to quantal response data.

BACKGROUND: To employ the benchmark dose (BMD) method in toxicological risk assessment, it is critical to understand how the BMD lower bound for reference dose calculation is selected following statistical fitting procedures of multiple mathematical models. The purpose of this study was to compare the performances of various combinations of model exclusion and selection criteria for quantal response data. METHODS: Simulation-based evaluation of model exclusion and selection processes was conducted by comparing validity, reliability, and other model performance parameters. Three different empirical datasets for different chemical substances were analyzed for the assessment, each having different characteristics of the dose-response pattern (i.e. datasets with rich information in high or low response rates, or approximately linear dose-response patterns). RESULTS: The best performing criteria of model exclusion and selection were different across the different datasets. Model averaging over the three models with the lowest three AIC (Akaike information criteria) values (MA-3) did not produce the worst performance, and MA-3 without model exclusion produced the best results among the model averaging. Model exclusion including the use of the Kolmogorov-Smirnov test in advance of model selection did not necessarily improve the validity and reliability of the models. CONCLUSIONS: If a uniform methodological suggestion for the guideline is required to choose the best performing model for exclusion and selection, our results indicate that using MA-3 is the recommended option whenever applicable.

Rollback Imaging as a Useful Tool in the Preoperative Evaluation of Osteoporotic Vertebral Fractures.

INTRODUCTION: When surgery is performed for osteoporotic vertebral fractures, the extent to which kyphosis can be corrected by the intraoperative position of the body is often determined by preoperative radiography in the extension position. However, patients have difficulty adopting an adequate extension position due to the pain associated with their vertebral fracture. We place a pillow beneath the fractured vertebral body before surgery and take radiographs in the supine position to evaluate the extent to which the kyphosis can be corrected. This study aimed to examine the usefulness of this imaging method by comparing postoperative radiographs with preoperative radiographs taken with a pillow placed beneath the fractured vertebral body. METHODS: Lateral preoperative radiographs were taken of the patients in seated flexion and extension positions and the supine position. Lateral radiographs (rollback) were also taken 5 min after placing a firm pillow 20 cm in diameter beneath the fractured vertebral body. The kyphotic angle was compared between preoperative lateral radiographs of patients in the flexion, extension, and supine positions, rollback, and postoperative lateral radiographs in the supine position. RESULTS: The mean kyphotic angle was 33.3° in the flexion position, 28.3° in the extension position, 14.8° in the supine position, and 5.6° in rollback preoperatively and 6.4° postoperatively. The preoperative kyphotic angle differed from the postoperative kyphotic angle by ≥11° in 91% and 83% of participants in the flexion and extension positions, respectively; the difference was ≤ 5° in 30% and 61% of participants in the supine position and rollback, respectively. Differences in the postoperative angle were small in the order of rollback, supine position, extension position, and flexion position. CONCLUSIONS: Compared with radiographs taken in the flexion, extension, and supine positions, rollback showed little difference from postoperative radiographs, which showed almost the same angle as the intraoperative kyphotic angle.

Pharmacological Properties of JTE-952, an Orally Available and Selective Colony Stimulating Factor 1 Receptor Kinase Inhibitor.

Colony stimulating factor 1 (CSF1) receptor (CSF1R) is a receptor protein-tyrosine kinase specifically expressed in monocyte-lineage cells, such as monocytes and macrophages. In this study, we characterized the pharmacological properties of an azetidine compound, JTE-952 ((2S)-3-{[2-({3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]azetidine-1-yl}carbonyl)pyridin-4-yl]methoxy}propane-1,2-diol), which is a novel CSF1R tyrosine kinase inhibitor. JTE-952 potently inhibited human CSF1R kinase activity, with a half maximal inhibitory concentration of 11.1 nmol/L, and inhibited the phosphorylation of CSF1R in human macrophages and the CSF1-induced proliferation of human macrophages. It also inhibited human tropomyosin-related kinase A activity, but only at concentrations 200-fold higher than that required to inhibit the activity of CSF1R in inducing the proliferation of human macrophages. JTE-952 displayed no marked inhibitory activity against other kinases. JTE-952 potently inhibited lipopolysaccharide-induced proinflammatory cytokine production by human macrophages and in whole blood. JTE-952 (≥3 mg/kg given orally) also significantly attenuated the CSF1-induced priming of lipopolysaccharide-induced tumor necrosis factor-alpha production in mice and arthritis severity in a mouse model of collagen-induced arthritis. Taken together, these results indicate that JTE-952 is an orally available compound with potent and specific inhibitory activity against CSF1R, both in vitro and in vivo. JTE-952 is a potentially clinically useful agent for various human inflammatory diseases, including rheumatoid arthritis.

Estimating the syphilis incidence and diagnosis rate in Japan: a mathematical modelling study.

OBJECTIVES: The reported number of syphilis cases is increasing in Japan. In this study, we aimed to estimate both the incidence of infection and diagnosis-and-reporting rate using a mathematical model that captures the time course of infection. METHODS: We analysed yearly notification data from 1961 to 2016 and stratified according to clinical stage and sex. We built a compartmental ordinary differential equations model to describe the natural epidemiological course of syphilis in which the incidence of infection and diagnosis-and-reporting rate were included as time-varying parameters that we estimated via the maximum likelihood method. RESULTS: From 2008 to 2016, the estimated number of new syphilis cases among men and women was 1070 (95% CI 1037 to 1104) and 302 (95% CI 287 to 318), respectively, which was increased from the previous period (1999-2007) with 269 (95% CI 256 to 282) and 71 (95% CI 64 to 78) cases, respectively. The diagnosis-and-reporting rate did not vary greatly over time. We estimated the number of undiagnosed syphilis cases from either incubating or early clinical (ie, primary or secondary) infections in 2016 to be 262 (95% CI 249 to 275) and 79 (95% CI 74 to 84) for men and women, respectively. CONCLUSIONS: The recent increase in reported cases of syphilis is owing to an increase in the number of infections. We found no evidence of time-dependent improvement in detection or reporting.

Threshold phenomena with respect to the initiation of depopulation in a simple model of foot-and-mouth disease.

Depopulation is one of the important interventions for the outbreak of animal diseases. Simulation models using actual case scenarios conclude that early depopulation is the most efficient in preventing the spread of foot-and-mouth disease (FMD). However, the long delay in its initiation was often seen in the actual cases and the theoretical analyses of FMD epidemiology with depopulation needs further elaboration. Here, we investigated the qualitative features of epidemic models when depopulation at a fixed capacity was delayed. We built a simple deterministic model for FMD based on state-transition, the SEIIR model whose unit is a single farm. The model settings and parameters were determined using the data from the 2010 epidemic in Miyazaki, Japan. By numerical calculation, we showed the existence of the threshold phenomenon with respect to delays in the initiation of depopulation and if the initiation of full-fledged depopulation surpasses the certain critical timing, the final size of the epidemic rapidly increases leading to a "catastrophic situation". We also revealed the mechanism of the threshold phenomenon from the relationship between the depopulation capacity and the increasing rate of infection. Although it can be delayed with lower transmission coefficients, the threshold phenomenon still exists. Thus, the existence of the critical timing for depopulation appears to be a universal feature of FMD epidemiology when depopulation is used as the main treatment for disease control.

Fabrication of tungsten tip probes within 3 s by using flame etching.

A tungsten (W) tip has been used as a standard tip probe because of its robustness at the highest boiling temperature; the use cases include a field emission (FE) electron source for scanning electron microscopy (SEM) and a scanning probe microscopy tip. The W tip probe has generally been fabricated through a chemical etching process with aqueous solutions. In this study, we propose a new method-flame etching. Without using aqueous solutions, a W tip probe was successfully fabricated within 3 s in air, which is very fast and convenient, and beneficial for mass production (additionally, no expensive setup is necessary). A W tip probe was obtained simply by putting a W wire into an oxygen-liquefied petroleum (O2+LP) gas flame (giving the highest temperature of ∼2300 K) through a microtorch for a few seconds. The obtained W tip provided atomically resolved scanning tunneling microscopic images. Also, since FE electrons were detected by applying ∼106 V/m, the tip can be used as an FE-SEM source. Generation and vaporization of WO3 on the W surface are important processes to form a tip shape.

Predicting the Epidemiological Dynamics of Lung Cancer in Japan.

While the prevalence of smoking has steadily declined over time, the absolute numbers of lung cancer cases and deaths have continued to increase in Japan. We employed a simple mathematical model that describes the relationship between demographic dynamics and smoking prevalence to predict future epidemiological trends of lung cancer by age and sex. Never-smokers, smokers, and ex-smokers were assumed to experience different hazard of lung cancer, and the model was parameterized using data from 2014 and before, as learning data, and a future forecast was obtained from 2015 onwards. The maximum numbers of lung cancer cases and deaths in men will be 76,978 (95% confidence interval (CI): 76,630⁻77,253) and 63,284 (95% CI: 62,991⁻63507) in 2024, while those in women will be 42,838 (95% CI: 42,601⁻43,095) and 32,267 (95% CI: 32,063⁻32,460) in 2035 and 2036, respectively. Afterwards, the absolute numbers of cases and deaths are predicted to decrease monotonically. Our compartmental modeling approach is well suited to predicting lung cancer in Japan with dynamic ageing and drastic decline in smoking prevalence. The predicted burden is useful for anticipating demands for diagnosis, treatment, and care in the healthcare sector.

Discovery of a novel azetidine scaffold for colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors by the use of docking models.

We report the discovery of a novel azetidine scaffold for colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors by using a structure-based drug design (SBDD) based on a docking model. The work leads to the representative compound 4a with high CSF-1R inhibitory activity (IC50 = 9.1 nM). The obtained crystal structure of an azetidine compound with CSF-1R, which matched our predicted docking model, demonstrates that the azetidine compounds bind to the DFG-out conformation of the protein as a Type II inhibitor.

Estimating the annual risk of tuberculosis infection in Japan from interferon-gamma release assay data.

To assess tuberculosis transmission frequency at a population level, the age-dependent Mantoux test has been used widely to estimate the annual risk of infection (ARI) with Mycobacterium tuberculosis. However, the widespread Bacille Calmette-Guerin (BCG) immunization program implemented in Japan in the 20th century has made natural infections with M. tuberculosis difficult to distinguish from immune responses against this vaccine. Consequently, a recognized alternative method for measuring the frequency of primary infections, the interferon-gamma release assay (IGRA), which partially decays as a function of time after infection, is used. We aimed to estimate the ARI in Japan from IGRA data along with its response decay information using mathematical modeling. Devising a partial differential equation system, we computed the probability of IGRA positivity as a function of time and age, accounting for the time-varying force of infection and decay function of the IGRA response. Jointly estimating the force of infection and the parameters governing the decay function of the IGRA response, we found that the age-dependent increasing pattern of the IGRA response was captured by the proposed simple model, yielding estimates of the time-dependent force of infection. ARI decreased as a function of time in the study subjects for all geographic locations. By the year 2030, our model showed that the median age of infection is predicted to be delayed by 40-50 years compared with that in 1940. The geographic variations in the ARI were striking, ranging from under 0.1% to 0.6% in 2018, which echoes the longstanding notion of highly heterogeneous geographical tuberculosis transmission in Japan.

Ternary crystal structure of human RORγ ligand-binding-domain, an inhibitor and corepressor peptide provides a new insight into corepressor interaction.

Retinoic acid-related orphan receptor gamma (RORγ) plays pivotal roles in autoimmune diseases by controlling the lineage of interleukin 17 (IL-17)-producing CD4+ T cells (Th17 cells). Structure-based drug design has proven fruitful in the development of inhibitors targeting the ligand binding domain (LBD) of RORγ. Here, we present the crystal structure of a novel RORγ inhibitor co-complex, in the presence of a corepressor (CoR) peptide. This ternary complex with compound T reveals the structural basis for an inhibitory mechanism different from the previously reported inverse agonist. Compared to the inverse agonist, compound T induces about 2 Šshift of helix 5 (H5) backbone and side-chain conformational changes of Met365 on H5. These conformational changes correlate to reduced CoR peptide binding to RORγ-LBD in the presence of compound T, which suggests that the shift of H5 is responsible. This crystal structure analysis will provide useful information for the development of novel and efficacious drugs for autoimmune disorders.

Modeling the elevated risk of yellow fever among travelers visiting Brazil, 2018.

BACKGROUND: Unlike the epidemic of yellow fever from 2016 to 17 in Brazil mostly restricted to the States of Minas Gerais and Espirito Santo, the epidemic from 2017 to 18 mainly involved São Paulo and Rio de Janeiro and resulted in multiple international disseminations. To understand mechanisms behind this observation, the present study analyzed the distribution of imported cases from Brazil, 2018. METHODS: A statistical model was employed to capture the risk of importing yellow fever by returning international travelers from Brazil. We estimated the relative risk of importation among travelers by the extent of wealth measured by GDP per capita and the relative risk obtained by random assignment of travelers' destination within Brazil by the relative population size. RESULTS: Upper-half wealthier countries had 2.1 to 3.4 times greater risk of importation than remainders. Even among countries with lower half of GDP per capita, the risk of importation was 2.5 to 2.8 times greater than assuming that the risk of travelers' infection within Brazil is determined by the regional population size. CONCLUSIONS: Travelers from wealthier countries were at elevated risk of yellow fever, allowing us to speculate that travelers' local destination and behavior at high risk of infection are likely to act as a key determinant of the heterogeneous risk of importation. It is advised to inform travelers over the ongoing geographic foci of transmission, and if it appears unavoidable to visit tourist destination that has the history of producing imported cases, travelers must be strongly advised to receive vaccination in advance.

Controlled Deposition Number of Organic Molecules Using Quartz Crystal Microbalance Evaluated by Scanning Tunneling Microscopy Single-Molecule-Counting.

Precise control of organic molecule deposition on a substrate is quite important for fabricating single-molecule-based devices. In this study, we demonstrate whether a quartz-crystal microbalance (QCM) widely used for a film growth calibration has the ability to precisely measure the number of organic molecules adsorbed on a substrate. The well-known Sauerbrey's equation is extended to formulate the relation between QCM resonant frequency shift and the number of adsorbed molecules onto the QCM surface. The formula is examined by QCM measurements of sublimation of π-conjugated organic molecules and direct counting of the deposited molecules one by one onto metal substrates, using ultrahigh vacuum low-temperature scanning tunneling microscopy (STM). It is revealed that the number of adsorbed molecules evaluated by QCM ( NQCM) show good agreement with those counted from the STM images ( NSTM) within the error of ±25%. The results ensure the QCM capability for controlling the deposition number of organic molecules with high accuracy, that is, if one needs to deposit 100 molecules on the substrate, QCM control promises deposition of 100 ± 25 molecules.